Cytokines

Cytokines

Concept of cytokines ❚

Cytokines are small molecules secreted by variety of cells in response to a stimulus.

❚

Cytokines are messengers for the whole immune system Inducing growth, differentiation, chemotaxis, activation, enhanced cytotoxicity and/or regulation of immunity.

Common features of Cytokines ❚ Low molecule weight and secreting peptides, usually glycosylation. ❚ After 6-8 hours of cell in culture activated, the cytokine could be detected in supernatant, then, in 24-72 hours reached the peak value ❚ Short life-span ❚ The same cell can produce several different cytokines. The same cytokines can be made by entirely different cell populations. ❚ Each cytokine often induce several different biological effects. Several cytokines may have similar activities, and some with opposing activities. Thus the resulting biological effect is the sum of all of these activities.

Common features of Cytokines(continued) ❚ Paracrine or autocrine,endocrine ❚ Express the efficacy must combine with its receptor on the target cell membrane first. The affinity is very high ， constant isolation usually is at 10 –12 ~10 -10 M 。 ❚ potential activity, nano （ 10-9 ） or pigo （ 10-12 ） M or less can express its physiological functions. ❚ Usually express growth efficiency ， but the terminal efficiency is the sum of dose, cell cycle, ligands and other cytokines association. ❚ Its efficiency is not MHC restricted, and non-antigen specific.

Cytokine nomenclature ❚ ❚ ❚ ❚

Monokines:secreted by monocytes ¯ophages Lymphokines:secreted primarily by lymphocytes Interleukins (IL): secreted primarily by leukocytes (IL-1, 2--18 and etc.) Chemokines: more than 50 members of small molecules possesss chemo-attractant for several cells like leukocytes of macrophages and others, direct cell migration; activate cells in response to infectious agents or tissue damage

❚ ❚ ❚ ❚ ❚

TNFs(tumor necrosis factor) IFNs(interferons,produced by a variety of cells in response to viral infection) TGF (transformation growth factor) CSF (Colony stimulating factor ): multiple-CSF(IL-3), M-CSF, MG-CSF Epo (erythropoietin)

Representative lymphokines and monokines Cytokine Produced by IL-1

Activity

MΦ,

epithelial Activates vascular endothelium,; tissue destruction ;

cells

increased the effector cell access, fever; activates lymphocytes; Mobilization of PMN, induction of APP and etc.

IL-2

T cells

IL-3

T&, thymic cells Proliferation, differentiation of hematopoietic cells

IL-4

Th2 cells mast B cell activation, proliferation, IgE response, induces cells

IL-5

Th2 and inhibits Th1 responses

Th2 cells, mast Eosinophil growth, differentiation, B cell activation, cells

IFNγ

Proliferation of T and NK cells

IgA response

T cells, NK cells MΦ and PMN activation, induces Th1 & inhibits Th2 response

How do cytokines tell cells what to do? ❚ Produced by cells as part of normal cellular activity and/or the result of environmental trigger ❚ Bind to receptors on cells ❚ Trigger signal transduction pathways ❚ Initiate synthesis of new proteins

Cytokines can act in three different manners ❚ Autocrine ❙ Cytokine binds to receptor on cell that secreted it

❚ Paracrine ❙ Cytokine binds to receptors on near by cells

❚ Endocrine ❙ Cytokine binds cells in distant parts of the body

Cytokine Actions ❚ Pleiotropy

❙ Act on more than one cell type (INFα /β )

❚ Redundancy ❙ More than one cytokine can do the same thing (IFNα /β and IFNγ )

❚ Synergy ❙ Two or more cytokines cooperate to produce an effect that is different or greater than the combined effect of the two cytokines when functioning separately (IL-12 and IL-8)

❚ Antagonism ❙ Two or more cytokines work against each other (IL-4 and IL-12)

Five cytokine receptor families ❚ Immunoglobulin superfamily receptors ❚ Class I cytokine receptor family (hematopoietin receptors) ❙ Binds most of the cytokines in the immune and hematopoietin systems

❚ Class II cytokine receptor family ❚ TNF receptor family ❚ Chemokine receptor family

Cytokines regulate the immune response ❚ Cells with the appropriate receptors become activated ❙ To differentiate ❙ To express receptors which will make them receptive to other cytokines ❙ To secrete other cytokines

Signal Transduction by cytokine receptors ❚ Cytokine receptors on different cell types trigger different events

Involvement of cytokines in the immune response ❚ Alert to infection.tumor/etc. ❚ Recruit cells to site ❚ Specify type of immune response ❚ Immune effector phase ❚ Immune downregulation ❚ Immune memory and resetting the system

❚ Early mediators (IFNα /β ) ❚ Chemokines (MCP-1α ) ❚ Early & late mediators (IL-2, IFNγ , IL-4, IL-5) ❚ Down-regulators (IL-10, TNFγ ) ❚ Maintenance of cytokines, etc. (GM-CSF, IL-3, IL-7, etc.) ❚ MCP(monocyte chemotactic protein )

Examples of therapeutic uses

❚ Soluble T-cell receptor ❚ Anti-IL-2R ❚ Interleukin analogs which bind receptor, but do not trigger activation (ties up receptor) ❚ Toxins conjugated to cytokines which kill activated T-cells ❚ Administration of cytokines to enhance immunity (side effects/ short half lives) ❚ Allergies