Neuroendocrinology Of The Skin

0163-769X/00/$03.00/0 Endocrine Reviews 21(5): 457– 487 Copyright © 2000 by The Endocrine Society Printed in U.S.A.

Neuroendocrinology of the Skin* ANDRZEJ SLOMINSKI

AND

JACOBO WORTSMAN

Department of Pathology (A.S.), University of Tennessee, Memphis, Tennessee 38163; and Department of Medicine (J.W.), Southern Illinois University, Springfield, Illinois ABSTRACT The classical observations of the skin as a target for melanotropins have been complemented by the discovery of their actual production at the local level. In fact, all of the elements controlling the activity of the hypothalamus-pituitary-adrenal axis are expressed in the skin including CRH, urocortin, and POMC, with its products ACTH, ␣-MSH, and ␤-endorphin. Demonstration of the corresponding receptors in the same cells suggests para- or autocrine mechanisms of action. These findings, together with the demonstration of cutaneous production of numerous other hormones including vitamin D3, PTHrelated protein (PTHrP), catecholamines, and acetylcholine that share regulation by environmental stressors such as UV light, un-

derlie a role for these agents in the skin response to stress. The endocrine mediators with their receptors are organized into dermal and epidermal units that allow precise control of their activity in a field-restricted manner. The skin neuroendocrine system communicates with itself and with the systemic level through humoral and neural pathways to induce vascular, immune, or pigmentary changes, to directly buffer noxious agents or neutralize the elicited local reactions. Therefore, we suggest that the skin neuroendocrine system acts by preserving and maintaining the skin structural and functional integrity and, by inference, systemic homeostasis. (Endocrine Reviews 21: 457– 487, 2000)

I. Introduction II. Structure of the Skin A. Developmental biology B. Anatomy and histology C. Physiology III. Skin as a Target for Neuroendocrine Signals A. CRH and urocortin receptors (CRH-R) B. Melanocortin receptors (MC-R) C. Opioid receptors D. GH receptor (GH-R) E. PRL and LH/CG receptors (LH/CG-R) F. Neurokinin receptors (NK-R) G. Calcitonin gene-related peptide receptor (CGRP-R) H. Vasoactive intestinal peptide receptor (VIP-R) I. Neutrophin (NT) receptors J. Miscellaneous neuropeptide receptors K. PTH and PTH-related protein (PTHrP) receptors L. Vitamin D receptor (VDR) M. Glucocorticoid and mineralocorticoid receptors N. Androgen and estrogen receptors O. Thyroid hormone receptors P. Cholinergic receptors Q. Adrenergic receptors R. Glutamate receptors S. Serotonin receptors T. Histamine receptors U. Miscellaneous receptors IV. Skin as a Source of Hormones and Neurotransmitters A. PTHrP

V. VI.

VII.

VIII.

B. Hypothalamic and pituitary hormones C. Neuropeptides and neurotrophins D. Neurotransmitters/neurohormones E. Thyroid hormones F. Sex steroid hormones G. Other steroid hormones Molecular and Structural Basis for the Organizational Integration of Neuroendocrine Elements of the Skin Regulation of Cutaneous Neuroendocrine System A. Solar radiation B. Hair cycle C. Cytokines D. Degradation or inactivation of hormones and neurotransmitters Regulation of Cutaneous Vitamin D Production A. Vitamin D3 production B. Precutaneous regulation C. Cutaneous regulation D. Postcutaneous regulation E. General comments Final Comments and Future Directions I. Introduction

T

he skin is the largest body organ and functions as a metabolically active biological barrier separating internal homeostasis from the external environment. Depending on anatomic localization and environmental influences, the skin shows remarkable functional and structural diversity (1– 4), since it is continuously exposed to fluctuating external information represented by solar and thermal radiation, mechanical energy, changes in humidity, and/or chemical and biological insults. The maintenance of skin structural integrity is therefore critical and must be served by rapid mechanisms to restore the barrier properties of the epidermis when disrupted by external trauma. Maintenance

Address reprint requests to: Andrzej Slominski, M.D., Ph.D., Department of Pathology, RM576-BMH Main, University of Tennessee, 899 Madison Avenue, Memphis, Tennessee 38163. E-mail: [email protected] * This work was supported by grants from National Science Foundation (NSF) (IBN-9604364, IBN-9896030, and IBN-9405242), and American Cancer Society, Illinois Division (no. 99 –51) to A.S., and internal funding from the Department of Pathology, University of Tennessee.

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of organ, and hence systemic homeostasis, requires a special cutaneous property, the capability to recognize and integrate appropriate signals with a high degree of specificity. Such sensory mechanism must be widely distributed, efficiently self-regulated in intensity and field of activity, and endowed with the capability of differentiating environmental noise from biologically relevant signals (5, 6). To some extent, these mechanisms are represented by the skin immune system, activated by biological insults or trauma (7); and in humans, by the pigmentary system, activated or modified by solar radiation (8 –10). However, as presented in this work, the main component in this critical skin function is the level of activity of the local neuroendocrine system. Over the last decade, it has become increasingly apparent that the skin, particularly the epidermis, has powerful metabolic and endocrine capabilities (11, 12). For example, the skin synthesizes vitamin D, which enters the circulation and, upon activation, exerts profound metabolic and endocrine effects (13, 14). Resident skin cells also synthesize and release the hormones parathyroid hormone-related protein (PTHrP) (15), POMC-derived MSH, ACTH, and ␤-endorphin peptides (5, 16, 17), the CRH and urocortin peptides (18, 19), the neurotransmitters catecholamines and acetylcholine (20, 21), and precursors to biogenic amines (9, 21–23). While production of some of these factors is not constitutive, it does respond to specific inductive stimuli. The skin is also a site for activation of steroid hormones such as the conversion of testosterone to 5␣-dihydrotestosterone or to estradiol, or the conversion of T4 to T3 (4, 11, 12). These locally generated hormones and neurotransmitters can act in a paracrine or autocrine fashion. Moreover, the presence of numerous nerve endings and a rich vascular network provide additional mechanisms for the expression of neuroendocrine functions, e.g., transmission of regulatory signals to the global or central systems via the vascular system, or through the afferent neural network. This emerging concept, of skin as a neuroendocrine organ, is a relatively new addition to the field of cutaneous biology; it combines concepts from immunology, endocrinology, and neurobiology to unravel the multidirectional communications between brain, the endocrine and immune systems, and peripheral organs (24 –28). In this regard, the skin has a unique role because of its location, size, and relative functional diversity. Moreover, cutaneous signals sent to neuroendocrine centers may play modulatory roles, although peripheral intraorgan or intersystemic communications are also necessary to maintain global and local homeostasis. We will presently review evidence on the production of hormones and neurotransmitters by the skin and on the expression of the corresponding receptors. Cutaneous regulation of neuroendocrine communication will be analyzed and its function discussed within the context of organ homeostasis. Data on the experimental characterization of receptors for neurohormones in skin cells will be reviewed, including regulation of expression, ligand production, and characterization of signal transduction pathways. Pertinent data will be included with the understanding that the mere presence of a substance in a culture system of skin cells does not necessarily imply that the substance has physiological relevance in vivo. Special attention will be given to intraorgan communication and to the potential systemic or central effects of skin-produced factors acting on

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sensory nerves, or skin-activated circulating cells, or through direct release into the circulation as neurohormones or mediators. This review will end by setting the stage for future basic and clinical research. II. Structure of the Skin A. Developmental biology

The epithelial skin structures, e.g., epidermis, hair follicle, and sebaceous, apocrine, and eccrine glands, all derive from the embryonal outer epithelium, which originates from ectoderm (29). Nonkeratinocytic cells of the epidermis and hair follicle that include melanocytes and Merkel cells are also of ectodermal origin, but melanocytes migrate to the epidermis from the neural crest (1, 3, 4, 29). Cell populations of mesodermal origin comprise the Langerhans cells and the T lymphocytes, which include the T␥␦ type expressed in mouse epidermis and hair follicle and the sparse, mostly T␣␤ cells expressed in human epidermis (7). All of the dermal components are of mesodermal origin, with the exception of nerves and specialized sensory receptors that develop from the ectoderm (1, 3, 4, 7, 29). The dermal cellular populations include fibroblasts/fibrocytes/myofibroblasts, adipocytes, monocytes/macrophages, mast cells, Langerhans cells, T lymphocytes, dendrocytes, smooth muscle cells, and vascular and lymphatic endothelial cells. Fibrocytes arise by differentiation of stellate mesenchymal cells present in the primordial dermis, whereas adipocytes differentiate from subdermal mesenchymal cells that surround newly formed blood vessels. Macrophages, mast cells, Langerhans cells, and dendrocytes migrate to the skin from the bone marrow. Formation of the adnexal structures results from precise mesenchymal epithelial interactions producing down growth of primordial adnexal structures to reach the reticular dermis and subcutis (1, 3, 4, 29 –31). The multidirectional interaction between cells of ectodermal and mesodermal origin results in a cohesive unified skin structure that, nevertheless, maintains a degree of heterogeneity expressed by marked regional differences (1, 4, 29). In the context of this review it must be noted that brain, peripheral nervous system, retina, and medulla of adrenal gland are also of ectodermal origin, whereas olfactory epithelium and olfactory nerves, anterior lobe of hypophysis, and epithelial elements of the mammary gland all derive from the outer epithelium (29). Mesodermal structures include the immune system, endothelium of blood vessels, adrenal cortex, and gonadal epithelium and stroma (7, 29). These embryologic associations may determine the potential capability for resident skin cells to produce molecules similar to their close or distant relatives. Thus, cellular lineage may predict neuroendocrine functional activity. B. Anatomy and histology

The skin is composed of two main compartments: the epidermis with the adnexal epithelial structures and the dermis with the nonepithelial elements of adnexa (1– 4). While not a skin component, the subcutaneous fat is closely related to the skin anatomically and functionally. Structure and

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thickness of both epidermis and dermis vary according to anatomic location; thus, the average thickness of the epidermis is 0.1 mm, but in the acral areas is up to 1.6 mm thick. The latter regions contain thick cornified and granular layers and numerous eccrine units and nerve endings but lack folliculosebaceous-apocrine units. In contrast, facial skin contains numerous vellus follicles with prominent sebaceous glands; skin in the axilla and groins is characterized by numerous apocrine glands, back skin has very thick reticular dermis, and scalp skin contains large terminal hair follicles routed deep into the subcutaneous fat. In furry animals, terminal hair follicles cover most of the body, serving as insulating cover and as touch organs (30 –32). The basal membrane zone separates the epidermis and epithelial adnexal structures from the dermis. Beneath the basement membrane is a thin zone of adventitial dermis that comprises the papillary dermis, between the epidermal folds and the periadnexal dermis surrounding adnexal structures. The papillary dermis is characterized by thin collagen bundles interspersed with elastic fibers, frequent fibrocytes, abundant matrix, and a rich vascular network composed predominantly of capillaries. The reticular dermis is composed predominantly of thick collagen bundles and elastic fibers and a lower concentration of stromal matrix, with comparatively fewer fibrocytes; there are also blood vessels, and adipocytes that extend upward from the subcutaneous fat. The skin immune system is composed of resident, recruited, and recirculating cell populations (7). The resident population is constitutively expressed in the skin under physiological conditions. This is represented by keratinocytes, fibroblasts, vascular and lymphatic endothelial cells, mast cells, tissue macrophages (histiocytes), T lymphocytes, and dendritic cells. The recruited population comprises monocytes, basophilic, neutrophilic, and eosinophilic granulocytes, as well as mast cells and T and B lymphocytes. The recirculating cell population is represented by dendritic cells, natural killer cells, and T lymphocytes. Recruited or recirculating cells reach the skin via circulation. The vasculature is arranged into a superficial (subpapillary) plexus, located in the upper reticular dermis, and a deep plexus positioned in the lower reticular dermis (1– 4). These plexuses are connected by communicating blood vessels, which are most numerous in the upper dermis and around folliculosebaceous and eccrine units. The vascular network provides rich capillary supply for the dermal papillae and periadnexal dermis. A lymphatic network accompanies the vascular bed, although it is a functionally separate entity. The skin contains an extensive neural network represented by cholinergic and adrenergic nerves and by myelinated and unmyelinated sensory fibers (1, 3, 4, 33, 34). The autonomic nerves supply arterioles, glomus bodies, hair erector muscles, and apocrine and eccrine glands. The terminal endings of sensory fibers are either surrounded by histologically distinctive structures, such as Pacini and Meissner’s corpuscles, Ruffini organs, Merkel disks, and mucocutaneous end organs, or supply directly individual Merkel cells. A rich network of free sensory endings surround and penetrate hair follicles, pilosebaceous units, eccrine and apocrine glands, papillary dermis, and epidermis. The sensory and autonomic

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networks do show regional differences according to anatomic sites and also have topographical specificity by distributing into well defined areas called dermatomes. The torso, extremities, posterior scalp, and neck are supplied by sensory nerves arising from dorsal root ganglia of the spinal cord, whereas face, most of the scalp, and upper anterior neck are innervated by trigeminal nerve branches. C. Physiology (1–22, 30 –35)

The most important function of the skin, determined by its location at the interface between external and internal environments, is that of physical barrier. This is established in the epidermis by a precisely regulated gradient of keratinocyte differentiation stages, which forms a highly impermeable protein-lipid layer at the outer-most segment. This layer prevents the destruction of living keratinocytes by environmental factors and reduces or minimizes water evaporation, maintaining a liquid environment to preserve skin structural integrity in the face of frequent mechanical trauma. The epidermal pigmentary system protects the skin against the damaging effect of solar radiation in humans and, in conjunction with the follicular pigmentary system, determines hair and skin color that play an important role in social communication and camouflage in many mammalian species. The epidermal and dermal immune elements provide defense against biological insults, and they are also involved in the integration of the response to foreign and self-antigens through interactions with the central immune system. Immune responses are involved in the reaction to viral or microbial infections, or to cancer development; dysregulated immune responses may be pathogenic in autoimmune diseases. The adnexal organs are epidermally derived structures that extend into dermis and subcutis. Their functional role is pleiotropic by participating in the formation of hair shafts from hair follicle, serving protective, thermoregulatory, and sensory (touch) functions, as well as being involved in social communication. The secretion of eccrine, apocrine, and sebaceous glands is important for thermoregulation, for preservation of the integrity of the physical barrier, for regulation of electrolyte balance, and for secretion of the pheromones and odorant-affecting behavior. The dermis, in addition to its structural role, is involved in mechanical protection and thermoregulation via its rich vascular network. The skin also provides the sensory reception for touch, pressure, vibration, temperature, pain, and pleasure through a neural network comprised of specialized receptors and free nerve endings. Finally, the skin, as a regulator of metabolism, transforms various hormones and can also inactivate potentially harmful substances of exogenous or endogenous origin. III. Skin as a Target for Neuroendocrine Signals

Skin resident and circulating immune cells express receptors for neuropeptides and neurotransmitters identical to those expressed in the central neuroendocrine systems. Examples of those receptors and their expression sites are listed in Table 1. Clinical observations made in diverse endocrine disorders associated with cutaneous changes also confirm that the skin is a target for hormones, neurohormones, and neurotransmitters (3– 6, 12, 16 –21, 35–38). That the skin is

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TABLE 1. Selected hormone and neurotransmitter receptors expressed in keratinocytes and melanocytes Cell type

Receptor repertoire

Keratinocytes

CRH-R1, MC1-R, ␮- and ␨-opioid-R, PRL-R, LH/CG-R, GH-R, CGRP-R, VIP-R, neurokinin-R, class II PTH/PTHrP-R, vitamin D-R, androgen-R, estrogen-R, glucocorticoid-R, mineralocorticoid-R, muscarinic-R, nicotinic-R, adrenoreceptors, glutamate-R, gastrin-releasing peptide-R, NPY-R, purinoreceptors, H1 and H2 histamine-R, somatostatin-R (?), bombesin-R, (?) CRH-R1, MC1-R, LH/CG-R, GH-R, CGRP-R, VIP-R, vitamin D-R, androgen-R estrogen-R, glucocorticoidR, adrenoreceptors, muscarinic-R, H2 histamine-R

Melanocytes

R, Receptor; (?), possible expression.

also a target of neural responses is supported by studies showing neural contributions to the etiology and clinical manifestations of inflammatory skin diseases and vitiligo (3, 4, 33, 34, 38, 39). A. CRH and urocortin receptors (CRH-R)

This group comprises the G protein-coupled membranebound CRH-R1 and CRH-R2 receptors (5, 40, 41), whose gene expression was recently documented in human and rodent skin (5, 18, 40, 42– 46). CRH-R1 expression has been detected in epidermal and follicular keratinocytes, melanocytes, and mast cells (5, 44, 46 – 49), and it is possible that these cells may coexpress CRH-R2 (5, 44, 46, 50, 51). While specific CRH binding sites were additionally seen in dermal fibroblasts, endothelial cells, and smooth muscle of blood vessels (5, 40, 44, 46, 52–54), it remains to be tested whether these binding sites represent CRH-R1, CRH-R2, or coexpression of both receptors. Signal transduction through cutaneous CRH receptors is linked to stimulation of cAMP production and increase of cytosolic Ca levels (46, 47, 50, 51). It remains to be tested whether other pathways coupled to different receptor subtypes specific for skin cells are also activated (46, 50). CRH and urocortin have a recognized role in skin pathophysiology through their actions on the skin immune system (5, 40, 48, 55–59). Thus, in the periphery, CRH can act as a proinflammatory agent (48, 55, 56) and, together with urocortin, induces degranulation of mast cells (48, 57). However, antiinflammatory effects have been also demonstrated in models of tissue injury, e.g., in thermally injured skin where local injection of CRH has an antiedema effect independent of hypothalamus-pituitary-adrenal (HPA) axis function, and in doxorubicin-induced eye lid inflammation that is reduced in severity by pretreatment of the eyelid with CRH (58 – 60). In addition, CRH has antinociceptive activity and accelerates wound healing (58 – 60). CRH and urocortin also inhibit proliferation of keratinocytes (51) and either stimulate or inhibit melanoma cell proliferation depending on culture conditions (Refs. 46 and 49 and A. Slominski and B. Zbytek, unpublished data). B. Melanocortin receptors (MC-R)

The membrane-bound G protein-coupled melanocortin receptors of type 1, 2, and 5 (MC1-R, MC2-R, MC5-R) have been identified in the skin (5, 8, 17, 61– 69). MC1-R was detected in melanocytes, keratinocytes, sebocytes, fibroblasts, endothelial cells, Langerhans cells, and dermal immune cells, while MC5-R was detected in the epithelial cells of eccrine, apocrine, and sebaceous glands (5, 8, 17, 61– 64). Although expression of the MC2-R gene has been detected in human

and mouse skin (65, 66), precise cell compartment(s) assignment will require further testing; possible expression sites include adipocytes, keratinocytes, and melanocytes (63– 66). The MC receptors are activated by ACTH, and by ␣-, ␤and ␥-MSH; ligand affinity varies according to receptor type and mammalian species (5, 8, 17, 61, 70). Signal transduction through MC1-R, MC2-R, and MC5-R has been linked to activation of adenylate cyclase (5, 8, 17, 61, 67– 69). The best recognized phenotypic effect of the POMCderived ACTH and MSH peptides is the stimulation of melanogenesis and its switching from pheo- to eumelanogenesis (5, 8, 16, 17, 61, 67–72), which can also be documented clinically (3–5, 8, 67, 72). There is a general agreement that ACTH, ␣-MSH, and ␤-MSH have the strongest melanogenic activity (8, 16, 67– 69). ␥-MSH peptides have low intrinsic melanogenic activity in human normal melanocytes and rodent malignant melanocytes (70, 71), similar to findings in frog and lizard melanophores (8, 67, 68, 73). However, it is possible that selected ␥-MSH peptides such as ␥2 and ␥3 could still modulate pigmentation indirectly, modifying cellular responses to the other melanotropins (71). Studies in cultured normal and malignant melanocytes show that MSH and ACTH, acting via cAMP-dependent pathways (5, 8, 16, 17, 61, 67– 69, 72, 74 –79), stimulate the expression and activity of enzymatic, structural, and regulatory proteins involved in melanogenesis (5, 8, 67– 69). Depending on species and cellular genotype, MSH and ACTH can inhibit or stimulate proliferation of malignant melanocytes (8, 67– 69, 72, 74 –78). However, most authors agree that in normal human melanocytes, ACTH and MSH act as stimulators of cell proliferation (8, 69, 79), dendrite production (5, 8, 67– 69, 74), and melanocyte migration (8) and decrease expression of intercellular adhesion molecule-1 (ICAM-1) (80). Epidermal, adnexal, vascular, and dermal structures represent additional targets for POMC peptides (5, 17, 35, 61– 64). Thus, ␣-MSH can modify proliferation and differentiation of keratinocytes as well as their immune activity and regulate activity of dermal fibroblast (5, 17, 64, 81, 82). In endothelial cells, ␣-MSH may play a crucial role decreasing their adherence and the transmigration of inflammatory cells, a prerequisite step for immune and inflammatory reactions. ␣-MSH and ACTH have strong immunomodulating activity in the skin that results in an overall immunosuppressive effect (5, 17, 64, 82). For example, ␣-MSH acts as antagonist to interleukin-1 (IL-1) suppressing production of proinflammatory cytokines while it induces production of the immunosuppressive cytokine IL-10. ␣-MSH is also capable of suppressing accessory molecule expression on antigen-presenting cells and may thereby serve as one of the

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signals responsible for anergy or tolerance induction (17, 64, 82). In addition to the regulation of hair pigmentation, ␣-MSH and ACTH have other actions on adnexal structures (5, 17, 35, 62, 83, 84). For example, in mink and mice, ACTH acts as inducer of anagen development (85, 86), whereas in mouse anagen skin it induces premature onset of catagen (83). ACTH and ␣-MSH also influence sebaceous gland function (35, 84): ␣-MSH specifically stimulates sebum secretion and lipogenesis in cutaneous sebaceous glands, enhancing wax and sterol ester biosynthesis, and stimulating production and release of female sex attractant odors and of male aggression-promoting pheromones (by specialized preputial glands) (35). ␣-MSH and perhaps ACTH may be important in overall rodent skin thermoregulation, by preventing overwetting of hairs, and in behavior regulation through its action on nonspecialized and specialized sebaceous glands (35, 84). It is likely that MSH and ACTH peptides also affect function of human sebaceous glands. C. Opioid receptors

␮-Opioid receptors, which bind with high-affinity ␤endorphin, were detected in cultured human epidermal keratinocytes (87). Further investigations using in situ hybridization and immunocytochemistry on skin biopsy specimens showed that the receptors are localized to keratinocytes in the epidermis and outer root sheath of the hair follicles, to the peripheral epithelial cells in sebaceous glands, and to the secretory component in sweat glands (87). The related ␨opioid receptor that binds enkephalins with high affinity has also been detected in human and mouse epidermal keratinocytes (88). Met-enkephalin has been shown to inhibit proliferation of mouse epidermal keratinocytes in vivo, in a circadian pattern (88), and both met- and leu-enkephalins can inhibit differentiation of human keratinocytes in vitro (89). In addition, ␤-endorphin and enkephalins have antinociceptive and immunomodulatory properties (7, 24, 25, 27, 28).

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hyperpigmentation, eccrine and apocrine hyperhidrosis, increased sebum secretion, growth of pedunculated fibromas, and thickening and hardening of the nails (1–3, 36, 37, 68). Transgenic mice overexpresssing GH show skin overgrowth with increased dermal thickness, significant dermal fibrosis, and replacement of subcutaneous adipose tissue by fibrous tissue (97). E. PRL and LH/CG receptors (LH/CG-R)

Receptors for the pituitary hormones PRL, LH, and human CG (hCG) are also expressed in the skin (98 –103). PRL receptors have been localized in rat epidermal and follicular keratinocytes by in situ hybridization (98) and in ovine dermal papilla fibroblasts and follicular keratinocytes with a radioligand binding assay (99). PRL binding sites exhibiting high affinity for the ligand were identified in membrane preparation from mink skin; the highest concentration of binding sites was found during the winter fur growth cycle (100). PRL stimulation of cultured human keratinocytes proliferation has been linked to the expression of high-affinity PRL binding sites on the cell surface (101). PRL can directly and indirectly modulate the hair growth, shedding, and molting cycle of furry animals, whereas in humans hyperprolactinemia has been associated with hirsutism (3, 31, 104 – 106). It has also been proposed that PRL participates in the regulation of sebaceous gland activity, since acne vulgaris can be associated with idiopathic hyperprolactinemia in the absence of altered androgen concentrations (3, 106). PRL has potent immunomodulatory properties (107), suggesting that it can also regulate functions in the skin immune system. Normal human skin also contains the mRNAs for the LH/CG-R and a 66-kDa protein capable of binding 125I-hCG (102). These receptors were detected in the epidermis, inner and outer root sheaths of the anagen hair follicle, sebaceous glands, and eccrine glands (103). Testing for expression of FSH receptors in normal human skin found it to be below the level of detectability (103).

D. GH receptor (GH-R)

The GH-R has been detected in human and rodent skin in epidermis, hair follicle, eccrine glands, dermal fibroblasts, adipocytes, and in Schwann and muscle cells (90 –93). Transcription of the GH-R gene has also been detected in cultured human melanocytes (91). These findings suggest that epidermal, adnexal, and dermal cell populations can be direct targets for GH. For example, GH can stimulate differentiation of rat sebocytes and modify melanocyte proliferation (94, 95). However, the phenotypic effects could also arise from an indirect effect such as the stimulation of cutaneous cells to produce insulin growth factor-1 (IGF-1). The cutaneous phenotypic effects of GH have been thoroughly described in patients with acromegaly, whose skin thickness increases considerably and acquires a doughy texture (1–3, 36, 37, 68). This effect is accompanied by increased fibroblasts activity and dermal glycosaminoglycans deposition that promotes water retention (96). Additional cutaneous signs of acromegaly are acanthosis nigricans, hypertrichosis with exception of the beard region,

F. Neurokinin receptors (NK-R)

Expression of the G protein-coupled neurokinin receptors NK-1R, NK-2R, and NK-3R has been reported in human and rodent skin (38, 108); however, others have detected only NK1-R in extracts from human skin (109). Either substance P (SP) or neurokinins A and B (NKA and NKB) could activate these receptors, through signal transduction pathways involving adenylate cyclase and phospholipases C and A2 (33, 34, 38). Human and rodent keratinocytes and endothelial cells express NK-1R to NK-3R, and mast cells, fibroblasts, and Langerhans cells express NK-1R (38). Activation of these receptors stimulates proliferation of keratinocytes, fibroblasts, and endothelial cells and neovascularization (4, 7, 33, 34, 38, 108 –113). NKA and SP stimulate mast cells release of histamine and tumor necrosis factor-␣ (TNF␣), and keratinocyte and endothelial cell function with production and release of proinflammatory cytokines, and expression of adhesion molecules (7, 33, 34, 38, 108 –115). SP stimulates hair growth in rodents (116).

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G. Calcitonin gene-related peptide receptor (CGRP-R)

J. Miscellaneous neuropeptide receptors

There is functional evidence that the G protein-coupled receptor CGRP-R is expressed in skin cells (3, 4, 7, 33, 38, 108, 110 –114, 117–120). CGRP is a potent vasodilator of small and large vessels, at least partly through direct activation of arteriolar smooth muscle cell receptors. CGRP also increases vascular permeability, producing dermal edema through indirect activation of mast cells or through stimulation of nitric oxide (NO) production by endothelial cells with consequent vasodilatation (4, 33, 38, 108, 114). CGRP stimulates endothelial cell, keratinocyte, and melanocyte proliferation (117, 119). Stimulation of keratinocyte proliferation has been linked to direct activation of adenylyl cyclase activity (117), and CGRP induces keratinocyte production and release of promelanogenic factors (120). CGRP modifies the activity of the skin immune system (7, 38, 110 –114, 118).

Somatostatin is known to affect skin immune functions and basal secretion of histamine and, thus, immune cells and keratinocytes probably express the corresponding receptors (38, 110 –112, 133). Similarly, the inhibition of cAMP production by neuropeptide Y (NPY) in human keratinocytes, the stimulation of keratinocyte DNA synthesis by bombesin, and the acceleration of skin wound healing by TSH (12, 33, 38, 110 –112, 117) suggest that specific receptors for these hormones may be also expressed in skin. There are, in fact, data showing that the gene coding for the TSH receptor is expressed in adipocytes and fibroblasts (134). Receptors for bombesin and somatostatin have been shown in dermal fibroblasts (33, 38, 111, 112).

H. Vasoactive intestinal peptide receptor (VIP-R)

VIP-Rs are present in skin, and their activity is linked to G protein-coupled stimulation of adenylyl cyclase activity with cAMP production (3, 4, 7, 33, 38, 108, 110 –113, 117, 118). VIP biding sites have been characterized in malignant human melanocytes (121), where VIP stimulates cAMP production (122).VIP also stimulates keratinocyte proliferation and sweat production (4, 38, 117). Peptide histidine-methionine (PHM) and GH releasing factor (GFR) have stimulatory effects on keratinocyte cAMP production and cell proliferation, thought to be mediated through the VIP-R (38, 117). Indirectly, VIP also participates in the wheal and flare reaction through the activation of mast cells histamine release, or through NO-induced vasodilatation (3, 4, 7, 33, 38, 108, 111, 112). I. Neurotrophin (NT) receptors

Both human and rodent skin express transmembrane receptor proteins of the tyrosine kinase (Trk) and p75 panneurotrophin (p75NTR) families, which show high and low affinity for neuron growth factor (NGF), respectively (33, 38, 108, 123–131). The high-affinity receptors for NGF and NT4 include TrkA and TrkB; TrkC serves as a high-affinity receptor for NT3, which also binds, but with low affinity, to TrkA and TrkB. The receptors for the Trk family and for p75NTR are expressed in epidermal and follicular keratinocytes, epidermal melanocytes, specialized dermal fibroblasts, mast cells, immunocytes, and cutaneous nerves (7, 33, 38, 108, 123–130). NGF stimulates melanocyte dendrite formation and prolongs melanocyte survival after UV damage (123, 124). NGF and other neurotrophins can regulate keratinocyte proliferation and differentiation (123, 125, 128 – 130), functions that in the mouse appear to be coordinated with the hair cycle (128). Lastly, NGF and other neurotrophins can act as mast cells secretagogs and can modulate dermal fibroblasts and dermal immune cells function (7, 33, 38, 108, 123–130). NGF and neurotrophins may have a physiological role in hair cycle and hair follicle morphogenesis (128 –130, 132), whereas NGF may protect human keratinocytes from UVB-induced apoptosis (125).

K. PTH and PTH-related protein (PTHrP) receptors

Dermal fibroblasts express class 1 PTH/PTHrP receptors, which respond to PTH or the PTHrP signal by increasing cAMP, production of cytokines and keratinocyte growth factor (KGF) (135, 136); however, the same receptor is not detected in keratinocytes (135, 137–139). Nevertheless, PTHrP has direct epidermal biological activity stimulating keratinocyte proliferation and differentiation both in vitro and in vivo, and hair follicle formation (15, 140, 141). The keratinocyte intracellular activation pathway differs from that stimulated by class I receptors; PTHrP, while producing intracellular calcium accumulation and protein kinase C stimulation, does not stimulate adenylate cyclase; instead it activates the phospholipase C pathway (138, 139, 142, 143). These PTH/PTHrP class II keratinocyte receptors have been partially characterized and found to also respond to PTH (138, 139, 143). PTHrP can indirectly regulate functional activity of the epidermis through the stimulation of KGF production by dermal fibroblasts (136). Furthermore, PTHrP can play a role during wound healing, helping restore epidermal homeostasis (144). Studies on the PTHrP knockout mouse model, and in mice overexpressing the peptide in the skin, document an important role of PTHrP on epidermal function and hair formation (15, 141). L. Vitamin D receptor (VDR)

Receptors for the active form of vitamin D [1,25-dihydroxyvitamin D (1,25-(OH)2D or calcitriol] are expressed in human and rodent epidermal and follicular keratinocytes (13, 145–151). In the mouse, hair cycle-dependent VDR expression has been reported: it is stronger in mid and late anagen and in catagen and weaker in the telogen and early anagen phases of hair growth (146). VDRs serve as targets mediating calcitriol induction of keratinocyte differentiation and inhibition of cell proliferation (13, 148). Because of these properties, vitamin D derivatives are being used therapeutically (topically) in psoriasis (3, 13, 14). The presence of alopecia in some forms of vitamin D-resistant rickets with decreased expression of VDR in dermal papilla cells indicates a role in hair growth (13, 150). Some authors have identified VDRs in human melanocytes and observed a modulatory effect of 1,25-(OH) 2D on melanogenesis (8, 151). This observation has not been confirmed universally (152). Skin

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immune cells may also express VDRs because of the finding of constitutive immunosuppressive activity for 1,25-(OH) 2D (153). Patients with mutations of VDR present with hypocalcemia, rickets, and significant cutaneous involvement expressed as sparse body hair and, sometimes, total alopecia that includes the eyebrows and eyelashes (150). In the latter subjects, VDR gene mutations result in premature stop signals or abnormal DNA binding and marked resistance to calcitriol therapy (150). Experiments performed on mice treated with topical calcitriol show normal hair regrowth after chemotherapy-induced alopecia (147). M. Glucocorticoid and mineralocorticoid receptors

Glucocorticoid receptors (GRs) are members of the superfamily of trans-acting transcriptional factors and are widely expressed in all skin compartments (3, 4, 12, 31, 154 –157). More specifically, GRs are expressed in epidermal and follicular keratinocytes, epithelial cells of eccrine and apocrine glands, sebocytes, melanocytes, immune cells of epidermis and dermis, dermal fibroblasts, and smooth muscle (154 – 157); activation of these receptors regulates or modulates specific functions in the corresponding cells. The role of glucocorticoids is best emphasized by the skin changes associated with hypercortisolism (3, 36, 37). In such states there are alterations in body fat distribution, general atrophy of the skin, impairment of wound healing, easy bruisability, mild acanthosis nigricans, acne, hirsutism, and alopecia. A glucocorticoid direct inhibitory effect on hair growth has been well documented in animal models (31). It must also be emphasized that glucocorticoids, whether administered topically or orally, are potent drugs used in the treatment of inflammatory skin diseases (3). Most recently, mineralocorticoid receptors (MRs) have been detected in keratinocytes of the epidermis and hair follicle and in sweat and sebaceous glands of human skin (158). The same cutaneous structures also expressed 11␤hydroxysteroid dehydrogenase (11HSD), which converts glucocorticoids to their inactive metabolites, thereby allowing the binding of aldosterone to MRs at much lower prevailing levels (158, 159). N. Androgen and estrogen receptors

Sex steroid receptors belong to the superfamily of transacting transcriptional factors, similar to glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) (36, 68). They are widely distributed in all skin compartments, and their density and expression level vary depending on anatomic site and gender (3, 4, 12, 160 –173). The well recognized androgen effects on hair growth and sebaceous gland functions are related to expression of the corresponding androgen receptors (ARs) in epithelial cells of those adnexal structures and in specialized dermal papilla fibroblasts that regulate hair morphogenesis (161–165). ARs are also expressed in other adnexal structures, in epidermal keratinocytes and melanocytes, dermal fibroblasts, and resident and circulating cells of the skin immune system (3, 4, 12, 31, 160 –165, 169). Similar to ARs, estrogen receptors (ERs) are also expressed in the epidermal, adnexal, and dermal compartments of the

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skin (3, 4, 12, 166 –168, 170 –173). ERs have been detected variably, depending on the sensitivity method and presence or absence of pathology, in epithelial cells of epidermis, hair follicle, sebaceous, eccrine and apocrine glands, in melanocytes, and in dermal fibroblasts. Thus, both estrogens and androgens regulate hair growth, sebaceous gland function, proliferation and differentiation of epithelial cells of the epidermis and adnexa, functional activity of dermal fibroblasts and fibrocytes, wound healing, and skin immune cells activity. There are also data showing that androgens and estrogens can modulate proliferation and melanogenesis in cultured melanocytes (169 –171). Lastly, transgenic male mice overexpressing GH show overgrowth of the skin that is androgen dependent, e.g., it is not observed in females or in castrated males (97). Clinical signs of androgen excess include acne, hirsutism, and androgenic alopecia (3, 36, 37, 163, 164). Acne results from follicular hyperkeratinization, increased sebum production, and from the release of lipases and proinflammatory mediators by Propionicum acnes. In these conditions, androgens [mainly dihydrotestosterone (DHT) and to a lesser degree testosterone] mediate the increased sebum production and follicular hyperkeratinization (3, 37, 163, 164). Hirsutism and androgenic alopecia are associated with increased production of DHT within the dermal papilla of androgen-responsive hair follicles of the face, chest, genital skin, and scalp (3, 12, 31, 37, 163). Conversely, in males with androgen deficiency, the skin remains thin and fine; sebaceous and apocrine glands and sexual hair follicles remain dormant; beard, axillary, and pubic hair do not develop and neither does androgenic alopecia; and there is also a general decrease in skin pigmentation (3, 37, 163). Increased estrogen levels, for example during pregnancy, can lead to hyperpigmentation of nipples, areolae, genital skin, and facial skin (3). The latter, known as melasma, is exacerbated by sun exposure (3). In addition, preexisting nevi and ephelides darken, and telangiectasia, spider angioma, and palmar erythema may develop (3, 37). The presence of actual ERs in malignant melanocytes has been questioned (174). However, studies with normal cultured melanocytes have demonstrated both the presence of receptors and phenotypic effects on cell proliferation (171). Nevertheless, the reports are truly conflicting as regards the estrogen effect on melanogenesis. Thus, while some have reported stimulation of tyrosinase activity and melanin synthesis by estrogens (170), others have shown an opposite inhibitory effect (171). These contradictory results indicate the need for additional work on the role of estrogens in melanocyte functions. O. Thyroid hormone receptors

The skin is a recognized target for T3 (3, 4, 12, 31, 36, 37, 157, 164, 175, 176). This hormone is involved in the process of epidermal differentiation and increases its responsiveness to growth factors. It also participates in the function of sebaceous, eccrine, and apocrine glands, in hair growth, and in the production of proteo- and glycosaminoglycans by dermal fibroblasts. All of these effects are probably mediated by interactions with the specific thyroid hormone receptors

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(TRs) that serve as transcriptional regulators. In fact, thyroid hormone receptors (c-erb-A) were detected by RT-PCR in human skin (177), and c-erbA␤ and c-erbA␣ mRNAs were detected in dermal fibroblasts, consistent with T3 binding to fibroblast nuclear extracts (178). Since T3 may have an inhibitory effect on melanogenesis in malignant melanocytes, it is likely that TR is also expressed in melanocytes (179). A potential role for thyroid hormones in the regulation of skin function is suggested by its changes in hyper- and hypothyroidism (3, 36, 37). In the former, the skin changes include erythema, palmoplantar hyperhidrosis, acropathy, and infiltrative dermopathy. Graves’ disease also may be associated with generalized pruritus, chronic urticaria, alopecia areata, vitiligo, and diffuse skin pigmentation. In hypothyroidism, the skin is cool, dry with pasty appearance; the epidermis is thin and hyperkeratotic; alopecia may develop, and there is diffuse myxedema. In contrast to the pretibial myxedema present in hyperthyroidism, the generalized myxedema of hypothyroidism is reversible with thyroid hormone therapy (37). P. Cholinergic receptors

Grando and associates (20, 180 –182) found that human keratinocytes express both nicotinic and muscarinic receptors in a differentiation-dependent manner. Specifically, human keratinocytes were found to express the ␣3, ␣5, ␣6, ␣7, ␤1, ␤2, and ␤4 nicotinic receptor subunits (20, 180, 181). Immunocytochemistry studies further showed that the number and subunit composition varies according to stage of epidermal keratinocyte differentiation (20, 181). The nicotinic receptors on keratinocytes represent functional ion channels mediating the influx of Na⫹ and Ca⫹2, and the efflux of K⫹, being thus essential for keratinocyte viability (20, 180, 181). Activation of nicotinic receptors stimulates keratinocyte motility and differentiation (20, 180, 181). Muscarinic receptors of several subtypes have been detected in vitro and in vivo in epidermal keratinocytes (20, 181, 182). The subtypes expressed include the m1, m3, m4, and m5 types, with both timing and level of expression being dependent on keratinocyte differentiation stage (20, 181, 182). Muscarinic receptors have been characterized also in malignant human melanocytes (183, 184), and there is strong evidence for their expression in normal melanocytes (Grando et al., unpublished observation). Q. Adrenergic receptors

Radioligand binding studies have shown cutaneous adrenergic receptors, with epidermal keratinocytes and eccrine epithelial cells expressing predominantly the ␤2 adrenoreceptors (4, 21, 185–187). In situ binding assays have further identified ␣1- adrenoreceptors in the epidermis (188). Stimulation of ␤-adrenergic receptors in epidermal keratinocytes results in increased cAMP production, calcium influx, and stimulation of keratinocyte differentiation (3, 4, 21, 187). ␤-Receptors are expressed in inflammatory cells of the dermis (185), thus explaining the ␤2-adrenoreceptor agonists inhibition of proinflammatory TNF␣ release (189). ␣- And ␤-adrenoreceptors are expressed in dermal blood vessels,

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and their activation induces vasoconstriction and decreases vascular permeability (4, 190, 191). Since the melanoma cell phenotype can be modified by adrenergic agonists, it is possible that normal mammalian melanocytes may express adrenergic receptors, similar to pigment cells of other vertebrates (8, 66, 192). The ␤1, ␤2, and ␤3 adrenoceptors are also present on adipocytes (193). R. Glutamate receptors

Immunocytochemical studies performed on rat skin demonstrated the presence of the G protein-coupled metabotropic receptors of the ionotropic glutamate-gated ion channels such as the N-methyl-d-aspartate (NMDA) and ␣-amino-3-hydroxy5-methyl-4-isoxazole propionate (AMPA) types of glutamate receptors in basal epidermal keratinocytes (194). In addition to receptor expression, the specific glutamate transporters have been also detected. Thus, EAAC1 was found in basal keratinocytes, GLT-1 in suprabasal keratinocytes, and the AMPA-type receptor clustering protein, GRIP, in basal keratinocytes (194). In the same rat model, epidermal expression levels of the NMAD receptor and the EAAC1 glutamate transporter were significantly related to wound healing and embryogenesis. Cultured human keratinocytes have shown expression of mRNAs for the NMDAR1 subunit and for GRIP (194). S. Serotonin receptors

The potential presence of serotonin receptors in the skin is suggested by the local effects of serotonin, e.g., pro-edema, vasodilatory, proinflammatory, and pruritogenic (3, 4, 34, 115, 195, 196). In mouse skin, serotonin-induced vascular permeability is mediated by the activation of 5-hydroxytryptamine type 1 (HT1) and HT2 receptors (197). The pruritogenic effect of serotonin may be mediated through direct activation of HT3 receptors or indirectly through mast cells (7, 27, 34, 198). Cutaneous expression of 5-HT2A receptors was detected in unmyelinated axons at the dermal-epidermal junction and in the nerve endings of Pacinian corpuscles (199). Because of serotonin proinflammatory activity, it is likely that cells of the skin immune system will also express the HT receptors generally found in the immune cells (7, 27). Such mechanism would explain the initiation of T celldependent contact sensitivity by serotonin released from human platelets (200), and also the release of prostaglandin E2 from rat skin in vitro (201). Since serotonin can stimulate epidermal keratinocyte proliferation in organ culture, these cells may also express HT receptors (202). T. Histamine receptors

After its release from mast cells, basophils, and platelets, histamine has pleiotropic phenotypic effects in the skin through interactions with H1, H2, and H3 receptors (3, 7, 115, 203). Histamine’s most prominent cutaneous effects are on the local vascular and immune systems, supporting the use of antihistamine drugs for the treatment of pruritus, urticaria, and angioedema (3, 7, 115, 195). Histamine receptors are expressed in the dermal compartment on immunocytes, endothelial cells, blood vessels, smooth muscle, fibroblasts, and nerve endings (3, 7, 115, 195, 203), whereas in the epi-

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dermis, H1 and H2 receptors are expressed on keratinocytes (204 –207). Epidermal melanocytes express H2 receptors (208). Activation of keratinocyte H2 receptors affect proliferation and differentiation via activation of the adenylate cyclase/phospholipase C pathway with associated increases in intracellular calcium levels (204, 205). In the same cell system, activation of the H1 receptor enhances UVB-induced IL-6 production (206), whereas H1 receptor antagonists inhibit ICAM-1 expression (207). Activation of the H2 receptors on melanocytes stimulates melanogenesis (208). Thus, both the dermal and epidermal compartments are clear targets for histamine, regulating cellular functions not directly connected with the previously described proinflammatory effects of this mediator. Of great interest is the proposed role for the mast cell as a coordinator of immune, neural, and endocrine activity on the central level and peripheral organs (115, 203); in this context the cutaneous actions of histamine through specific receptors would also be addressed at coordinating the local cutaneous neuroendocrine system responses (203). U. Miscellaneous receptors

A number of studies suggest that epidermal keratinocytes express purinoreceptors that, when activated by adenosine or adenine nucleotides, will stimulate cAMP and IP3 production, respectively (209, 210). Purinoreceptor activation inhibits keratinocyte proliferation (211). Functionally active adrenomedullin receptors (AM-R), which are G-protein linked and coupled to adenylyl cyclase activity, have been identified in epithelial cells of epidermis, hair follicle, sebaceous and eccrine glands, and in melanoma cells (212). AM binding sites have been characterized in cultured keratinocytes and in melanoma cells; in the latter system AM stimulates DNA synthesis (212). Calcium sensing receptors identical to those found in the parathyroid glands have been identified in cultured normal human keratinocytes (213). There is also experimental data suggesting the existence of receptors for l-tyrosine and l-DOPA (214), since both ltyrosine and l-DOPA can act as regulators of melanogenesis (10, 23), and l-DOPA can suppress lymphocyte activity (215). Finally, the modulatory effect of melatonin on keratinocyte proliferation and inhibition of melanogenesis suggests that melatonin receptors are expressed also in mammalian skin (216 –218). Nevertheless, the evidence is based solely on the detection of melatonin binding sites, while specific receptors for melatonin remain to be characterized. In lower vertebrates, skin melatonin receptors are well characterized, and melatonin is recognized to play an important role in skin pigmentation, acting as a lightening agent (8, 67, 68).

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IV. Skin as a Source of Hormones and Neurotransmitters

Hormones and neurotransmitters produced by epidermal and adnexal structures and dermal cells are listed in Table 2. Neuropeptides released by cutaneous nerve endings or produced by skin are listed in Table 3. The production of vitamin D is covered separately because it is synthesized in the skin, and its systemic effects have been well characterized. A. PTHrP

PTHrP is a protein made ubiquitously throughout the body and expressed most intensely in embryonal and fetal tissues (15). Its gene is encoded in chromosome 12 and, when expressed and processed in human keratinocytes, yields three or more isoforms (5, 137). Three transcripts that have been best characterized are 139, 141, and 173 amino acids long (137). The N-terminal region of PTHrP shows a high degree of homology with PTH, with which it shares 8 or 9 of the first residues. Likewise, PTHrP can bind to the classic bone and renal receptors for PTH (type I), producing hypercalcemia (219). In the skin, PTHrP is highly expressed in the granular layer of the epidermis and outer root sheath of the hair follicle and at much lower levels in basal keratinocytes and melanocytes (15, 220). Pathologically, PTHrP is frequently expressed in squamous carcinomas and in their corresponding cutaneous form (15, 143). Expression of PTHrP has also been reported in metastatic melanoma (221, 222). In addition, during wound healing PTHrP is produced by granulation tissue cells that include myofibroblasts and infiltrating macrophages (144). It is of interest that PTHrP is the main cause for the syndrome of humoral hypercalcemia of malignancy (HHM) and that it is produced predominantly by squamous cell tumors (223). However, cutaneous squamous cell carcinomas, which have a high incidence of about 39/100,000, may have resulted in only a few documented cases of HHM (223). The reason for this discrepancy is unclear but may be related to lower levels of expression, release of mostly inactive fragments, or of inability of PTHrP molecules to cross the basement membranes and reach the systemic circulation (219). Presumably, such a barrier is broken in some cases of advanced squamous cell carcinoma of the skin that develop hypercalcemia. HHM associated with increased serum levels of PTHrP has also been described in metastatic human melanoma (221); and, in at least one case, clear evidence is provided that melanoma cells themselves have been the source of PTHrP (222). The reported patient had no signs of bone metastases, and PTHrP immunoreactivity was detected in melanoma cells on autopsy specimens but not in a biopsy

TABLE 2. Selected hormones and neurotransmitters produced in the skin Compartment

Hormones and neurotransmitter repertoire

Epidermis Dermis and adnexal structures

a

Vitamin D, PTHrP, androgens, T3, L-DOPA, catecholamines, acetylcholine, serotonin, glutamate, aspartate, CRH, urocortin, ␣-, ␤-, ␥-MSH, ACTH, ␤-endorphin, enkephalins, TRH Vitamin D, PTHrP, estrogens, androgens, L-DOPA, serotonin, glutamate, aspartate, CRH, urocortin, ␣-, ␤-, ␥-MSH, ACTH, ␤-endorphin, enkephalins, GH, histamine catecholamines,a acetylcholinea

In the dermis, catecholamines and acetylcholine originate predominantly from cutaneous nerve endings.

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TABLE 3. Selected neuropeptides generated in the skin Source

Neuropeptide

Resident and circulating skin cells

Gastrin-releasing peptide, somatostatin, NPY, atrial natriuretic peptide, PHM/PHI, galanin, neurokinins, substance P, neurotensin, CGRP, VIP, bradikinin, cholecystokinin, endothelins, CRH, urocortin, ␣-, ␤-, ␥-MSH, ACTH, ␤-endorphin, enkephalins Substance P, neurokinins, neurotensin, CGRP, VIP, somatostatin, NPY, atrial natriuretic peptide, gastrin-releasing peptide PHM/PHI, bradikinin, galanin, cholecystokinin, endothelins, ␣-, ␥-MSH, ␤-endorphin, CRH, urocortin, dynorphin, enkephalins

Nerve endings

specimen of the melanoma obtained before onset of hypercalcemia (222). B. Hypothalamic and pituitary hormones

1. CRH and related urocortin peptide. The skin is one of the organs producing all the peptides hormones that are central components of the HPA, the main mediator of the systemic response to stress (5, 6, 9, 16 –19, 25, 28, 36, 56). Among the hormones involved in this classic neuroendocrine pathway are hypothalamic CRH and, more recently, the related peptide urocortin (18, 19). In the skin, CRH gene expression has been detected in cultured human keratinocytes and melanocytes with actual production of the peptide, as shown by RIA and RP-HPLC; furthermore, the CRH antigen has been localized in situ to epidermis, hair follicle, nerve bundles, and dermal blood vessels (18, 42– 44, 46, 49). In mouse skin, which does not express the CRH gene, high concentrations of CRH have been detected by RIA, and chemical identification of CRH was documented by RP-HPLC analysis (44, 46). Since the CRH immunoreactivity was localized to epidermal and follicular keratinocytes and in nerve bundles (43, 44), it was postulated that CRH is imported to the mouse skin by cutaneous nerve endings (43, 44, 46); alternatively, mouse skin could express a related gene, with high homology to CRH (46). We recently observed expression of the urocortin gene in mouse skin and also detected the actual urocortin peptide (19). Urocortin tissue levels were highest in telogen skin and decreased progressively during hair cycle to the lowest level in late anagen (19). This pattern is opposite to the hair cycleassociated production of CRH as determined in the same model (44). Expression of the urocortin gene has also been documented in whole human skin, human keratinocytes, human melanocytes, and in hamster melanoma cells (19). Similar to CRH, expression of urocortin peptide was detected in situ in the epidermis, hair follicle, sweat glands, melanocytic nevi, smooth muscle, and wall of blood vessels (19). The reported expression of CRH and urocortin in lymphocytes (224, 225) strongly suggests that cells of the skin immune system may also contribute to the cutaneous pool of those peptides. Therefore, the hormone products that initiate HPA activation at the central level are also readily available in the skin. 2. POMC. There is a large body of data documenting expression of POMC gene in whole human and rodent skin and in cultured skin cells that include keratinocytes, melanocytes, dermal fibroblasts, and endothelial cells, Langerhans cells, monocytes/macrophages, T lymphocytes, and leukocytes (5, 16, 17, 64, 83).

a. Human skin. The POMC peptides ACTH, ␣-MSH, and ␤-MSH and ␤-endorphin peptides have been detected by immunocytochemistry in normal and pathological melanocytes, keratinocytes, Langerhans cells, and mononuclear dermal inflammatory cells (5, 17, 226, 227). Studies with RPHPLC and Western blotting in cultured human melanocytes and keratinocytes showed multiple forms of those peptides such as ACTH 1–10, acetyl-ACTH 1–10, ACTH 1–17, ACTH 1–39, desacetyl-␣-MSH, ␣-MSH, and ␤-endorphin (5, 17, 228 –230). Human dermal endothelial cells and fibroblasts did not only produce, but also released, ␣-MSH and ACTH immunoreactivity into the medium (17, 64, 82, 108, 231). The other POMC peptide, ␤-MSH, was detected by immunocytochemistry in human skin in epidermal and follicular keratinocytes, malignant keratinocytes, melanoma cells, and dermal inflammatory mononuclear cells (5). ␥3-MSH has also been detected in keratinocytes, melanoma cells, neutrophils, and in nerve endings (5, 232). b. Rodent skin. ACTH, ␣-MSH, and ␤-MSH antigens were detected in epidermal and follicular keratinocytes of mouse skin (5, 17, 83), and ACTH and ␣-MSH were also detected in nerve bundles and smooth muscle; ␤-endorphin has been identified only in the sebaceous glands (5, 83). Cultured murine and hamster melanoma cells expressed the ACTH, ␣-MSH, ␤-endorphin, and ␥3-MSH antigens (5, 16). As regards the POMC gene expression, the transcription of shorter and longer POMC mRNA forms has been identified in epidermal and dermal cells (5, 17). This pattern was accompanied by translation of a 30-kDa POMC precursor and its subsequent processing to ACTH, ␣-MSH, ␤-MSH, ␤-endorphin, and ␥3-MSH peptides (5, 17). Detection of the processing enzymes PC1 and PC2 convertases in human and rodent skin indicates that processing of POMC in skin is similar to that in the hypothalamus and pituitary (17, 108, 232a). It must be noted that one group has reported only 80% homology between the human cutaneous POMC mRNA and its pituitary counterpart (233); however, subsequent analysis of the reported sequence by others showed contamination with murine pituitary POMC cDNA (234). Therefore, the information above is convincing evidence of POMC peptide production in the skin and its processing to ␣-MSH, ACTH, and ␤-endorphin-related peptides. Definition of local production of other products of POMC processing will require additional research. 3. Other pituitary hormones. Studies with in vitro systems have shown that human dermal fibroblasts express PRL mRNA 150 kb longer than the pituitary form (235). However, the fibroblasts synthesized and secreted PRL peptide, immunologically and electrophoretically identical to pituitary PRL

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(235). The data are also consistent with earlier observations of PRL production by normal human connective tissue (236), and with detection of PRL immunoreactivity in sweat glands (237, 238). Expression of the human GH gene has also been detected by RT-PCR in cultured dermal fibroblasts (239); human endothelial cells express the PRL gene (240); and human immune cells produce both PRL and GH (25, 241– 243). Our most recent studies indicate restricted expression of GH gene in the dermal compartment, that failed to detect production of PRL mRNA in whole human skin (243a). Therefore, actual GH and PRL production by the main cutaneous cell compartments has yet to be determined. C. Neuropeptides and neurotrophins

1. Enkephalins. Met-enkephalins (Met-E) and leu-enkephalins (Leu-E), which are products of the larger protein precursor proenkephalin A (PEA) (36, 68), are also produced by mammalian skin (88, 244 –249). Met-E immunoreactivity has been detected in normal human skin and is increased in areas affected by psoriasis (88, 244, 245). The corresponding antigen is located in epidermal keratinocytes and in inflammatory infiltrate components such as T lymphocytes, macrophages, and leukocytes. Met-E has been also detected in the keratinocytes of basal, spinous, and granular layers of human and murine epidermis (88, 245, 250). The detection of PEA mRNA in lesional psoriatic skin further supports local production of the Met-E peptide (244). The cellular source expressing PEA could be mesenchymal dermal cells (248, 249) or immune cells including mast cells (24, 25), since regulated PEA mRNA expression and production of final enkephalin peptides has been detected in rodent skin mesenchymal cells (249), and circulating immune cells express the PEA gene (251). The Met-E peptide has been also detected in epidermal Merkel cells and Langerhans cells (246, 247). Upon further review of the data, it appears that cell type and conditions necessary for expression of the PEA gene remain to be determined. Similar research is needed to determine the cellular source of pro-dynorphin-related peptides, the presence of which has been reported in mammalian skin (252). 2. Nonopioid neuropeptides. Mammalian skin expresses a variety of neuropeptides that include tachykinins SP and NKA, CGRP, VIP, NPY, somatostatin (SOM), galanin, atrial natriuretic peptide (ANP), peptide histidine methionine/peptide histidine-isoleucinamide (PHM/PHI), bradykinin, cholecystokinin (CKK), and gastrin-releasing peptide (GRP) (4, 7, 33, 34, 38, 108 –114). In normal human skin, the most abundant of these peptides are SP, CGRP, VIP, and NPY, although detectable but lower levels of NKA, SOM, and ANP are also present. Neuropeptides are synthesized by nerve cells and released predominantly by unmyelinated afferent C fibers characterized as C-polymodal nociceptors (C-PNN) and by small myelinated A␦-fibers (33, 34, 38, 108). To a lesser extent, autonomic efferent nerves also release the neuropeptides (4, 33, 34). In general, nerves penetrating into the epidermis contain SP, NKA, and CGRP, whereas those innervating dermal structures contain SP, CGRP, VIP, and NKA (33). The neuropeptides are synthesized in dorsal root ganglia, where they are processed and sorted in the Golgi network and then

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migrate, within dense core vesicles through retrograde axonal transport, to nerve endings in the skin (34). The skin concentration of neuropeptides varies by anatomical site, reflecting, probably, regional differences in innervation (4, 33, 253). It is generally accepted that afferent or efferent nerves are the main source for the cutaneous neuropeptides listed above. An additional source of cutaneous neuropeptides is their synthesis and secretion by resident and circulating skin cells, present in inflamed or even normal skin (4, 7, 24, 25, 27, 28, 38, 110, 111, 115, 254, 255). For example, Merkel cells express antigens that are recognized by antibodies against CGRP, SP, NKA, VIP, PHI, NPY, SOM, and galanin (38, 111, 112, 255). Likewise, Langerhans cells express CGRP, SP, GRP, VIP, SOM, and NKA antigens (110, 254). It remains to be tested whether expression of those antigens is connected to actual transcription and translation of the corresponding genes. Several immunocytochemical studies have reported the presence of VIP, SOM, SP, CGRP, NPY, and NKA in dermal and epidermal immune cells from skin affected with psoriasis, urticaria pigmentosa, allergic dermatitis, and, in some cases, uninvolved normal skin (4, 7, 38, 110, 111, 254, 255). NPY has been additionally detected in epidermal and follicular keratinocytes of normal skin and SOM in basal epidermal keratinocytes of atopic dermatitis skin (38, 133, 254). Thus, skin cells definitively can produce neuropeptides; however, the conditions necessary for such production and the precise identity of the producing cells remain to be defined. 3. Neurotrophins. The skin can produce the neurotrophins NGF, NT-3, NT-4, and brain-derived neurotrophic factor (BDNF) (7, 123–125, 128 –130, 256 –258). NGF is synthesized and secreted by keratinocytes, Merkel cells, and dermal fibroblasts and mast cells (7, 123, 128, 256 –258). In human skin, production of NT3 has been detected in dermal fibroblasts (124), whereas in the mouse it is more widely expressed since NT3 is found in epidermal and follicular keratinocytes of developing skin, and in adult animals it is detected in keratinocytes of hair follicle and DP fibroblasts (128 –130). Hair follicle keratinocytes can synthesize NT4 and NGF (128 –130), and dermal Schwann cells can synthesize NGF, NT-3, and NT-4. Locally produced neurotensin can induce mast cell degranulation (203). It may be speculated that the pleomorphism of neurotrophin cutaneous expression could be related to their significance in regeneration, a functional capability vital for the maintenance of homeostasis. D. Neurotransmitters/neurohormones

1. Acetylcholine. Cultured human keratinocytes can synthesize, secrete, and degrade acetylcholine (180, 181, 259). Keratinocyte acetylcholine is synthesized by choline acetyltransferase from acetyl coenzyme A and choline; in turn, acetylcholine is hydrolyzed by acetylcholinesterase to acetate and choline. Activities of both enzymes, choline acetyltransferase and acetylcholinenesterase, have been detected and characterized in homogenates of cultured keratinocytes. Immunolocalization studies have shown that choline acetyltransferase is consistently present in all layers of the human

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epidermis, while acetylcholinesterase is restricted to basal keratinocytes (180, 181, 259). Acetylcholinesterase activity has been also detected in situ in epidermal melanocytes (260). In addition to local synthesis, acetylcholine is also released by cholinergic nerve endings supplying dermal structures (34). 2. Catecholamines. The human epidermis has the capability to synthesize the catecholamines dopamine, norepinephrine, and epinephrine (21, 22, 187, 261–263), which is consistent with previous findings of phenylethanolamine-Nmethyl transferase immunoreactivity in human epidermal keratinocytes (264). The synthetic activity of cutaneous catecholamines resides predominantly in keratinocytes that express biopterin-dependent tyrosine hydroxylase and phenylethanolamine-N-methyl transferase (21, 187, 261, 262). Catecholamine production takes place in human and rodent melanoma cells (265, 266), which suggests that normal melanocytes may also produce catecholamines (267). Catecholamines can be inactivated directly in the epidermis by the enzymes monoamine oxidase (MAO) and by catechol-methyl transferase, the enzyme already characterized in keratinocytes and melanocytes (187, 268, 269). l-Tyrosine, a precursor for both catecholamines and for melanin, is also synthesized in human keratinocytes and melanocytes from l-phenylalanine by phenylalanine hydroxylase (20, 21, 187, 262, 270). Moreover, phenylalanine hydroxylase and tyrosine hydroxylase activities are dependent on the cofactor 6BH4, which is also synthesized and recycled by human keratinocytes and melanocytes (21, 22, 187, 261). Lymphocytes may also represent an additional source of catecholamines (271). It has been proposed that l-tyrosine and its hydroxylation product l-DOPA would have hormone- and neurotransmitterlike roles (23, 214, 272), with melanocytes being the main site of cutaneous l-DOPA production through the tyrosine hydroxylase activity of tyrosinase (8, 273). l-DOPA produced by melanocytes can, in fact, be released into the extracellular environment. As for norepinephrine, an important cutaneous source is its dermal release from adrenergic nerve fibers (4, 33, 34). 3. Other neurohormones. Serotonin may be also synthesized in the mammalian skin, since rodent mast cells can synthesize serotonin, although this property is not shared by human mast cells (7, 27, 115, 195). Serotonin has also been detected in Merkel cells and human melanocytes and melanoma cells (266, 274, 275). In rodent skin serotonin can be transformed into N-acetylserotonin (NAS), and the responsible enzyme arylalkylamine N-acetyltransferase, together with its gene, are correspondingly expressed (196, 276, 277). In hamster skin NAS can be further metabolized to melatonin and 5methoxytryptamine (278). Finally, the neurotransmitters glutamate and aspartate have been detected by immunocytochemistry in epidermal keratinocytes and in dermal and epidermal dendritic immunocytes (279). E. Thyroid hormones

Human skin may be an extrathyroid site of conversion of T4 into the more active T3 (12, 280 –282). This metabolic trans-

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formation would occur in the epidermal keratinocytes through the action of type 2 deiodination pathway (280, 281), with efficiency inversely related to the serum T4 (12). The human epidermis is also the site of T3 deiodination to 3,3⬘diiodothyronine (12). More recent data suggest, however, that at least rodent skin expresses only deiodinase type 3, which catalyzes the 5-deiodination of thyroid hormones (283–285). Since the cutaneous expression of three deiodinases in rodent skin changes during embryonal development, this area needs to be reexamined with modern methods, as it applies to human skin (284, 285). F. Sex steroid hormones

The skin can transform the steroids dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) into active androgens and estrogens (4, 160, 286 –288). Specifically, enzymatic activity corresponding to 3␤-hydroxysteroid dehydrogenase/⌬5–⌬4 isomerase (3␤-HSD) has been localized to the sebaceous glands and, to a lesser degree, in hair follicles, epidermis, and eccrine glands, while 17␤-hydroxysteroid dehydrogenase (17␤-HSD) has been localized to follicular and epidermal keratinocytes (287–291). 3␤-HSD converts DHEA into 4-androstenedione, and 5-androstene-3␤,17␤-diol into testosterone, while 17␤-HSD converts DHEA into 5-androstene-3␤,17␤-diol, 4-androstenedione into testosterone, and androstanedione into DHT (4, 36, 160). Testosterone is also converted into DHT through the action of a 5␣-reductase, detected in dermal and dermal papilla fibroblasts, follicular and epidermal keratinocytes, and sebaceous and apocrine glands (4, 160, 164, 286, 289 –297). There are two isozymic forms of the 5␣-reductase, but the skin expresses predominantly the type I in a highly specific cellular and regional distribution (290 –296). Nevertheless, cutaneous expression of 5␣-reductase type 2 has been also reported, but at much lower levels; this form has been immunodetected in hair follicles of human scalp (295, 296). The skin immune system can also convert DHEA into 5-androstene-3␤,17␤-diol and into 5-androstene-3␤,7␤,17␤-triol. Cutaneous conversion of testosterone into estradiol is mediated by an aromatase expressed in dermal fibroblasts and adipocytes, but not in keratinocytes (4). However, in keratinocytes 17␤-HSD can transform 17␤-estradiol into estrone or estrone into 17␤estradiol (286). G. Other steroid hormones

The presence of 17␤-HSD indicates that skin can dehydrogenate pregnenolone into progesterone, although the reaction does not proceed in cultured keratinocytes (286). The skin expresses genes for cytochromes P450SCC, P450c17, and P450c21 (66). Immunocytochemistry localization of the antigens for cytochrome P450SCC and P450C17 showed the former in epidermal keratinocytes and eccrine glands and the latter in epidermal and follicular keratinocytes, and in sebaceous and eccrine glands (102). These findings, together with the expression of the ACTH and of the MC2-R gene, suggest that the skin could potentially synthesize glucocorticoids (66). In fact, early studies have shown that whole human skin can metabolize progesterone (PROG) (4), while

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human keratinocytes can transform DOC into 5␣-dihydroDOC (286). We have recently reported that skin-derived malignant melanocytes can indeed metabolize exogenous PROG to DOC, corticosterone, and 18OHDOC, and that it can also metabolize DOC to corticosterone and 18OHDOC (Fig. 1) (298). A more physiological preparation, whole skin from the rat, can transform PROG into DOC and metabolize DOC to corticosterone-like and to 11-dehydrocorticosteronelike molecular species (Fig. 2) (299).

V. Molecular and Structural Basis for the Organizational Integration of Neuroendocrine Elements of the Skin

It is apparent from the massive amount of data summarized in this work that the skin function extends beyond that of static barrier organ. Thus, in addition to separating the external environment from internal homeostasis, the skin also exerts important endocrine and exocrine activities (cf. Fig. 3). The well characterized exocrine function is performed by the adnexal structures that comprise eccrine, apocrine, and sebaceous glands and hair follicles. These are important in strengthening the epidermal barrier, in thermoregulation, and in the defense against microorganisms (3, 4, 7, 11). Formation of the hair shaft together with the secretions of eccrine, apocrine, and sebaceous glands also plays an important role in social communication. Furthermore, at least in furry animals, the skin plays an important role in behavioral regulation, ascribed to the exocrine activity of the specialized and nonspecialized sebaceous glands that produce and secrete odorants and pheromones (35). As regards the newly recognized endocrine function of the skin, this is performed by cells compartmentally arranged into endocrine units (Fig. 4). These units are composed of cells of epithelial, neural crest, mesenchymal, and bone marrow origin that form the epidermal, dermal, and adnexal structures (cf. Figure 3). As listed in Tables 1 and 2, these cutaneous cells and adnexal structures can concomitantly produce hormones and express the corresponding receptors (see Section III), indicating that the predominant mechanisms of interaction within the different cutaneous compartments are auto- and paracrine in nature. For example, the common skin stressor, UV radiation, stimulates epidermal production and secretion of the POMC-derived MSH and ACTH peptides. In turn, these peptides interact with MC receptors on melanocytes, keratinocytes, and Langerhans cells (LC) to modify their functional activity and increase cutaneous melanin pigmentation (5, 9, 17, 64) and also generate local antiinflammatory and immunosuppressive effects (17, 64, 108). Immunosuppression, mediated predominantly by ␣-MSH, is expressed as functional antagonism to IL-1, down-regulation of accessory molecules expression on antigen presenting cells, and stimulation of IL-10 secretion (17, 64, 82, 108). At the dermal level these immunosuppressive effects include modulation of local cytokine production, and inhibition of endothelial cells expression of adhesion molecules necessary for inflammatory cells transmigration through the capillary network (7, 17, 64, 82, 108). Dermally produced ␣-MSH and ACTH modify hair pigmentation and sebaceous gland func-

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tion, whereas ACTH modifies hair growth (5, 16, 35, 61, 83, 86). Cutaneously produced CRH and urocortin affect epidermal proliferation of keratinocytes and melanocytes (18, 19, 46, 51), and in the dermis these peptides can modify local immune responses and act as vasodilators and mast cell segregators (40, 48, 56 – 60, 203). There is important neural representation in the skin, and one of its components is the epidermal cholinergic system (20). Its neurotransmitter, acetylcholine, is produced by the keratinocytes in which, through interactions with muscarinic and nicotinic receptors expressed predominantly in the basal or suprabasal epidermal layers, keratinocyte proliferation, migration, and differentiation are regulated (20, 181, 259). Acetylcholine availability is determined by the local concentration of acetylcholinesterase, which is highest in the basal layer and decreases gradually along the vertical axis to reach its lowest levels below the stratum corneum (20, 181). The adrenergic system, represented by the catecholamines produced by keratinocytes, interacts with adrenergic receptors expressed on the same cells to regulate their phenotype (21, 187, 300). The local production of the nonessential amino acid l-tyrosine from l-phenylalanine by melanocytes and keratinocytes ensures its availability for catecholamine synthesis and melanogenesis in the epidermal unit, independent of systemic supply (21, 22, 261). Both l-DOPA, a product of local l-tyrosine hydroxylation, and catecholamines can potentially modify cutaneous immune responses (215, 271). As regards sex hormones actions, testosterone by itself, or after conversion to DHT in keratinocytes and dermal fibroblasts modifies hair growth and sebaceous glands function (4, 163, 164). Dermally produced estradiol (4) can affect function of adnexal structures and the wound healing process (172, 173). As discussed in the section on the vitamin D receptor, the active vitamin D3 metabolite 1,25-(OH)2D3 inhibits keratinocytes proliferation and stimulates their differentiation via interaction with the VDR (13, 14). Evidence for the epidermal conversion of vitamin D into 1,25-(OH) 2D3 (301) would further support local (auto- and paracrine) mechanisms of action. PTHrP produced in the epidermis and hair follicle has a similar effect on keratinocytes through interaction with a receptor different from the classic class 1 PTH/PTHrP receptor (15, 302). Both vitamin 1,25-(OH) 2D3 and PTHrP can affect hair growth (13–15, 302). Notwithstanding their overwhelming local action, hormones produced in the skin can also enter superficial and deep vascular dermal plexuses, or vessels supplying adnexal structures, with long distance effects. Such a true endocrine role is most apparent in the case of hormones and cytokines produced in the dermis that have rather free access, by diffusion to local capillary vessels. Limiting factors for this diffusion are the distance between production site and vasculature, adhesiveness to the extracellular matrix, and local rate of degradation. In contrast, epidermally produced hormones and cytokines must penetrate the basement membrane (BM) before traversing the extracellular matrix (EM) of the papillary dermis; therefore, the permeability barrier and the adhesiveness to the BM and EM limit their access to the most superficial capillary vessels. An example of the relative restriction posed by the dermal-epidermal junction is the

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FIG. 1. Metabolism of progesterone to DOC, corticosterone, and 18OHDOC in malignant melanocytes. A, TLC separation of 14C-progesterone metabolites produced by melanoma cells. B, RP-HPLC identification of 3H-18OHDOC as a metabolite of 3H-DOC. Upper panel, UV detection of 18OHDOC standard; lower panel, radioactivity in eluted fractions with arrow indicating 3H-18OHDOC peak. C, Enzyme-linked immunosorbent assay (ELISA) identification of corticosterone (B) in RP-HPLC-separated fractions. Upper panel, UV detection of corticosterone (B) standard; lower panel, immunoreactive corticosterone (arrow) in media from human melanoma cells incubated with progesterone. Control represents media from cells cultured without progesterone added. DOC, 11-Deoxycorticosterone; B, corticosterone; Aldo, aldosterone; 11dehydro-B, 11-dehydrocorticosterone; 18ODOC, 18-hydroxycorticosterone. [Reproduced with permission from A. Slominski et al.: FEBS Lett 445:364 –366, 1999 (298). Experimental conditions are detailed in Ref. 298.]

rarity of patients showing systemic effect (hypercalcemia) from cutaneous PTHrP, a hormone produced abundantly in the epidermis (15, 302). Still, epidermally produced vitamin D (14), urocanic acid (303, 304), and, perhaps, PTHrP do enter the systemic circulation and are able to modify the functional

activity of distant organs, providing evidence for endocrine effects by factors produced in the epidermis. Urocanic acid produced in the stratum corneum of the epidermis can also enter the systemic circulation and have immunosuppressive effects (4, 123, 303, 304). As mentioned above, epidermal

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FIG. 2. Active steroidogenesis in normal rat skin. Both panels show TLC separation of steroid products. The right lanes marked 14C-PROG (A) or 14C-DOC (B) show radioactive steroid intermediates generated in rat skin. The left lanes marked controls represent nonenzymatic transformation of 14C-PROG (A) or 14C-DOC (B) incubated in culture media only. Experimental conditions are detailed in Ref. 299. PROG, Progesterone; DOC, 11-deoxycorticosterone; B, corticosterone; Aldo, aldosterone; A, 11-dehydrocorticosterone; 18OHB, 18-hydroxycorticosterone. [Reproduced with permission from: A. Slominski et al.: Biochim Biophys Acta 1474:1– 4, 2000 (299). © Elsevier Science.]

PTHrP may play predominantly para- or autocrine roles (15, 141). It could, however, have a distant effect after release by pathological conditions (skin cancer) (222, 223). Cutaneous neuroendocrine elements are therefore tightly organized and arranged into epidermal and dermal endocrine units, as determined by the physical separation between those compartments (Figs. 4 and 5). These units, which become fully expressed in a field-restricted stress-dependent manner, have broad bidirectional communications. This is accomplished through soluble factors able to penetrate the basement membrane and, also, through sensory nerve endings connecting epidermis and dermal structures (Figs. 4 and 5). Sensory nerve fibers provide anterograde or retrograde transmission of impulses through axon reflexes with release of neuropeptides at epidermal or dermal nerve endings (33, 34, 38). The latter intracutaneous communication mechanism

represents therefore a high-speed and extremely specific connection for the transfer of information, sensed externally or internally, to specific target cells. Target cell activation may then be mediated by neuropeptides (cf. Table 3 and Section IV.C) synthesized and released predominantly by the unmyelinated C fibers described as C-polymodal nociceptors (C-PNN), or by myelinated A␦-fibers (33, 34, 38). There are specific roles for each of the different neuropeptides released by afferent nerve endings in the functional regulation of epidermal barrier properties, skin immune activity, vascular activity, hair growth, and adnexal functions. Those topics, as well as their mechanism of action, have been discussed in comprehensive reviews on the subject (5, 7, 33, 34, 38, 56, 110 –112, 128, 203). It is apparent from neuroimmunocytochemistry studies that nerve subpopulations containing different neuropeptides, such as SP, NKA, CGRP, VIP, SOM,

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FIG. 3. Localization of the cellular components of the exocrine and endocrine skin units. The epidermis is represented by the upper layer, separated from the dermis by the basement membrane. The listed cell types have the capability to produce hormones, neural mediators, and cytokines; they also express the corresponding receptors indicating auto- and paracrine mechanisms of action.

NPY, PHM, enkephalins, CRH, and ␥- and ␣-MSH, do enter cutaneous structures. The presence of this neural network with fibers penetrating all the vital layers of the epidermis and branching into dermal structures, adnexa, Merkel cells, epidermal Langerhans cells, melanocytes, and dermal mast cells provides, therefore, the support for a dual role for those cells, as effectors and regulators (33, 34, 38, 110, 114, 115, 118, 119, 128, 203, 300, 305–313). Within this local branching neural network, disturbances of local homeostasis expressed as production of chemical mediators can be sensed in a specific manner and transmitted to local subunits to counteract noxious stimuli or protect against further damage. The neural branches can be also activated directly by neurohormones and bioactive peptides produced locally, such as histamine, eicosanoids, or NO (33, 34, 38, 112, 203, 312, 314); or, by physicochemical agents such as changes in pH, cation, and free radical concentration (cf. Ref. 34). Indirect neural modulation may be provided by the cytokine networks that modify the chemical environment surrounding the nerve endings. As compared with this neural mechanism, humoral communication, dependent on local diffusion, results in a much slower response. The special role of autonomic nerves in the cutaneous neuroendocrine organization is limited by the predominant dermal ending of their fibers. Thus, they can only regulate function in the dermal endocrine unit although neurotransmitters released in the proximity of the basement membrane could potentially diffuse into the epidermal compartment. It is also possible that autonomic nerves could enter the epi-

dermis; however, this hypothesis still requires experimental investigation. The bidirectional interaction between skin elements and local neural network is perhaps best illustrated by the changes in murine skin during the hair cycle, which are dependent on appropriate dermal and adnexal innervation (128, 300, 311). In this process, the hair cycle-associated tissue remodeling is accompanied by a tightly regulated sprouting and regression of specific afferent and efferent nerve fibers that form a neural and neurotransmitter network. Its cutaneous expression is highly specific and tightly determined by the actual phase of the hair cycle (128, 300, 311). The epidermal and dermal endocrine units with their bidirectional communication pathways, which proceed via soluble mediators or via antidromic axon reflexes through the nerve branches that link both compartments, combine to form the skin neuroendocrine organization (Fig. 5). In general, this neuroendocrine organization functions to coordinate the epidermal and dermal changes necessary for reinforcing the physical barrier and maintaining its structural integrity. To implement these objectives, it modulates sensory reception, melanin pigment production and distribution, activity of the local immune system, vascular functions, thermoregulation, exocrine secretion, and metabolic transformation of prohormones or hormones into other molecules of different biological activity. The skin neuroendocrine system is thus continuously sensing environmental components and, when activation threshold levels are reached, a reaction is triggered with

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FIG. 4. Diagram demonstrating the proposed flow of information between dermal and epidermal endocrine units and their systemic connections. For functional purposes, cells with endocrine capability become activated in response to environmental stimuli in a stressdependent manner, organized according to anatomic compartment of residence. They communicate by humoral signals (central arrows) and sensory nerve endings (arrows on the left). The efferent neural regulation is provided by the autonomic nerves (right), and also by sensory nerves (left) via antidromic conduction.

production of specific biological factors. Some of these factors may be released to the extracellular compartment to activate sensory nerve endings, directly enter the circulation, or activate circulating immune cells. The sum of these actions sets the optimal mode for dealing with deleterious environmental changes (Fig. 6). Humoral signals that could directly enter the circulation include cytokines and hormones and vitamin D3. The latter represents a marker for a cutaneous action in response to an environmental component (UV-B), which results in well defined systemic effects on calcium homeostasis (14). An analogous example in amphibians is the skin regulation of pituitary function through TRH and skin peptide tyrosine-tyrosine (SPPY) (315, 316). Environmental factor(s) determine concentrations of TRH and SPPY in frog skin, which are higher than in any neuroendocrine organ; skin TRH reaches the pituitary to stimulate production and release of PRL and ␣-MSH, while SPPY inhibits production of ␣-MSH (315, 316). In mammals, there are other local hormonal factors that could potentially enter systemic circulation after UV radiation exposure or in pathological conditions. Among those are POMC-derived ␣-MSH and ␤endorphin (5, 9, 108, 230), met-enkephalin (245), PTHrP (15, 302), or DHT, estradiol, and T3 (4, 11, 12). Skin cytokines can also directly affect the functional activity of distant immune and nonimmune organs (7, 11, 17, 27, 108), whereas circulating cytokines are known to affect hypothalamo-pituitary axis function (24 –28). Thus, IL-1, IL-6, interferons, and TNF␣ can access brain and pituitary to up-regulate production and release of selected hypothalamic and pituitary hormones.

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FIG. 5. Organization and function of the skin neuroendocrine system. The epidermal and dermal endocrine units modulate functional activity of epidermal and dermal compartments. Endocrine units coordinate their actions by humoral signals (central arrows) and/or by the local neural network (connecting arrow on the left).

Cytokines may have similar action on the regulation of adrenal gland function (28, 317). Intermediates of melanogenesis l-DOPA and products of its metabolism in the melanocytes might also have systemic effects when, under pathological conditions, they are released into the circulation (10, 23, 318). Many epidermally or dermally derived molecules are incapable of migrating because of insignificant concentration in the vicinity of blood vessels; however, a systemic effect is still theoretically possible. Thus, direct stimulation of dermal, adnexal, or subcutaneous cellular components could secondarily result in the production of biological mediators with definite systemic effects. An example of this amplification mechanism is represented by the cytokines IL-1 and TNF␣, which can stimulate leptin production by adipose tissue in the deep dermis and/or subcutis (319, 320). In this manner, small amounts of cutaneous cytokines could affect feeding behavior and energy balance (319). Another example is the activation of skin immune cells that can enter the circulation and have distant immunological or regulatory effect (7, 27). Similar to the humoral model of communication in the cutaneous endocrine system, with potential cytokine-mediated stimulation of the HPA axis, the cutaneous neural signaling system could also activate central nervous system pathways. The latter connections have the advantages of being more rapid with higher specificity (Fig. 6). Thus, changes in the skin physicochemical environment generated by physical, chemical, or biological trauma, UV radiation, or local disease processes could be sensed by afferent nerve ending, and thence transmitted via the spinal cord to the brain. However, before the information is sent to the brain,

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the spinal cord to other organs without ever reaching the higher centers. To summarize, the skin can generate rapid (neural) or slow (humoral) moving signals to induce responses at the general or systemic level or at the organspecific level. These responses are designed to counteract the damaging effect of environmental insults or to adjust the homeostatic system to the optimal mode that would buffer environmental noxious agents most efficiently. VI. Regulation of Cutaneous Neuroendocrine System

There are number of environmental and intrinsic factors that regulate the cutaneous neuroendocrine system activity level. The most prominent environmental factor affecting the skin is solar radiation, particularly within the UVA and UVB wavelengths. Temperature, humidity, and concentrations of chemical and biological agents represent other factors. Some internal factors affecting the skin neuroendocrine system are changes in the physicochemical microenvironment or in biological modifiers; these may be generated in reaction to environmental signals or result from local cyclic biological rhythm associated with hair cycling, or from local or general disease processes. Of the endocrine factors produced by the skin the most important is vitamin D, which is not only a regulator of the calcium metabolism but has other systemic effects (13, 14, 145). For example, epidemiological evidence suggests that sunlight deprivation with associated reduction in the circulating levels of vitamin D3 derivatives may result in increased incidence of the carcinomas of breast, colon, and prostate (145). A. Solar radiation FIG. 6. Systemic effects of skin neuroendocrine system products. In response to noxious stimuli, the skin endocrine system mounts a progressive, intensity-dependent, highly coordinated response. In the case of high-magnitude stimuli, the generated signals travel through humoral or neural pathways to reach the central nervous system, immune system, and other organs.

it may be modulated by the local cutaneous neuroendocrine units through the direct activation of nerve receptors by neurohormones and neurotransmitters, or by neuropeptides (cf. Tables 2 and 3), histamine, eicosanoids, NO, and other proinflammatory mediators (5, 7, 27, 33, 34, 108, 113, 203, 314). Alternatively, stress released cytokines and proinflammatory biological modifiers could affect signal type and neural sensor availability through indirect mechanisms, e.g., activation of other cells to produce and release factors activating afferent receptors. In this context, mast cells, melanocytes, Langerhans cells, and Merkel cells could be particularly important because of their close contact with nerve endings (33, 34, 110, 111, 119, 203, 305–308). Secondary changes in hydrogen ions, cations, free radical and NO concentrations or eicosanoids produced by cytokine-activated keratinocytes or immune cells could have similar effects on sensory nerve endings. In the visceral organs the cytokine IL-1, IL-6, and TNF␣ signals can be potentially transmitted through an indirect mechanism via the vagus nerve to the central nervous system (26, 28, 321). Lastly, upon leaving the skin, some afferent neural signals may also be relayed from

UV light is a form of electromagnetic energy that includes the wavelength between 100 to 400 nm of the solar spectrum. Although it includes vacuum UV, UVC, UVB, and UVA, only the 290 – 400 nm wavelengths that comprise UVA and UVB reach the surface of the earth, because of the partial absorption by atmosphere. UVB (290 –320 nm) interacts very efficiently with the skin, inducing sunburn and pigmentation (3, 4, 9). UVA (320 – 400 nm) has better penetration through the atmosphere but lower efficiency in inducing erythema and melanogenesis. It is classified as UVA1 (320 –340 nm) and UVA2 (340 – 400 nm), and it has been proposed that the photobiological mechanism of action for UVA1 is similar to that of UVB; the effects of UVA2 would involve distinctive oxygen-dependent photochemistry. The cutaneous effects of UV radiation are dependent on the penetration and absorption of the particular wavelength. In human skin UVB is absorbed predominantly by stratum corneum and to a lesser degree by the epidermis. The very small fraction of UVB that reaches the dermis, however, has significant biological effects inducing immediate and delayed erythema (3, 4, 9). Transmission of UVA through epidermis of white skin is high, resulting in approximately 50% of energy reaching the dermis. UVA has only 1/1,000 of UVB biological activity, but it also contributes to the cutaneous actions of solar radiation (3, 4, 9). Thus, it has a major effect in aging of the skin, it has a more limited role in the induction of skin cancer, and it does not produce burning of the skin. In general, the biological

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responses to solar radiation are dependent on individual susceptibility determined by skin pigmentation, prior exposure to UV radiation (decreases the threshold for subsequent responses), region affected, radiation field size, and environmental conditions (3, 4, 9). There is, nevertheless, a high degree of precision and predictability of the cutaneous response to UV, demonstrating that mechanisms have evolved to transform some of the solar energy into a catalyst activating a recording system (9). Such a recording role could be served by the local neuroendocrine system, whose activation is designed to buffer or counteract the damaging effect of UV. 1. CRH-POMC system. UVB stimulates production of CRH peptide in normal melanocytes without noticeable changes in CRH mRNA levels, suggesting posttranscriptional regulation (322). UVR can stimulate/induce POMC gene expression in the skin in human and rodent normal and malignant keratinocytes and melanocytes maintained in cell culture (5, 9, 17, 64, 108, 230, 323). The stimulation of ACTH, ␣-MSH, ␤-LPH, and ␤-endorphin production and secretion in response to UVB is dose dependent in normal and malignant epidermal cells, and in dermal endothelial cells; POMC mRNA production is correspondingly increased (17, 64, 108, 323). UVA can also stimulate POMC gene expression with subsequent MSH and ACTH production in human keratinocytes and endothelial cells (17, 64, 108). This stimulation of POMC gene expression and production of POMC peptides are observed after a 10-h latency period; production becomes significant at 10 –24 h (17). Of interest, humans and horses exposed to sunlight exhibit increases in the circulating levels of ␣-MSH and ACTH, and experimental whole-body exposure to UVR in humans increases ␤-LPH and ␤-endorphin serum levels (5). In the case of ␤-LPH the response is abrogated by UV-absorbing topical sun blockers, implicating mediation by a photoreaction (324). UVB can also up-regulate expression of MC1-R on normal and malignant cultured melanocytes and keratinocytes (5, 17, 323). This UVB up-regulation of MSH receptors expression is associated in melanocytes, with increased responsiveness to MSH in terms of stimulation of melanogenesis, as shown in both cell culture and in vivo conditions (75, 323, 325). These experimental findings are consistent with the effects of exogenous MSH and ACTH in humans, which cause increased skin pigmentation affecting predominantly the sun-exposed areas. Clinically, the similarly increased skin pigmentation of patients with Addison’s disease is most striking in the sun-exposed areas. These experimental and clinical observations led Pawelek and colleagues (9, 75, 325) to propose that the effects of UVB on cutaneous melanogenesis do not represent random (unrelated) events but, instead, a highly coordinated sequence in which expression of MSH receptors and local production of POMC-derived MSH and ACTH peptides are important intermediate steps. 2. Immunoregulatory molecules. UV radiation influences the immune system at both local and systemic levels with the net effect being immunosuppressive (7, 17, 64, 82, 108, 114, 326, 327). The mechanism for this action can be either direct absorption of light energy by cells of skin immune system that include resident and nonresident (circulating cells) or

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indirect through UV-induced activation of nonimmune cells in epidermis and dermis with release of cytokines and chemical mediators (7, 9, 17, 64, 82, 108, 114, 326 –333). Important in this regard is trans-urocanic acid (UCA) which, after absorption of UVB, or to lesser degree of UVA energy, isomerizes into cis-UCA in the stratum corneum (303, 304). cis-UCA acts as a potent local and systemic immunomodulator and immunosuppressor (7, 303, 304). Keratinocytes stimulated by UVR can produce and secrete the cytokines IL-1, IL-6, IL-8, IL-10, IL-12, IL-15, TNF␣, and macrophage inhibitory factor (MIF), eicosanoids, basic fibroblast growth factor (bFGF), IGF-I, transforming growth factor (TGF-␣), and endothelins (7, 17, 108, 114, 326 –333). This effect is rapid (within 1–3 h) and predominantly mediated by UVB, although UVA also stimulates IL-10 and, to a lesser degree, IL-6 production. UVR also switches the local cytokines and mediators release profile of nonepithelial components of epidermis and dermis including lymphocytes, macrophages, mast cells, endothelial cells, and melanocytes. The cytokines IL-1, IL-6, TNF␣, and MIF exert local activity, which does not preclude systemic effects upon entering the circulation. 3. Neuropeptides, neurotrophins, and neurotransmitters. UVA, but not UVB, irradiation increases the skin levels of metenkephalin, and multiple whole-body UVA exposure can also increase the plasma level of the peptide (245). For its part, UVB induces release of CGRP, SP, and NKA from cutaneous sensory nerves (38, 108). CGRP appears to have immunosuppressive properties, while SP and NKA enhance cutaneous neuroinflammation (38, 108, 114). UVB also stimulates NO production by keratinocytes, melanocytes, and NO release from sensory nerve endings (9, 108, 314). Also, UVB induces production and release of the neutrophin NGF by epidermal keratinocytes (123, 256). Schallreuter et al. (334, 335) have shown that UVB enhances tetrahydrobiopterin production and phenylalanine hydroxylase activity, with net increase in the epidermal supply of l-tyrosine. l-Tyrosine is a precursor for both catecholamine biosynthesis and melanogenesis. Stimulation of melanogenesis by UVB is associated with increased production of the biologically active products l-DOPA, dihydroxyindole (DHI), and DHI carboxylic acid (9, 123). B. Hair cycle

Hair growth and the cyclic activity of the hair follicle are timed by a “biological clock,” which in rodents changes periodically the physiology and morphology of the entire skin (30, 31). In mice, the expression of POMC gene and production of the POMC peptides ␤-endorphin, ACTH, and ␣-MSH are synchronized with hair follicle cycle (5). POMC production is lowest in telogen (resting phase), increases during anagen (growing phase), and decreases in catagen (involution phase). These changes correlate closely with the local expression of the MC1 gene (65). The intracutaneous concentration of CRH and expression of CRH-R1 exhibit similar changes coupled with the hair cycle, being highest during anagen and lowest during the catagen and telogen phases (44). A similar phenomenon has been described for

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SP, with maximal levels occurring in early anagen and minimal levels occurring in catagen skin (116). Thus, the biological clock regulating the cyclic activity of hair follicles appears to regulate simultaneously the local production or release of neuropeptides and the expression of the corresponding receptors. The hair cycle is associated with striking changes, which are qualitative in distribution and quantitative in expression levels of the neutrophins NT-3 and NGF and their corresponding receptors in the skin of the C57 BL/6 mouse (128 – 132). Furthermore, the pattern of sensory and sympathetic innervation of different cutaneous structures including the hair follicle itself, shows significant hair cycle-dependent changes (128, 300, 311). The changes in adrenergic innervation are accompanied by specific patterns of follicular ␤2adrenergic receptor expression. Therefore, the whole cutaneous neural network involved in the regulation of hair growth undergoes cyclic changes (128, 300, 311), which can potentially affect the function of other cutaneous structures, sensory skin responsiveness, and transmission of afferent signals to the spinal cord. Because of the extent and magnitude of the hair cycle-dependent changes, it is likely that these are regulated within the skin itself, under the control of the “biological clock” governing hair cycle.

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context peptide hormones and neuropeptides can be degradated by neutral endopeptidases (NEP) and angiotensin converting enzyme (ACE), which are present in dermal fibroblasts, endothelial cells, and keratinocytes (34, 38, 108, 337). NEP activity is not static, but can be stimulated by proinflammatory cytokines, by factors raising intracellular cAMP, and glucocorticoids (38); in addition, its cutaneous pattern of expression changes during wound healing (337). Other proteolytic enzymes such as mast cells-derived tryptase or chymase can degrade neuropeptides, effectively attenuating their activity (7, 34, 38, 108, 115, 203). Catecholamines and other biogenic amines can be inactivated directly in the epidermis, by the action of MAO and/or by catechol-methyl transferase (21, 268, 269); the latter enzyme has been already characterized in keratinocytes and melanocytes. Acetylcholine is degraded to acetate and choline by epidermal acetylcholinesterase (20, 259). The skin is, in addition, a well recognized site for the transformation of glucocorticoids and sex hormones to molecular forms with higher or lower hormonal activity, or overtly inactive (4, 11, 160, 297). VII. Regulation of Cutaneous Vitamin D Production A. Vitamin D3 production

C. Cytokines

Similar to its effects at the central level, the proinflammatory IL-1 has significant local stimulatory/inductory effects on POMC gene expression and production of POMC peptides in normal and malignant epidermal melanocytes and keratinocytes, dermal endothelial cells, and circulating immune cells that include macrophages (5, 17, 64, 108, 230). Another cytokine, TNF␣, stimulates production of POMC mRNA in normal dermal fibroblasts, while TGF-␤ inhibits it in keratinocytes and normal dermal fibroblasts, but not in keloid fibroblasts (231). TNF␣ also stimulates production of the POMC products ␤-endorphin and ACTH peptides (336). Many cytokines can up-regulate expression of the MC-1 gene and of functional cell surface MSH receptors in normal and malignant melanocytes (5, 17, 64, 323). Those include Il-1␣, IL-1␤, endothelin-1 (ET-1), adult T cell leukemia-derived factor/thioredoxin (ADF/TRX), INF-␣, INF-␤, INF-␥, (Bu)2cAMP, and the hormones ␣-MSH, ␤-MSH, and ACTH. IL-1 can also stimulate MC-1 receptor expression in normal and malignant human keratinocytes and in human dermal microvascular endothelial cells (HDMEC) (17, 64, 230). Conversely, TNF␣ inhibits MC1 expression in melanocytes. Thus, selected cytokines regulate precisely (“fine-tuning”) the level of expression of POMC and MC1-R. The roles of cytokines in the cutaneous regulation of epidermal cholinergic system, production of catecholamines, steroid synthesis and metabolism, and synthesis of neuropeptides CRH, urocortin, and enkephalins remain to be investigated. D. Degradation or inactivation of hormones and neurotransmitters

One important mechanism regulating the availability of locally produced hormones is their degradation in situ. In this

The recognition that the skin could react with an invisible component of sunlight to make a factor indispensable for the mineralization of bone vitamin D represents a remarkable scientific accomplishment (14). Vitamin D3, or cholecalciferol, is formed from the precursor steroid 7-dehydrocholesterol (7-DHC), which is normally concentrated to the plasma membrane of basal epidermal keratinocytes (80% of skin content). Upon stimulation with sunlight photons of UVB light (290 –310 nm wavelength), 7-DHC undergoes photolysis with breakage of the 9,10-carbon bond generating the thermolabile intermediate previtamin D3. At normal skin temperature previtamin D3 molecules convert into vitamin D3 through internal rearrangement (Fig. 7). Vitamin D3 enters the circulation bound with high specificity to vitamin D binding protein (DBP) to exert its systemic actions (338). When newly formed previtamin D3 and vitamin D3 continue to be irradiated, they convert into additional steroids such as lumisterol, pyrocalciferol, and tachysterol, which are practically devoid of vitamin D3 activity (14). Although light and temperature are the only variables involved in the biosynthetic process, they do not account entirely for the rates of biosynthesis observed in tissues. Thus, irradiation of 7-DHC dissolved in isotropic organic solvents such as hexane generates only one tenth of the amount observed in similarly irradiated skin (14). The explanation for this discrepancy was obtained in experiments with artificial liposomes, which uncovered the crucial role played by plasma membrane phospholipids in the kinetics of the reaction. Thus, through amphipatic interactions, previtamin D3 remains stabilized in its “cholesterol like” cZc– conformation, the only one leading to conversion to vitamin D3. Furthermore, the fastest rate of previtamin D3 isomerization was seen in association with phospholipids containing 18 carbon atoms in the hydrocarbon chain (339).

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FIG. 7. Cutaneous synthesis of vitamin D3. Under exposure to UVB, cutaneous 7-dehydrocholesterol molecules undergo photolysis to the secosteroid product cZc-previtamin D3 (this cis-conformer is the only form that can be converted into vitamin D3). Thermal energy produces intramolecular rearrangement of cZc-previtamin D3 with a 1,7-sigmatropic hydrogen transfer from C-19 to C-9, to yield vitamin D3. [Modified from X. Q. Tian and M. F. Holick: J Biol Chem 274:4174 – 4179, 1999 (339), by permission from the Journal of Biological Chemistry. © The American Society for Biochemistry and Molecular Biology.]

Once formed in the skin, vitamin D is translocated to the circulation over a period of 30 h or longer. It reaches peripheral tissues bound with high specificity (98%) to vitamin D binding protein (also known as group-specific component or GC). This is in contrast to orally derived vitamin D2 (ergocholecalciferol), which circulates only 50% bound to vitamin D binding protein, with the remaining fraction being bound to cholesterol containing lipoproteins (14). Vitamin D is metabolized (activated) to 25-hydroxyvitamin D (in the liver) and to 1,25 dihydroxyvitamin D (in the kidney) (14). According to the level of action, the physiological and pathological factors that modify the systemic supply of cutaneous vitamin D3 can be classified into precutaneous, cutaneous, and postcutaneous. B. Precutaneous regulation

1. Environment dependent. This category includes geographic latitude. Thus, as the earth experiences its seasonal tilting during fall and winter, sunlight arrives at an angle at the more polar latitudes crossing the atmosphere almost tangentially during winter, and lessening transmission of UVB wavelengths. For example, during winter in Boston, Massachusetts (latitude 42.2 oN) these wavelengths disappear (339), and a similar situation is observed in the Southern Hemisphere, where vitamin D3 photosynthesis is extremely low during winter in Cape Town, South Africa (latitude 35oS), but almost unchanged throughout the year in Johannesburg (26oS)(340). Another environmental variable is the time of day, since vitamin D3 synthesis is maximal at midday, with only very small amounts being formed before 0800 h or after 1700 h. In fact, in Cape Town, only negligible amounts of previtamin D3 are formed in the winter before 0010 h and after 1500 h. In general, latitude, season of the year, and time of day affect the cutaneous photosynthetic process in a highly coordinated, mutually dependent manner (14). 2. Environment independent. a. Clothing. Garments provide significant protection against the damaging effects of solar light that include erythema, accelerated aging, and development of skin cancer. Experiments on transmission of UVB light through different fabrics showed significant effects on the photosynthesis of vitamin D3 (341). Of fabrics with similar thread density, black wool had the highest light absorption coefficient followed,

respectively, by black polyester, black cotton, white cotton, white wool, and white polyester. All of the fabrics produced significant attenuation of the shorter wavelengths (UVB), and studies in volunteers wearing garments made of the same materials showed complete obliteration of the normal serum vitamin D3 photosynthetic response to one MED (minimal erythema dose) of UVB (341). This absence of vitamin D serum response persisted after whole-body irradiation was increased to the equivalent of 6 MEDs. In addition, regular street clothing, even that worn during summer, also produced significant suppression of the vitamin D3 response to UVB (341). b. Sunscreens. These agents prevent skin penetration of solar radiation. Thus, PABA (para-aminobenzoic acid), the common active ingredient of sunscreens, has an absorption spectrum that overlaps the spectrum responsible for the photosynthesis of vitamin D3 (342). As would be expected, application of PABA to skin pieces blocked the conversion of 7-DHC to previtamin D3 that normally follows exposure to simulated sunlight. Moreover, in healthy volunteers, coverage of the whole body with sunscreens abolished the serum vitamin D3 response to UVB light delivered in a phototherapy unit (342). Also patients with photodependent cutaneous disorders such as skin cancer, who must use sunscreen chronically, have lower serum levels of 25-hydroxyvitamin D as compared with matched controls (343). Nevertheless, it must be noted that these lower 25-hydroxyvitamin D levels have not been associated with secondary hyperparathyroidism or metabolic bone disease (344). C. Cutaneous regulation

1. Regional (anatomical) activity of solar radiation. The segmental body contributions to the supply of vitamin D3 were evaluated in healthy individuals who had sunscreens applied to selected areas of the body before UVB irradiation (345). Significant and almost equivalent serum vitamin D3 increases occurred after selective irradiation of either trunk, legs, or the entire body. UVB exposure of only the head and neck or arms produced a lesser rise in vitamin D3 serum levels, which did not reach statistical significance (345). 2. Race-related skin pigmentation. Melanin is not a “neutral density” light filter, but exhibits varying absorption coefficients, with maximal absorption for the shorter wavelengths

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of the spectrum (⬃ 300 nm) (346). Thus, melanin has a significant effect on the synthesis of vitamin D3. As would be expected, the highest vitamin D3 response to UVB is seen in white individuals, followed by Orientals (East Asians) and Indians (South Asians) and is extremely attenuated in blacks (African Americans) (347). This race effect is also associated with lower prevailing levels of 25-hydroxyvitamin D, although the serum concentrations of 1,25-dihydroxyvitamin D are similar among race groups. The latter results from the intrinsic properties of the renal enzyme l␣-hydroxylase, which can compensate for wide differences in availability of 25-hydroxyvitamin D (348). Asian Indian individuals, who have additional peculiarities in their vitamin D metabolism, are particularly sensitive to the development of clinical vitamin D deficiency, rickets and osteomalacia, when living in areas with low levels of ambient sunlight (349). The UVB light threshold that produced measurable synthesis of vitamin D3 was 18 mjoules/cm2 in a population of white subjects with similar cutaneous photosensitivity (skin type III of the Fitzpatrick-Pathak classification; 1 MED⫽30 mjoules/cm2), although every dose tested was associated with blood levels higher than baseline (350). Serum GC is another factor involved in the availability of vitamin D3 that could be race dependent. Thus, anthropologists have identified a large number of variants, each related to different human populations. By isoelectric focusing, the observed GC suballele frequencies appear to correlate with skin pigmentation, but electrophoretically identical variants were also found in populations widely differing genetically and geographically (351). From the functional point of view, there is no evidence for differences in vitamin D binding among those variants. Moreover, the serum concentration of GC is similar across race groups that include blacks, whites, Orientals, and Asian Indians (347). 3. Suntanning. In the setting of suntanning, vitamin D3 formation is affected in a complex manner. As already mentioned, both previtamin D3 and vitamin D3 are photosensitive substrates that, if irradiated continuously, undergo further conversion to inactive metabolites while still in the skin (14). Nevertheless, measurements performed in tanned white subjects showed elevated vitamin D3 serum levels with correspondingly higher serum 25-hydroxyvitamin D concentration (352). Acute exposure to UVB radiation resulted, however, in attenuated serum vitamin D3 response, presumably the result of acquired cutaneous melanization (352). 4. Aging. Elderly individuals have lower serum levels of 25-hydroxyvitamin D as compared with their younger counterparts. This aging effect is due to progressive decrease in epidermal 7– dehydrocholesterol substrate content (353). As would be expected, acute irradiation with UVB in older subjects results in blunted serum vitamin D3 responses (354). 5. Cutaneous disease. The only cutaneous disorders in which vitamin D3 formation has been systematically studied are the epidermal disease, psoriasis (355), and the connective tissue disease, progressive systemic sclerosis (356). The latter, although predominantly a dermal disorder, is often associated with epidermal atrophy. Acute irradiation experiments in these two groups of patients did show similar vitamin D3

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responses in patients and controls. Moreover, the responses were unrelated to the extent of cutaneous involvement. These results probably reflect the small fraction of irradiated body surface required to sustain the normal vitamin D3 requirements. A small fraction of vitamin D3 formation does occur in the dermis (⬍10%), which has a much lower 7-DHC content than the epidermis and is less exposed to the lowpenetrance shorter light wavelengths responsible for vitamin D3 formation. As mentioned above, the dermal disease, progressive systemic sclerosis, even when widespread, does not interfere with the vitamin D3 response to UVB (356). D. Postcutaneous regulation

1. Obesity. Overweight appears to represent the only postcutaneous factor interfering with vitamin D3 photosynthesis. Obese individuals have lower serum 25-hydroxyvitamin D levels than lean controls and also have blunted response to UVB. Oral absorption of vitamin D2 is also decreased in obesity. In vitro experiments of irradiation of skin pieces from obese and lean individuals showed similar epidermal 7-DHC content and in vitro response to UVB. These results are suggestive of defective translocation of the vitamin into the circulation, or defective plasma transport (357). Of note, obesity is also associated with increases in plasma FFA, which can displace vitamin D3 from plasma vitamin D binding protein (358). E. General comments

An important consideration on the physiology of vitamin D3 synthesis is that it represents a mostly biophysical reaction. Thus, the serum vitamin D3 response to UVB is not altered by the oral administration of pharmacological doses of vitamin D2 (359) or of 1,25-dihydroxyvitamin D (360). There are nevertheless local regulatory mechanisms that can influence the process. When exposure to sunlight is excessive, inactivation of previtamin D3 and vitamin D3 itself are well known consequences. Moreover, when high irradiance levels are sustained, melanocyte activity is enhanced, resulting in tanning and blunted response to acute UVB exposure. The opposite situation, decreased exposure to UVB with reduced vitamin D3 production, can be compensated, at least partly, by enhanced activity of the renal 1␣-hydroxylase enzyme (348). Lastly, there has been some controversy regarding the significance of findings in acute vs. chronic studies evaluating the vitamin D response to UVB. Within this context, it must be noted that acute studies are performed under more stringent conditions, i.e., mostly during the winter, to prevent the interference of ambient sunlight, which involves exposure of the whole body to UVB, and require a phototherapy unit that must be continuously calibrated. It is then apparent that biological significance is better evaluated in larger populations. Thus, small acute responses that do not reach statistical significance, such as those observed after selective irradiance of the upper extremities or head and neck, or after subthreshold doses of UVB, may still result in normal vitamin D3 levels, when irradiation is continued through much longer periods. A similar explanation would be operative in

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black individuals, who show lack of response to acute UVB irradiance, yet also exhibit the normal seasonal variance (UVB dependent) in 25-hydroxyvitamin D serum levels (361).

VIII. Final Comments and Future Directions

The present work provides a conceptual framework for the organization of the cutaneous neuroendocrine system into epidermal and dermal units. Further, it develops an understanding of the integrated pattern of regulation of those endocrine units, and of the exquisite coordination in expression of their functional effects to achieve the best strategy for dealing with the continuous interactions between skin and environmental agents. Among the recently uncovered regulatory mechanisms are a myriad of precise interactions with receptors for hormones, neurotransmitters, and neuropeptides, e.g., hypothalamic, pituitary, and steroid hormones, PTH and PTHrP, vitamin D, neuropeptides, neurotrophins, and with nicotinic, muscarinic, adrenergic, serotonin, and glutamate neurotransmitter receptors, all widely expressed in cutaneous compartments. Surprisingly, the source of ligands for these receptors is the skin itself, sometimes the same histological compartment, or even the same cells. Thus, the conclusive documentation now available demonstrates that in addition to vitamin D3, the skin produces PTHrP, CRH, urocortin, POMC-derived peptides, enkephalins, catecholamines, acetylcholine, and neurotrophins. The skin is also involved in steroidogenesis and sex hormone conversion. Intriguing experimental data showing interconversion of thyroid hormones, however, require further confirmation. Existing data also justify further studies on cutaneous production and metabolism of neurohormones serotonin and melatonin and the neurotransmitters aspartate and glutamate. Rapid and efficient communication between the different cutaneous compartments is provided by the existing rich sensory innervation with its reservoir of neuropeptides and neurotransmitters, affording a high degree of specificity. A physiological role for this system is underscored by its effects on systemic immunity, by the production of vitamin D3 with its action on calcium homeostasis and bone mineralization, and by the generation of afferent neurogenic signals connecting the skin with the rest of the body. Concomitant functional studies have helped further clarify its function by disclosing that cutaneous neuroendocrine system activity can be effectively modified by exposure to common environmental factors such as solar radiation, by intrinsic signals such as those associated with hair cycling, by biological modifiers (cytokines/chemokines), or by local or systemic pathological conditions. This field represents, therefore, a fertile ground for future studies on cutaneous biology, including the application of more advanced methodology to confirm previous findings; the determination of other hormonal factors that could be produced by the skin; and the further definition of existent or yet-to-be-discovered regulatory pathways. Moreover, the potential clinical implications cannot be overlooked, as this area opens the possibility for multiple points of interaction on ongoing pathological processes. Possible pathological tar-

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get conditions include not only inflammatory diseases, but benign hyperproliferative skin disorders, vasculopathic and autoimmune reactions, disorders of pigmentation and hair cycling, and malignant processes such as melanoma development and epidermal carcinogenesis. Specifically, locally produced POMC peptides ACTH and ␣-MSH can affect skin functions by enhancing melanogenesis, stimulating hair growth and sebaceous gland functions, and attenuating inflammatory responses. CRH, in addition to its local vasodilatory and proinflammatory effects, may also inhibit proliferation of epidermal keratinocytes. Vitamin D is already used in the therapy of psoriasis, and glucocorticoids are drugs of choice in the treatment of inflammatory skin disorders. Finally, the multidirectional communication between skin, endocrine, immune, and central nervous systems suggests that the skin may be an important regulator of global homeostasis acting as a sensor for external or internal disturbances, and as an effector/producer of humoral or neural signals sent to other coordinating centers. In this context, the possibility of pathological consequences for dysregulation in this cutaneous neuroendocrine system poses a powerful challenge that can only be addressed with a strong, coordinated, and multidisciplinary approach. Acknowledgments We thank Drs. C. Gomez-Sanchez, O. Johansson, W. B. Malarkey, J. Orloff, M. F. Holick, S. Asa, D. L. St. Germain, S. Grando, T. Smith, E. Wei, and L. Y. Matsuoka for their help in the preparation of the manuscript. The excellent secretarial work of Ms. LuEllen Giera is acknowledged.

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