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CYTOKINES LECTURE BY HILLARY SEBUKOTO MDII KCM-COLLEGE, TANZANIA
- 1. Cytokines
- 2. Objectives • At the end of the lecture you will be able to – Describe cytokine and cytokine receptor families – Describe the mechanism of action – Describe the cytokine production by T-cell subsets – Describe the cytokine network
- 3. Introduction • Cytokines are small (low molecular weight) signalling proteins • Secreted by activated lymphocytes, macrophages, monocytes and some other cells • More than 200 cytokines have been identified • An individual cytokine has one or more specific functions
- 4. Introduction … • Binding to its appropriate receptor sets off a cascade leading to induction or inhibition of transcription of a number of cytokine regulated genes • Initiate intracellular signals through ligand- induced aggregation of receptor components • The cytokine-receptor reactions influence each other and intersect at different points
- 5. Properties of Cytokines • Produced by cells involved in both natural and specific immunity • Function as intercellular messengers • Regulate the expression of their own receptors • Bind to receptors with high affinity • Mediate and regulate immune responses
- 6. Properties of Cytokines • Secretion is brief and tightly regulated – synthesis initiated by gene transcription – require new mRNA and protein synthesis – mRNA short-lived - secreted only when cell is activated – not stored preformed - produced as need arises – cellular responses to cytokines are slow
- 7. Properties of Cytokines … • Pleiotropic – any given cytokine may have different biological effect on different target cells – can be produced by many cell types and act on many cell types
- 8. Properties of Cytokines … • Influence action of other cytokines – Synergistic • combined effect of two cytokines is greater than the additive effect of each alone – Antagonistic • the effects of one cytokine inhibit or offset the effects of another – Redundant • two or more cytokines mediate similar/same functions
- 9. Functions of cytokines • Controls every function of the immune response including – enhance or suppress production of other cytokines – exert positive or negative regulatory mechanisms for immune responses – Induction of • phagocytosis • cytotoxicity • inflammation
- 10. Functions of cytokines • Resistance against viral infection • Chemotaxis and chemokinesis • Growth inhibition • Apoptosis • Promotion of extracellular adhesion • Proliferation and differentiation of specific T- and B-cell clones
- 11. Origin of Immune Cells Biocarta.com
- 12. Cellular responses to cytokines • Cells responding to cytokine can be: – same cells (autocrine) – nearby cells (paracrine) – distant cells by circulation (endocrine)
- 13. Cytokine Network • Cytokines form an intracellular “cytokine network” that can initiate multiple events leading to a particular cellular response • Many cytokines have effects on many cells and organ systems in addition to functions in innate/acquired immune systems
- 14. Autocrine Function of IL-2 Class II MHC APC Resting Activated T cell T cell IL2 IL4 IL7 T cell Binds to IL-2 receptor Division T cell T cell T cell T cell Receptor decay T cell T cell T cell T cell
- 15. Cytokine (paracrine) effects on various cells T cell B cell Stimulation of division IL-2 Monocyte secretion T cell Stimulation Activation of division and IFN gamma release (and other NK mediators) Increase in NK Cell activity
- 16. Cytokine (paracrine) effects on various cells B NK LAK cell T cell Proliferation, Proliferation, Activation of cells of Differentiation, Differentiation, immune system Cytokine production Ig secretion Cytokine and selection production IL1 I L2 IL I L4 1I IL5 L2 IL6 IL IFN 4 γ Macrophage Lymphocyte cytokines
- 17. Cytokine (endocrine) effects on various cells IL1 TNF IFNα Fibroblasts IFNβ IFNγ Fibrogenesis IL1 Extracellular TNF matrix Lymphocyte Macrophage cytokines Many cell types cytokines Anti-viral state IL1 TNF s FN γ C SF L 1I IL3 FI TN Endothelial cells Tissue Bone marrow Fibrinogen remodeling Hematopoiesis Permeability change Tissue repair adhesion Angiogenesis Fibroblast Extracellular cytokines matrix Osteoclasts
- 18. Cytokine (endocrine) effects on organ systems Hypothalmus IL1 Fever IL 6T NF Pituitary IL1 IL6 TNF ACTH Lymphocyte Macrophage cytokines Adrenal A gland HE l+D t iso Corticosteroid or 6 -c IL Liver Acute phase proteins
- 19. Mediators and Regulators of Natural Immunity • Tumor Necrosis Factor-alpha (TNF-α) • Chemokines (Chemotactic cytokines) • Type I Interferons (IFN-α and IFN-β) • Interleukins
- 20. Tumor Necrosis Factor (TNF-α) • Produced by activated macrophages • Most important mediator of acute inflammation, especially G-neg LPS • Mediates recruitment of neutrophils and macrophages to site of inflammation • Acts on hypothalamus to produce fever • Promotes production of acute phase proteins
- 21. 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
- 22. Interferon IFN-α and β • IFN-α is a family of many proteins produced by macrophages • IFN-β is a single protein produced by many cells • Both IFNs inhibit viral replication • Both increase expression of class I MHC • Both activate NK cells
- 23. Interferon IFN-γ • Produced by Th cells, Tc and NK cells • Numerous functions in both natural and specific immunity
- 24. NK Th1 cell > Tc cell Granulocyte Endothelial cells Activation Activation IFN gamma NK Increase in Macrophage secretion NK Activation cell activity Many cell types Many cell types B T cell cell Weak anti-viral activity, Differentiation, Induction of class I Stops cell division, T cell activation Stops cell division and class II MHC Stops hematopoiesis
- 25. Interleukin-1 (IL-1) • Produced by activated macrophages • Inhibit viral replication • Increase expression of class I MHC • Activate NK cells
- 26. Interleukin-2 (IL-2) • Produced by Th and Tc • Main growth factor for T cells
- 27. 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
- 28. Interleukin-5 (IL-5) • Produced by Th2 cells • Promotes growth and differentiation of eosinophils • Activates mature eosinophils • Helminths opsonized with IgE can be killed by activated eosinophils
- 29. Interleukin-10 (IL-10) • An inhibitory cytokine produced by activated macrophages, Th2 cells • Inhibits – co-stimulatory molecules on macrophages – expression of class II MHC – production of IFN-γ by Th1 cells needed to activate macrophages
- 30. 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
- 31. Stimulators of Hematopoiesis Colony-Stimulating Factors (CSF) • Granulocyte-macrophage Colony- Stimulating Factors (G/M-CSF) promotes growth and differentiation of bone marrow progenitors – Granulocyte CSF stimulates production of PMN leucocytes – Macrophage CSF is involved in development and function of monocytes and macrophages
- 32. Origin of Immune Cells Biocarta.com
- 33. Families of Receptors • Receptors of different types may have same signal transduction action – Immunoglobulin superfamily receptors – Class I cytokine receptor family – Class II cytokine receptor family – Interferon receptor family – TNF receptor family – Chemokine receptor family
- 34. Regulation of the cytokine network • Molecules homologous with the cytokine and able to bind to its receptor without leading to signal transduction act as competitive inhibitors
- 35. Regulation of the cytokine network • The extracellular domains of TNF and IL-1 receptors can be shed • They bind their cytokine in the fluid phase, and so stop the cytokine from reaching receptors on cell membranes
- 36. Regulation of the cytokine network • Other mediators, acting through quite separate receptors, can exert opposite effects on the cell
- 37. Regulation of the cytokine network • Some cells express cytokine-binding molecules (deceptors) which do not activate the cell
- 38. Cytokine production by T-cell subsets • Local cytokine expression help to select lymphocyte effector mechanism • The polarised response of CD4+ TH cells is based on the profile of cytokine secretion by the TH1 Cells or TH2 cells
- 39. Cytokine production by T-cell subsets • TH1 produce – IFN-γ – IFN-β – IL-2 • TH1 cells are associated with cell-mediated inflammatory reactions through the production of – IgG2a opsonizing antibodies – Complement fixing antibodies – Macrophage activation – Antibody-dependent cell-mediated cytotoxicity – Delayed-type hypersensitivity
- 40. Cytokine production by T-cell subsets • TH2 produce – IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13 • TH2 are associated strong Ab and allergic responses by providing optimal help for humoral responses including – IgG1 and IgE isotype class switch – Mucosal immunity – Stimulation of mast cell and eosinophil growth and differentiation – IgA synthesis
- 41. Differentiation of CD4+ TH cells
- 42. Selection of effector mechanisms by T-cells
- 43. TH1 and TH2 Cell Development • Cytokine Cross-Regulation – IFN-g and IL-2 (secreted by TH1 subset) promote IgG2a production by B cells but inhibit IgG1 and IgE production – IL-4 (secreted by TH2 cells) promotes production of IgG1 and IgE and suppresses production of IgG2a – IL-10 does not inhibit TH1 directly but acts on macrophage and interferes with their ability to stimulate TH1 cells • Progression of some diseases may depend on the balance between TH1 and TH2 subsets
- 44. Therapeutic Uses of Cytokines • Purified Cytokines – regulation of response to alloantigens (organ transplants) • try to block activation of TH and TC cells to prolong transplants • use of IL-1 soluble receptors to block TH activation • Use of anti-TAC antibodies to block IL-2 receptor • toxin tagged cytokines (IL -2) to kill TH cells (only responding cells have IL-2R) • Use in LAK cell stimulation • Treatment of allergy (block IL-4 using IL-12)