Ch. 12 Cytokines- essential for cell-to-cell communication

1. Ch. 12 Cytokines- essential for cell-to-cell communication Properties of cytokines Receptors Agonists and antagonists Secreting cells Cytokine-related diseases Therapeutics

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8. Activity was noted long before cytokines could be isolated Present in very small amounts Hard to characterize Process was helped along by: gene cloning technology cytokine-dependent cell lines monoclonal antibodies

9. General structure of cytokines Small (<30 kD) Proteins or glycoproteins Are assigned to families based on structure; four families identified so far

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13. Summary of (some) functions: • Regulate hematopoiesis • Colony-stimulating factors • IL-3 can cause many types of cells to divide • IL-7 differentiation into pre-B and pre-T cells 2. Innate immune responses IL-1, IL-6, TNF-, INF- and INF- produced mostly by macrophages and neutrophils fever, acute-phase response, recruit leukocytes to site of damage

14. 3. Inflammation all of the above (part 2) IFN-- activates macrophages TGF-- terminates inflammatory response 4. Specific immune responses IL-2 T cell growth factor IL-4 T and B cells IL-5 and IL-6 B cell proliferation and differentiation 5. Chemokines: attract leukocytes IL-8 RANTES (see Ch. 12 for more extensive list)

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17. Be advised: Most of these activities were described in non-physiological conditions and at non-physiological concentrations No cytokine acts alone Many act in cascades; not always clear which is the real effector Many are pleiotropic How is this activity regulated?

18. Cytokine receptors Cytokines must bind to specific receptors to activate cells A particular type of receptor may be expressed on many cells Families of receptors:

19. Immunoglobulin Class I cytokine receptor Class II TNF receptor Chemokine

20. These vary in: Structure Distribution Can be sorted into categories because they have characteristic structures Many cytokines involved in immune and hematopoietic function are class I

21. Class I and class II receptors tend to have multiple subunits: one involved in binding and one in signal transduction Signal transduction subunit may be common to many

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25. Cytokine antagonists- two mechanisms Inhibitor binds to receptor and blocks it (e.g., IL-1Ra) Soluble receptors bind to cytokines so they can’t bind to membrane-bound receptors (soluble IL-2 receptor among many others; released in chronic T-cell activation)

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27. TH1 and TH2 subsets secrete different cytokines TH1- cell-mediated functions; inflammation TH2- humoral immunity

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29. TH1 and TH2 subsets regulate each other

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32. Cytokine-related diseases Bacterial septic shock endotoxins (cell walls) stimulate production of IL-1 and TNF- Cancers of lymphoid system- overproduction of cytokines such as IL-6 (B-cell) or IL-5 (Hodgkin’s disease) or IL-2 (adult T-cell leukemia) Chagas’ disease (parasitic)- suppression of -subunit of IL-2 receptor

33. Cytokine therapies Interferons IFN-- certain types of tumors IFN-- multiple sclerosis these are antiviral IFN-- chronic granulomatous disease IL-2- certain types of cancer infusion LAK (lymphokine-activated killer) cells TILs (tumor-infiltrating lymphocytes) GM-CSF- immune deficiencies

34. TNF (tumor necrosis factors) TNF- and  In some cases inhibit proliferation of tumor cells but not normal cells May damage vascular endothelial cells in tumors, thus inhibiting blood supply to the tumor

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37. Toxin-conjugated cytokines: kill TH cells and prevent graft rejection Problems: rapidly cleared from system can be very toxic doses are hard to control Possible solutions: ex vivo cell culture conjugate cytokines to other molecules modify cytokines? p. 323: Cytokine therapies in clinical use

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