Cytokines

1. Cytokines Department of Microbiology

2. Important terms Cytokines: Proteinaceous messenger molecules of low molecular weight (usually of less than 30kDa), secreted by cells of immune system that allow to establish communication between them and thereby exerts a variety of effects. Terms related to cytokines and used frequently, interchangeably, are: - Monokines - Lymphokines - Interleukin - Chemokines - Interferons

3. Cytokine: Properties • Proteins • Low molecular weight • Secreted by various cell types (Macrophages, Th1, Th2 cells etc.) • Secretion is brief and self limited • Bind to receptor on either the cell which has produced it or any another cell • Receptor binding triggers a signal • Signal results in altered pattern of gene expression

4. Important terms • Monokines: Cytokines secreted by Monocytes and Macrophages. • Lymphokines: Cytokines secreted by Lymphocytes. • Interleukins: Glycoproteins secreted by Leukocytes and act upon other leucocytes. Interleukins are designated by numbers reflecting their order of discovery. Approximately 30 interleukins are known. • Chemokines: A sub group of cytokines, having chemo tactic activities. Usually they are of less than 8 kDa. Eg: IL-8 • Interferon: A group of proteins having antiviral activity and capable of enhancing and modifying the immune response. • Cytokines: Umbrella term for all low molecular weight protein molecules having messenger function.

5. Cytokine generating cells • Innate immunity • Macrophages • Endothelial cells • Fibroblasts • Adaptive immunity • T lymphocytes • Macrophages • NK cells

6. Cytokine activity • Cytokines exert their effect by binding to specific receptors present on the cells. • Because of very high affinity between cytokines and their receptors, cytokines can exert their effect even at Pico molar concentrations. • Cytokines regulates the immune response by stimulating or inhibiting the activation, proliferation, and/ or differentiation of various cells. • They can also work in cascading pattern and induce production of other cytokines.

8. Cytokine action: on the basis of Target Cells • Autocrine action: When cytokines exerting their effect on the same cell that has produced it. Example: IL-2 secreted from Th1 cells can act on the same cells and induce their proliferation. • Paracrine action: When cytokines exert its effect on a target cell that is in close proximity to the producer cell. Example: Interferon’s produced by the virus infected cells act on the neighboring cells and induces antiviral state in them. • Endocrine action: A few cytokines can exert its effect by binding to target cells placed in distant parts of the body. Example: TNF-alpha secreted from macrophages can act on distantly placed neoplastic or cancerous cells.

9. Cytokines can act in three different manners • Autocrine • Cytokine binds to receptor present on the same cell that secreted it • Paracrine • Cytokine binds to receptors present on near by cells • Endocrine • Cytokine binds to receptors on cells present in distantly placed parts of the body

11. Cytokines exhibits pleiotropy, redundancy & synergy • Pleiotropic action: A cytokine having different biological effects on different target cells. Example: IL-4 induces proliferation and differentiation of B cells but thymocytes only undergo proliferation under influence of IL-4. • Redundant action: When two or more than two cytokines having similar functions, they are called redundant in action. Example: IL-2, IL-4 and IL-5, all three cytokines induce proliferation of B cells. • Synergistic action: The combined effect of two cytokines is greater than the additive effects of the individual cytokines. Example: IL-4 and IL-5 acts synergistically and help in “Class Switching” towards IgE.

12. Cytokines exhibits antagonism, and cascade induction • Antagonistic actions: The effects of one cytokine inhibit or offset the effects of another cytokine. Example: IFN-γ inhibits the action of IL-4 in mediating class switching towards IgE. • Cascade Induction: When one cytokine induces target cells to produce one or more cytokines, which in turn may induce other target cells to produce other cytokines. Example: IFN-γ secreted by T helper cells acts on Macrophages which in turn secrete IL-12. This IL-12 again acts on T helper cells.

13. Pleiotropy • Pleiotropic action: A cytokine having different biological effects on different target cells. Example: IL-4 induces proliferation and differentiation of B cells but thymocytes only undergo proliferation under influence of IL-4.

14. Redundancy • Redundant action: When two or more than two cytokines having similar functions, they are called redundant in action. Example: IL-2, IL-4 and IL-5, all three cytokines induce proliferation of B cells.

15. Synergy & Antagonism • Synergistic action: The combined effect of two cytokines is greater than the additive effects of the individual cytokines. Example: IL-4 and IL-5 acts synergistically and help in “Class Switching” towards IgE. • Antagonistic actions: The effects of one cytokine inhibit or offset the effects of another cytokine. Example: IFN-γ inhibits the action of IL-4 in mediating class switching towards IgE.

16. Cascade Induction • Cascade Induction: When one cytokine induces target cells to produce one or more other cytokines, which in turn may induce other target cells to produce other cytokines. Example: IFN-γ secreted by T helper cells acts on Macrophages which in turn secrete IL-12. This IL-12 again acts on T helper cells.

19. Biological Functions of Cytokines: • Among the numerous physiologic responses that require cytokine involvement are: - Development of cellular and humoral immune responses, - Induction of the inflammatory response, - Regulation of hematopoiesis, - Control of cellular proliferation and differentiation, and - healing of wounds.

20. 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

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