CYTOKINES

CYTOKINES

SEETU GULIA MSC. BIOTECHNOLOGY CENTRAL UNIVERSITY OF HARYANA

DEFINITIONPROPERTIES OF CYTOKINESNOMENCLATURECLASSIFICATIONCYTOKINE RECEPTORSCYTOKINE SIGNALINGCYTOKINE ANTAGONISTTH1 AND TH2CYOKINE RELATED DISEASESCYTOKINE THEARPYCYTOKINE IN HEMATOPOIESIS

TOPICS

PROPERTIES

CYTOKINE FAMILIESHEMATOPOIETIN FAMILY

INTERFERON FAMILY

CHEMOKINE FAMILY

TUMOR NECROSIS FACTOR FAMILY

Non specificity of cytokines conflicts with established specificity of immune system

How does this work?-Careful expression of the receptors for those cytokines on specific cells-Receptors are often only expressed after exposure to antigenCytokine act in an antigen-non specific manner

IL-2R is the most thoroughly studied cytokine receptor-Expressed by T cells for proliferation -Also called CD25, surface marker in mature T cells-Complete receptor has 3 subunits

-Majority of cytokine receptors are in Class I and Class II families

-These cytokine receptors lack signaling motifs, this was puzzling to researchers-IFN- was studied because of its ability to block viral replication like other interferonsHowever, this IFN plays immunoregulatory role which lead to understanding the process of signal transduction through cytokine receptorsCYTOKINE SIGNALING

-Ligand Binds Subunit-Ligand Binding Causes Dimerization of Receptor-JAKs Get Activated#Phosphorylation of tyrosine residues on receptor#Phosphorylation of JAKs themselves-STATS Dock Receptor#Phosphorylation of STATs by JAKs-Dimerized STATs Translocate To Nucleus-Gene Expression

CYTOKINE ANTAGONISTNumber of proteins can inhibit cytokine activityCan bind to receptor ORCan bind to cytokine, disabling itEnzymatic cleavage of receptors and release of these can bind cytokines in the bloodMarker of chronic T cell activation (transplant rejection, AIDS)Viruses have developed strategiesCytokine homologsCytokine binding proteinsHomologs of cytokine receptorsInterference with intracellular signalingInterference with cytokine secretion

CD4+ TH cells exert most of helper functions through secreted cytokines2 populations based on secreted cytokines:TH1Cell-mediated functions delayed hypersensitivity, activation of TC cells, production of opsonization-promoting IgG antibodiesTH2Stimulates eosinophil activation, provides help to B cells, promotes production of large amounts of IgM, IgE, and noncomplement activating IgG isotypesSupports allergic reactionsSome TH cells do not show TH1 or TH2 profilesTH1 AND TH2

-Promote growth of subset that produces them-Inhibit development and activity of other subset-Progression of some diseases depends on balance between TH1 and TH2-Cytokines profiles are cross regulated.

TRANSCRIPTION FACTORS-T-bet Expression Results In TH1-T-bet Suppresses TH2-GATA-3 Results In TH2-GATA-3 Suppresses TH1-IFN- Regulates Expression of T-bet (Stat 1)-IL-4 Regulates Expression of GATA-3 (Stat 6)

CYTOKINE RELATED DISEASES-SCID Genetic defects in cytokines, their receptors-Defective receptor for IFN-Susceptible to mycobacterial infections

Bacterial Septic ShockCertain Gram- bacteriaSymptoms: drop in blood pressure, fever, diarrhoea, blood clottingEndotoxins bind TLRs on dendritic cells and macrophagesOver-produce IL-1 and TNF-Cytokine imbalance causes abnormal temp, abnormal respiration, capillary leakage, tissue injury, organ failureNeutralization by monoclonal antibodies may help

-Bacterial Toxic Shock-Superantigens-Bind simultaneously to Class II MHC and T cell receptor, activating T cell despite antigenic specificity-Symptoms similar to sepsis

-Abnormalities in production of cytokines or receptors are associated with certain types of cancer

-Chagas Disease-Caused by Trypanosoma cruzi-Severe immunosuppression-Evidence that soluble factor produced by T. cruzi leads to reduction in T cell IL-2 (CD25) receptor

CYTOKINE THERAPY

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Problems with cytokine therapies:

-Effective dose levels-Short half-life-Potent biological response modifiers-Can cause unpredictable side effects

-Cytokines play essential role in hematopoiesis

Cytokines are low MW proteins that are produced and secreted by a variety of cell types .The biological activities of cytokines exhibit pleiotropy , redundancy , synergy , antagonism and cascade induction.Families of cytokines : hematopoietin , interferons , chemokines and TNF.Cytokine receptors: Ig superfamily , class 1,class 2,TNF and chemokine receptors.Cytokine- induced multimerization of class 1 and class2 receptors activate JAT/STAT signal transduction pathway.SUMMARY

Therapies based on cytokines and cytokine receptors have entered clinical practiceCytokines have role in hematopoiesisSUMMARY

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