CYTOKINES Infection and Immunity I 362 712 viraphng@kku.ac.th Revised Jul 06 References Abbas AK, Lichtman Ah, Pober JS. Cellular and Molecular Immunology, 4 nd ed., 2000, page 235-69 Roitt IM, and Delves PJ. Essential Immunology, 10 th ed., 2001, page 177-199. Cytokines - Grad 2 1
Presentation Outline What is cytokines? Properties of cytokines Classification of cytokines Cytokines receptors Some important cytokines Some examples of cytokine network Cytokine assays Cytokines - Grad 3 What is cytokines? Polypeptides or glycoproteins produced in response to various antigens. Play role in innate and acquired immunity Produce from various kinds of cells, e.g. macrophages = monokines lymphocytes = lymphokines Cytokines that induce chemotaxis of leukocytes are referred to as chemokines (chemotactic cytokines) Cytokines - Grad 4 2
Properties of cytokines Based on production: Depends on Ag stimulation Short-timetime By more than one type of cells One cytokine can stimulate or inhibit the production of other cytokines Cytokines - Grad 5 Properties of cytokines Based on function: Hormone-like action: autocrine, paracrine, endocrine One cytokine can affect more than one types of cells - Pleiotropism Different cytokines can perform some similar functions - Redundancy One cytokine can influence the function(s) and/or production of other cytokines Interleukins cytokines interact between cells of the immune systems Cytokines - Grad 6 3
Cytokines - Grad 7 Classification of cytokines Based on functions, cytokines can be divided into 3 groups: 1. Mediate and regulate innate immunity 2. Mediate and regulate adaptive immunity 3. Regulate hematopoiesis Cytokines - Grad 8 4
Cytokine receptors Different receptors activate distinct signal transduction ti pathways Based on structure of extracellular domains 1. Type I cytokine receptors 2. Type II cytokine receptors 3. Members of the Ig supefamily 4. TNF receptors 5. Seven transmembrane α-helical receptors Cytokines - Grad 9 1. Type I cytokine receptors Hemopoietin receptors 1 domain(s) with two conserved pairs of cysteine + WSXWS motif Consist of unique ligand-binding chains and 1 signal-transducing chain(s) Cytokines - Grad 10 5
2. Type II cytokine receptors Cytokines - Grad 11 3. TNF receptors Similar to type I cytokine receptors Two extracellular domains with conserved cysteines without WSXWS motif Consist of one ligand-binding polypeptide chain and one signal- transducing chain Receptors with conserved cytstein- rich ih extracellular lll domains Receptor activation leading to apoptosis and/or gene expression Cytokines - Grad 12 6
4. Seven transmembrane α- helical recpetors Serpentine receptros Signaling pathways involved GTP-binding proteins Mainly receptors for chemokines Cytokines - Grad 13 Cytokines - Grad 14 7
1. Cytokine that mediate and regulate innate immunity Type 1 Interferons (IFN) Tumor necrosis factor Interleukin 1 Interleukin 12 Chemokines etc. Cytokines - Grad 15 Type 1 Interferon Consists of INF-α (leukocyte INF) and INF-β (fibroblast INF) INF- α mainly produced by macrophage Play role in viral protection Cytokines - Grad 16 8
Cytokines - Grad 17 Tumor necrosis factor - TNF TNF-α and TNF-β (lymphotoxin) TNF-α mainly produced by macrophage Play role in inflammatory response to infection and is responsible for many systemic complications of severe infections e.g. disseminated intravacular coagulation (DIC) Cytokines - Grad 18 9
Cytokines - Grad 19 Interleukin-1 Mainly produced by activated macrophage Similar role as TNF-α but less toxicity Cytokines - Grad 20 10
Interleukin-10 Negative feedback regulator (produced by activated macrophages to inhibit their function) Inhibits the production of IL-12 and TNF Inhibits the expression of co- stimulators and MHC class II on macrophages and dendritic cells Cytokines - Grad 21 Interleukin-12 Produce from macrophages Potent inducer of INF-γ production by T and NK cells Promote differentiation of CD4+T cells to TH1 cells Enhances cytolytic ti activity it of activated NK and CD8+T cells Cytokines - Grad 22 11
Cytokines - Grad 23 Chemokines Chemotactic cytokines A large family of structurally homologous cytokines that stimulate leukocyte movement and regulate the migration of leukocytes from the blood to tissues Polypeptides with 8-12 kd and 2 internal disulfide loops 2 major subfamilies - CC chemokines: act mainly on neutrophils - CXC chemokines: act mainly on lymphocytes, y monocytes, and eosinophils Produced by leukocytes and several types of tissue cells, e.g. endothelial cells, epithelial cells and fibroblasts. Cytokines - Grad 24 12
2. Cytokine that mediate and regulate adaptive immunity Interleukin-2, 4, 5, 13, 16 and 17 Interferon-γ TGF-β Lymphotoxin Cytokines - Grad 25 Interleukin-2 Mainly produced from CD4+ T cells Growth factor for T, B and NK cells Cytokines - Grad 26 13
Cytokines - Grad 27 Interleukin-4 Mainly produced form CD4+ T cells Growth and differentiation factor for T (naïve CD4+Tcells to TH2 cells) and B cells Growth factor for mast cells (+IL-3) Necessary for IgE production Cytokines - Grad 28 14
Cytokines - Grad 29 Interleukin-5 Produced by TH2 cells, activated mast cells Activate mature eosinophils and stimulated the growth and differentiation of eosinophils Stimulate the proliferation of B cells and IgA production Cytokines - Grad 30 15
Immune or gamma interferon (INF-γ) Plays critical roles in innate and cell-mediated immunity Produce from activated CD4+ +andcd8+t +T cells, and by NK cells INF-γ plays role in immune response in the effector phase - activate macrophage (previously known as macrophage-activating activating factor-maf) - enhance NK, neutrophil activities - help differentiation of T (to TH1) and B cells (to opsonizing Ab) The net effect of INF-γ activities is to promote macrophage- rich inflammatory reactions. Cytokines - Grad 31 Cytokines - Grad 32 16
Transforming Growth Factor-β (TGF-β) TGF-β1, TGF-β2, TGF-β3 encoded by distinct genes TGF-β1 produced by antigen-stimulated T cells, LPS-activated mononuclear phagocytes, and many other cell types TGF-β1 inhibits the proliferation and differentiation of T cells and the activation of macrophages Inhibit immune and inflammatory responses TGF-β1 stimulates IgA class switching Cytokines - Grad 33 Induction of T H 1 and T H 2 subsets Cytokines - Grad 34 17
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Cytokines - Grad 37 Examples Features Comparative features of the cytokines of innate and adaptive immunity Innate Immunity Adaptive Imunity TNF-α, IL-1, IL-2, IFN-γ IL-2, IL-4, IL-5, IFN-γ Major cell source Mφ, NK cells T cells Principal functions Stimuli Amounts produced Local or systemic effects Roles in disease Inhibitors of synthesis Mediators of innate immunity and inflammation Bacterial cell wall, viral RNA, T- cell-derived cytokines May be high; detectable in serum Both Systemic diseases (e.g. septic shock) Corticosteroids Regulation of lymphocyte growth and differentiation; activation of effector cells Protein antigens Gennerally low; usually undetectable in serum Usually local only Local tissue injury (e.g., granulomatous inflammation) Cyclosporine, FK-506 Cytokines - Grad 38 19
3. Cytokines that regulate hematopoiesis Many cytokines generated during innate and acquired immunity it stimulate t the proliferation and differentiation of bone marrow progenitor cells. Stem cell factor (c-kit ligand) Interleukin-3 Colony-stimulating cytokines - Granulocyte-monocyte CSF (GM-CSF) - Monocyte CSF (M-CSF) - Granulocyte CSF (G-CSF) Cytokines - Grad 39 Stem cell factor (c-kit ligand) Synthesized by stromal cells of the bone marrow as transmembrane or secreted protein It is needed to make stem cells response to other CSFs Cytokines - Grad 40 20
Interleukin-3 Multilineage colony-stimulating factor Produce from CD4+ T cells Promote proliferation and differentiation of immature bone marrow cells and pluripotent stem cells to various mature cell types Cytokines - Grad 41 Colony Stimulating Factors Produce from activated T cells, macrophages, endothelial cells etc. In bone marrow, stimulate production of inflammatory leukocytes At inflammatory site, enhance immobilization of inflammatory leucocytes from the bone marrow Cytokines - Grad 42 21
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