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Cytokines

Cytokines. Non-antibody proteins acting as mediators between cells, termed: Monokines – mononuclear phagocytes Lymphokines – activated T cells, especially helper T cells Interleukins – abbreviated IL with a number. Properties of Cytokines.

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Cytokines

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  1. Cytokines Non-antibody proteins acting as mediators between cells, termed: • Monokines – mononuclear phagocytes • Lymphokines – activated T cells, especially helper T cells • Interleukins – abbreviated IL with a number

  2. Properties of Cytokines • Produced by cells involved in both natural and specific immunity • Mediate and regulate immune responses • Secretion brief and limited - not stored pre-formed - synthesis initiated by gene transcription - mRNA short-lived - cytokines produced as needed

  3. Receptor for: IL-2 IL-15 IL-7 IL-9 IL-4 IL2 Rα IL2 Rβ IL2 Rγ IL15 Rα IL2 Rβ IL2 Rγ ? IL7 R IL2 Rγ IL9 R IL2 Rγ IL4 R IL2 Rγ Properties of Cytokines(continued) • Can be produced by many cell types and act on many cell types (pleiotropic) • Can have similar actions (redundant)

  4. Properties of Cytokines (continued) 6. Can influence synthesis of other cytokines - produce cascades - enhance or suppress production of other cytokines - exert positive or negative regulatory mechanisms for immune responses • Influence action of other cytokines - can be antagonistic, additive, synergistic

  5. Properties of Cytokines (continued) • Bind to receptors with high affinity • Cells responding to cytokine can be: - same cell (autocrine) - nearby cell (paracrine) - distant cell by circulation (endocrine) • Cellular responses to cytokines are slow, require new mRNA and protein synthesis

  6. Mediators and Regulators of Natural Immunity • Tumor Necrosis Factor-alpha (TNF-α) • Interleukin-1 (IL-1) • Chemokines (Chemotactic cytokines) • Type I Interferons (IFN-α and IFN-β) • Interleukin-12 (IL-12) • Interleukin-10 (IL-10)

  7. Tumor Necrosis Factor (TNF-α) • Produced by activated macrophages • Mostimportant mediator of acute inflammation in response to microbes, especially Gram-negative bacteria (LPS) • Mediates recruitment of neutrophils and macrophages to site of inflammation • Acts on hypothalamus to produce fever • Promotes production of acute phase proteins

  8. Interleukin-1 (IL-1) • Produced by activated macrophages • Effects similar to those of TNF-α

  9. Chemokines • Produced by many different leukocytes and tissue cells • Large family of >50 substances • Recruit leukocytes to sites of infection • Play a role in lymphocyte trafficking

  10. Type I Interferons (IFN-α and β) • IFN-α a family of many proteins produced by macrophages, IFN-β a single protein produced by many cells • Both IFNs inhibit viral replication • Both increase expression of class I MHC • Both activate NK cells

  11. Interleukin-12 (IL-12) • Produced by activated macrophages and dendritic cells • Stimulates production of IFN-γ • Induces differentiation of Th cells to become Th1 cells • Enhances cytolytic functions of cytotoxic T cells and NK cells

  12. Interleukin-10 (IL-10) • Produced by activated macrophages, Th2 cells • An inhibitory cytokine • Inhibits cytokine production by activated macrophages • Inhibits expression of class II MHC and costimulatory molecules on macrophages

  13. Mediators and Regulators of Specific Immunity • Interleukin-2 (IL-2) • Interleukin-4 (IL-4) • Interleukin-5 (IL-5) • Interleukin-10 (IL-10) • Interferon-gamma (IFN-γ)

  14. B cell Stimulation of division T cell T cell IL-2 secretion Monocyte Stimulation of division and IFN gamma release (and other mediators) Activation NK Increase in NK Cell activity Interleukin-2 (IL-2) • Produced by Th>>Tc • Main growth factor for T cells

  15. Resting T cell Class II MHC APC IL2 IL4 IL7 T cell T cell T cell T cell T cell T cell T cell T cell Activated T cell T cell Binds to IL-2 receptor Division Receptor decay Autocrine Function of IL-2

  16. Interleukin-4 (IL-4) • Produced by Th2 cells • Stimulates Ig class switching to IgE isotype • Stimulates development of Th2 cells from naïve Th cells • Promotes growth of differentiated Th2 cells

  17. Interleukin-5 (IL-5) • Produced by Th2 cells • Promotes growth and differentiation of eosinophils • Activates mature eosinophils • IL-4 and IL-5 can work together Helminths opsonized with IgE can be killed by activated eosinophils

  18. Interleukin-10 (IL-10) • Produced by activated macrophages, Th2 cells • Inhibits production of IFN-γ by Th1 cells needed to activate macrophages

  19. B cell Endothelial cell Activation T cell Th1 cell > Tc cell Activation IFN gamma secretion Increase in NK cell activity Macrophage Activation Many cell types Many cell types Granulocyte NK NK Weak anti-viral activity, Stops cell division, Stops hematopoiesis Induction of class I and class II MHC Differentiation, Stops cell division T cell activation Interferon-gamma (IFN-γ) • Produced by Th cells >> Tc and NK cells • Numerous functions in both natural and specific immunity

  20. Stimulators of Hematopoiesis Colony-Stimulating Factors (CSF) • Granulocyte-macrophage CSF (GM-CSF) promotes growth and differentiation of bone marrow progenitors • Macrophage CSF (M-CSF) is involved in development and function of monocytes and macrophages • Granulocyte CSF (G-CSF) stimulates production of polymorphonuclear leucocytes (PMN)

  21. Cytokines Regulate Ig Class Switching • Fc region of antibodies determines effector function in different anatomical locations • Class (isotype) switching produces class or subclass of antibody most effective in host defense • Cytokines acting alone or in combination regulate class switching

  22. Cytokine Network • Many cytokines have effects on many cells and organ systems in addition to functions in immune systems • Referred to as the “cytokine network”

  23. B cell Lymphocyte T cell Macrophage NK LAK Effects on Cells of Immune System Activation of cells of immune system Proliferation, Differentiation, Ig secretion and selection Proliferation, Differentiation, Cytokine production Cytokine production IL1 IL2 IL4 IL1 IL2 IL4 IL5 IL6 IFNγ cytokines

  24. Hypothalmus IL1 IL6 TNF Fever Pituitary IL1 IL6 TNF Lymphocyte ACTH cytokines Adrenalgland -cortisol +DHEA Corticosteroid Macrophage IL 6 Liver Acute phase proteins Cytokine Effects on Organ Systems

  25. IL1 TNF IFNα IFNβ IFNγ Fibroblasts Fibrogenesis Extracellular matrix IL1 TNF cytokines Many cell types Endothelial cell Anti-viralstate cytokines Lymphocyte IL1 TNF IL3 CSFs TNF IL1 IFNγ Tissue remodeling Tissue repair Endothelial cells Bone marrow Fibrinogen Permeability change adhesion Hematopoiesis Macrophage Angiogenesis Fibroblast Extracellular matrix Osteoclasts cytokines Cytokine Effects on Various Cells

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