Cytokines and Chemokines PDF

Cytokines, chemokines and their receptors Dr Felix N. Toka, DVM, PhD, DSc., DACVM Professor, Veterinary Virology & Immunology Department of Biomedical Sciences 1 Objectives of the topic Define what cytokines and chemokine...

Cytokines, chemokines and their receptors Dr Felix N. Toka, DVM, PhD, DSc., DACVM Professor, Veterinary Virology & Immunology Department of Biomedical Sciences 1 Objectives of the topic Define what cytokines and chemokines are Describe the manner of action of cytokines and chemokines Describe biological functions of cytokines and chemokines Describe cytokine and chemokine receptors 2 CYTOKINES An effective immune response is possible only when interaction between hematopoietic, lymphoid and inflammatory cells is possible Interaction between these cells is coordinated by a group of proteins called CYTOKINES Cytokines are low molecular weight proteins or glycoproteins mainly produced by lymphocytes and other cells in the body 3  Originally, these proteins were called lymphokines or monokines Many cytokines are called INTERLEUKINES (IL) because they are produced by leukocytes and they act on leukocytes The number of known IL now stands at 40 but is still growing 4  CHEMOKINES are another group of molecules important in communication of leukocytes They recruit and activate leukocytes CHEMOTAXIS – a phenomenon in which cells move from an area of low chemical signal to an area of high chemical signal 5  Properties of Cytokines Cytokines bind to their receptors on target cells thus initiate activating or suppressive signals Cytokines have high affinity for their receptors. Low concentrations are enough to initiate cytokine signalling 6 Properties – cont’d 7  A cytokine can bind to a receptor located on the same cell that produced the cytokine and activate that cell This way a cytokine has AUTOCRINE action 8  When a cytokine binds to a receptor found on a cell in the proximity to the producer cell it exerts a PARACRINE action Cytokine producing cell 9  ENDOCRINE action of a cytokine is when it binds to a receptor found on a cell located in a distant part of the body 10  Cytokines have pleiotropic action, redundant action, synergistic action, antagonistic action and cascade action Such properties allow cytokines to regulate activity of immunocompetent cells in a coordinated manner 11  PLEIOTROPIC action – a given cytokine exerts different biological effects on different target cells 12  REDUNDANT ACTION – two or more cytokines exert the same biological effect on the same cells 13  SYNGERGISTIC action – the effect of two cytokines on a particular cell is greater than the additive effect of individual cytokines 1+1≠2 1 + 1 = 4 OR MORE 14  ANTAGONISTIC action – action of one cytokine inhibits the effects of another cytokine 15  CASCADE action – action of a cytokine leads to induction of one or more cytokines which in turn induce production of other cytokines 16 Cytokines act in an antigen-nonspecific manner i.e., they will bind to any cell that expresses a receptor for that cytokine 17 Similarities and differences between cytokines, hormones and growth factors All three are secreted factors that elicit biological effects at picomolar concentrations by binding to receptors Expression is different Growth factors are expressed constitutively Hormones and cytokines are expressed in response to discrete stimuli Cytokine secretion is short-lived (few hours to a few days) 18  Hormones act at long range in an endocrine manner while cytokines act in an endocrine, autocrine or paracrine manner Hormones are produced by specialized glands whereas cytokines are produced by many different cells 19  Biological functions of cytokines Development of cellular and humoral immunity Induction of inflammatory responses Regulation of hematopoeisis Regulation of proliferation and differentiation of cells Regulation of intensity and duration of immune response Wound healing 20 Biological functions – cont’d 21 Biological functions – cont’d 22 Cytokines belong to different groups of proteins Hematopoeitins Interferons Chemokines (e.g., IL-8/CXCL-8) Tumor necrosis factor family (TNF) 23 Cytokine receptors Cytokines exert their effect by binding to their receptors Cytokine receptors belong to 4 protein families 24 25 26 27 28 Organisation of the cytokine receptor Most receptors are composed of a few subunits At least one subunit is required for cytokine binding and a second subunit is required for signal transduction 29  Some receptors belonging to the Class I receptors form receptor subfamilies A common feature of such subfamilies of receptors is possession of an identical signalling subunit but different cytokine binding subunit 30 31 32 33 IL-2 receptor Has three chains α, β and γ IL-2R is found in three different forms of different affinities to IL-2 34 Monomeric IL-2Rα of low affinity for IL-2 Dimeric IL-2Rβγ of intermediate affinity for IL-2 Trimeric IL-2Rαβγ of high affinity for IL-2 35 Chemokines A superfamily of small polypeptides approx. 90-130 aa Selectively regulate the adhesion process, chemotaxis and activation of various populations and subpopulations of leukocytes Well known for regulation of leukocyte migration during homeostasis and inflammation 36  Chemokines are produced in peripheral lymphoid tissue cells, bone marrow or other tissues e.g., skin Chemokines that participate in inflammatory processes are induced by TNF-α Apart from the function in inflammation, chemokines have other physiological roles: Wound healing Development of blood vessels (angiogenesis) Development of brain and heart tissue (CXCL12) 37 Regulation of leukocyte migration by chemokines Microbes or cytokines (TNFα) induce secretion of chemokines Increase of chemokine receptors and other adhesion molecules on leukocytes and endothelium Leukocytes adhere to the endothelium After diapedesis leukocytes follow the chemokine gradient to the site of inflammation 38 Chemokine receptor expression profile on leukocytes 39 Structural organization of chemokines Currently, 43 chemokines are known They have 4 conserved cysteins Depending on the location of the first 2 conserved cysteins, chemokines are divided into subgroups: C chemokines – the first 2 conserved cysteins are bound by side disulphide bonds 40  CC chemokines – the first 2 conserved cysteins are positioned one after another and each has a side chain CXC chemokines – between the 1st and 2nd conserved cysteins there is an aa (“X”) other than cystein CX3C chemokines – three amino acids other than cystein are located in between the first 2 conserved cysteins and there is a mucin domain 41  Chemokine receptors Chemokines act through their receptors Receptor structure: Extracellular domain for chemokine binding 7 transmembrane domains Intracellular domains α, β and γ, associated with the G-protein (G-coupled proteins) 42 43  The name of the receptor indicates the type of chemokine that binds to that receptor e.g.,: CR denotes a receptor for C chemokines CCR denotes a receptor for CC chemokines CXCR denotes a receptor for CXC chemokines CX3CR denotes a receptor for CX3C chemokines 44 Pro-inflammatory chemokine panel MCP-1 (CCL2), MIP-1β (CCL4), RANTES (CCL5), MIG (CXCL9), IP-10 (CXCL10), MIP-3α (CCL20), ENA-78 (CXCL5), Eotaxin (CCL11), GROα (CXCL1), TARC (CCL17), I-TAC (CXCL11) MIP-1α (CCL3), IL-8 (CXCL8) 45