Cytokines modulate the functional activities of individual cells and tissues both under normal and pathologic conditions Interleukins,

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1 Cytokines the_immune_response.html Cytokines modulate the functional activities of individual cells and tissues both under normal and pathologic conditions Interleukins, monokines, lymphokines, chemokines, term CYTOKINE includes all of them. 1

2 Cytokine Basics Cytokines behave like classical hormones in that they act at a systemic level, affecting: inflammation, septic shock, acute phase reactions, wound healing, the neuroimmune network Unlike hormones, cytokines are not produced by specialized cells or in specialized glands they have no single organ source (this helps clear some of the confusion) 2

3 Cytokine Network CKs are part of complex system that regulates the immune system. CKs are primarily produced by immune system but many other organs (liver, brain, endocrine glands) make CKs to influence immune response. 3

4 T helper and Macrophage Interaction tion.php?ani=319&cat=biology Effector T cell Th cells control immune system through CKs. 4

5 Cytokines have important features: redundancy pleiotropism. Redundancy : several cytokines secreted during an immune response have very similar properties. For example, TNF and IL-1 have similar affects. These cytokines synergize with one another (have additive effects). This is important clinically, because attempts to block the effects of cytokines may not always guarantee clinical outcomes. Anti-TNF monoclonal antibodies are successful at preventing joint damage in rheumatoid arthritis, for example, but do not completely prevent disease because IL-1 is also mediating damage. 5

6 Pleiotropism :many cytokines affect several different types of cell. Same cytokine has different effects on cells can be activating or inhibiting. This is also clinically important: the antiviral effects of IFN-α are used to treat hepatitis B virus infection, BUT IFN-α makes patients feel unwell because it induces an acutephase response. IL-10 can be inhibitory to macrophages and Th1 cells yet activating for Th2 cells and B cells 6

7 Cytokines also act as part of a complex network. synergizing with one another can also inhibit each other. For example, IFN-γ: promotes T-helper 1 (T H 1) responses inhibits the development of T H 2 responses, mediated by IL-4. This can contribute to the unexpected effects seen when cytokines are administered or blocked during treatment Also, multiple cytokines often have overlapping activities A single cell frequently interacts with multiple cytokines with seemingly identical responses cross-talk Synergism, redundancy, antagonism 7

8 Action of Cytokines Pleiotropy Affects multiple cell types Redundancy Multiple cytokines affects cells of the same type Synergy Cytokines acting in concert on the same cell Antagonism Competing actions Cascading Cytokines acting sequentially 8

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10 Action of Cytokines Pleiotropy Affects multiple cell types Cascading Cytokines acting sequentially 10

11 Redundancy Multiple cytokines affects cells of the same type Synergy Cytokines acting in concert on the same cell Antagonism Competing actions 11

12 Properties of Cytokines Pleiotropy Redundancy Synergy Antagonism 12

13 Names of Cytokines Source e.g.,lymphokines Function e.g.,chemokines Intercellular action e.g., Interleukins 13

14 Cytokine Names Interleukins - produced exclusively by leukocytes Lymphokines - produced by lymphocytes Monokines - produced exclusively by monocytes Interferons - involved in antiviral responses Colony Stimulating Factors - support the growth of cells in semisolid medias Chemokines - promote chemotaxis. 14

15 Autocrine Affects the generating cell (self) Paracrine Affects cells in the immediate vicinity Action of Cytokines Cytokines can bind receptors & alter gene expression Cytokine-Receptor interactions supply specificity to three primary functions IL-2 for T-cell activation binds the secreting cell binds another cell close by T-cell help for B cells Inflammatory cytokines Endocrine Affects cells remote from the secreting cell bind another cell far away 15

16 Cytokines: Soluble messenger molecules Low MW proteins Secreted by a variety of cells Important role in the induction and regulation of immune responses Cytokines can activate many cells Properties of cytokines Stimulus is required for production High affinity binding to specific receptors Induce gene activation 16

17 Cytokine Categories Four structural families of cytokines Hematopoietin family (IL-2, IL-4) Interferon family Chemokine family Tumor Necrosis Factor Family Primary source of cytokines T H cells and macrophages Secreted cytokines are multifunctional, short-lived, non-specific activators of a variety of cellular processes Cytokines secreted by T H can affect B-cells, CTLs, M, NK 17

18 Cells That Make Cytokines And Their Function A Variety Of Cells Are Capable Of Making Cytokines However The Biggest Producers: M and T H Cytokines Are Involved In Hematopoiesis Adaptive Immunity Innate Immunity Inflammation 18

19 Inflammation, the response of tissue to injury, is characterized in the acute phase by increased blood flow and vascular permeability along with the accumulation of fluid, leukocytes, and inflammatory mediators such as cytokines. Inflammatory cytokines can be divided into two groups: those involved in acute inflammation and those responsible. Cytokines are regulators of host responses to infection, immune responses, inflammation, and trauma. Some cytokines act to make disease worse (proinflammatory cytokines), whereas others serve to reduce inflammation and promote healing (anti-inflammatory cytokines). Proinflammatory Cytokines A proinflammatory cytokine is a cytokine which promotes systemic inflammation. Anti-inflammatory Cytokines The anti-inflammatory cytokines are a series of immunoregulatory 19 molecules that control the proinflammatory cytokine response.

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22 Functions Of Cytokines CK Secreted Primary target Hallmark IL-1 Macs, Increases CAMs Proendothelium Activates macs Inflammatory IL-2 Th cells Th1, Tc, NK cells Th1 cytokine IL-4 Th2 cells Th2 cells, B cells Th2 cytokine IL-6 Macs Th2 cells Th2 cells, B cells ProInflam/Th2 IL-7 Bone marrow Stem cells Hematopoiesis IL-8 Neutrophils Endothelial cells Chemokine IL-10 Th2 cells, Macs, Th2 and B cells Th2 cytokine IL-12 Macrophages, dendritic cells TNF- Macs, T, B endothelial TNF- Th1 cells Pro- Inflammatory Inflammatory IFN- IFN Neutrophils, endo/epithelial Th1 cells, macrophages Th1, Tc, NK cells tumor cells, macs, B cells, T cells macrophages, Th1 cells, Uninfected cells macrophages, Th1 Th1 cytokine Anti-viral cytokines Th1 cytokine Inflammatory 22

23 CD4 + T helper Subsets Th1/Th2 Cytokine Bias CD4+ T helper cells can be divided into subsets based on their cytokine production. T h 1 cells produce IL-2, IFN-, TNF- CKs which activate cell mediated immunity T h 2 cells activate IL-4, IL-6, IL-10 CKs that activate humoral immunity These Th subsets were originally identified using mouse T cell clones. 23

24 Mouse Th Subset Cytokine Th1 Th2 24

25 Role for Th1 vs Th2 in Immune Response Both subsets activated in lymph nodes (LN) immune responses to complex antigens. Th1 cells leave LN to find activated endothelium tissue to activate macrophages. Th2 cells can stay in LN to activate B cells. 25

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28 Cytokines of the innate immune system are often secreted at low levels over a short range (e.g., chemokines directed at attracting neutrophils to the site of infection), It can be secreted at high enough levels (measurable in blood samples) where they act like hormones of the endocrine system. Because most cytokines are secreted in response to infection, they are only secreted transiently. o For example, IL-2 is only secreted by activated T cells for about 8 hours. o Any longer secretion would cause potentially dangerous prolonged immune-system activation. o Once infection is resolved, cytokine secretion tends to fall. o In addition, toward the end of an immune response, inhibitory cytokines such as IL-10 and transforming growth factor β (TGF-β) may be produced to ensure the immune response does not continue. Cytokine receptors are also often only expressed transiently. The complete IL-2 receptor is only transiently expressed by activated T cells. Again, this mechanism has evolved to prevent inappropriate activation of the immune system. 28

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30 CYTOKINE RECEPTORS AND SIGNALING MOLECULES Most cytokines use one of three types of receptors that are linked to signal transduction molecules. The three main types of receptor are: the general cytokine receptor family, the chemokine receptor, the TNF receptor. Most cytokines use broadly similar receptor molecules (sometimes called the hemopoietin receptors) includes cytokines that act as growth factors and the IFNs. These receptors consist of one or more transmembrane molecules with extracellular domains conferring specificity for particular cytokines. The receptors for IL-2, IL-4, and IL-7 consist of three separate polypeptide chains, but share a common γ chain. The gene for the γ chain is defective in X-linked severe combined immunodeficiency disease (SCID). 30

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32 Most cytokine receptors are not expressed in high numbers in completely resting cells; they tend to be upregulated after a cell has been activated (e.g., after a T cell has been activated through its T-cell receptor). After upregulation, the cytokine receptors are normally spread across the surface of the cell. When cytokine binds to its receptor, it causes aggregation of the receptors at the cell surface. Ligand Binding Causes Dimerization of Receptor JAKs Get Activated Phosphorylation of tyrosine residues on receptor Phosphorylation of JAKs themselves STATS Dock Receptor Phosphorylation of STATs by JAKs Dimerized STATs Translocate To Nucleus Gene Expression There are several JAK and STAT molecules. 32

33 THE ROLES OF CYTOKINES IN IMMUNE RESPONSES 1. Initiating inflammation, 2. T-cell priming, 3. The development of T-cell specialization, 4. The winding down of the immune response. Gut Immunity T H 1 Responses induces class switch from IgM to IgA T H 2 Responses 33

34 Development of Specialized T-Cell Responses Gut Immunity Gut-derived T cells secrete a cytokine called transforming growth factorβ (TGF-β). TGF-β induces class switch from IgM to IgA, which has a major role in mucosal immunity. TGF-β also has potent antiinflammatory effects and inhibits the effects of most T-cell populations, macrophages, and proinflammatory cytokines. So most of the immune response in gut is skewed toward the production of IgA. 34

35 T H 1 Responses Intracellular pathogens stimulate APCs to secrete IL-12 and type 1 IFNs. Induce the T-cell transcription factor T-bet, which leads to IFN-γ secretion and a T H 1 phenotype. T H 1 cells favor the production of IgG by B cells, stimulate phagocytosis. B-cell IgG production can be supported by IL-6, which acts as a growth factor for B cells. When intracellular pathogens cannot be cleared, there is additional high-level TNF secretion, leading to granuloma production 35

36 T H 2 Responses Worm infections tend to favor T H 2 responses. Worm infection APC induce signal induce GATA3 (T-cell transcription factor ) secrets IL-4 IL-4 favors B-cell production of IgE which activates mast cells, and produce more IL-4. T H 2 cells secrete other cytokines (IL-3, IL-5, and the chemokine eotaxin), which help the T H 2 response by stimulating the maturation of mast cells and eosinophils. 36

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39 Cytokines In Therapy The many specific activities of individual cytokines have been the basis for current concepts of therapeutic intervention - particularly, hematopoietic malfunctions and tumor therapy Applications involve the support of chemo- and radiotherapy, bone marrow transplantation, and general immunostimulation - adoptive immunotherapy 39

40 Chemokines Chemoattractant Cytokines Small (8-10kd) secreted heparin-binding Promote recruitment and activation of leukocytes Can be divided into subclasses by virtue of structural properties Most chemokines have 4 cysteine residues which form disulphide bonds CC class The first two cysteines are adjacent (example: MCP-1, RANTES) CXC class- The first two cysteines are not adjacent (example: IL-8) C class Only has 2 cysteines not 4 (example: Lymphotactin) CX3C class Has 3 amino acids between the first two cysteines and a different N-terminal 40

41 Chemokine Function Recruitment of inflammatory cells to infection Provide immune homeostasis Important in host defense against bacteria, parasitic and viral infection Role in wound healing Role in hematopoesis and angiogenesis under study 41

42 Chemokine Function Chemokines promote chemotaxis in the direction of highest concentration 42

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