Transcript Cytokines
CYTOKINES AND RECEPTORS Chapter 12 What Is A Cytokine? • • • • • • • Low molecular weight proteins (30 KDa) Bind receptors, alter gene expression Can bind the secreting cell (autocrine) Can bind another cell close by (paracrine) Few cases bind another cell far away (endocrine) Very low Kd receptors (10-10-10-12 M) Cytokines regulate immune responses Cytokines • Cytokines can activate many cells • Ex. Cytokines secreted by TH can affect Bcells, CTLs, M, NK • A cytokine can be pleiotropic (different effect on different cells) • Synergism, redundancy, antagonism • Interleukins, monokines, lymphokines, chemokines, term CYTOKINE includes all of them Cytokine Categories • 4 Categories – – – – TNF family Chemokine family Interferon family Hematopoietin family • Hematopoietin family – – – – -helical structure prevalence Little or no -sheet Ex. IL-2 and IL-4 Amino acid sequences vary considerably Cells That Make Cytokines And Their Function • A Variety Of Cells Are Capable Of Making Cytokines • However The Biggest Producers: M and TH • Cytokines Are Involved In – – – – Hematopoiesis Adaptive Immunity Innate Immunity Inflammation • See Appendix For Complete List And Function • Activities Established Thru Recombinant Cytokines (Simplistic Approach), In Vivo Function Can Vary Cytokines Are Non-Specific • How Does Immune Specificity Fit With NonSpecific Cytokines • Answer 1: Thru Receptors – Receptors Expressed On Antigen Activated Cells • Answer 2: Close Proximity To Cytokine Secreting Cells. – Ex. APC-TH – Cytokine Concentrations (TH) Are High Locally – Only Interacting APC Gets Activated • Answer 3: Short Half Life – Short ½ Life Ensures Local Activity Cytokine Receptors • 5 Major Families – – – – – Immunoglobulin Superfamily Hematopoietin Receptor Family (Class I) Interferon Receptor Family (Class II) TNF Receptor Family Chemokine Receptor Family • Class I and II (Majority Of Receptors) – Multimeric – Upon Receptor Engagement, Tyrosine Phosphorylation Hematopoietin Receptor Family (Class I) Receptor Signalling (IFNR) • 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 Antagonists • Antagonists Exist In 2 Forms – Receptor Antagonists (Bind Receptor, No Activation) – Bind Cytokine (Prevent Cytokine From Binding Receptor) • Well Studied Example: IL1Ra • In Many Cases Antagonist Is A Soluble Receptor – Derived From Proteolytic Cleavage Of Extracellular Domain Of Particular Receptor – IL-2, IL-4, IFN, IFN • Viruses Produce Cytokine Mimics Or Cytokine Binding Proteins – Ex. Poxviruses Produce IL-1-Binding Protein And TNF-binding-protein – These Agents Offer Viruses An Advantage TH1 vs TH2 • CD4+ TH Cells Secret A Variety Of Cytokines • Evidence For 2 Subsets – TH1 – TH2 • Distinction Is Based On Cytokine Secretion • Cytokine Environment Determines Which Subset Will Develop – IFN for TH1 (IL-12 and IL-18 from M,DCs) – IL-4 for TH2 Transcription Factors TH1 And TH2 • • • • • • 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)