Cytokines cHAPTER 12 TABLE 12.1 Functional groups of selected cytokines Cytokine Secreted by Targets and effects SOME CYTOKINES OF INNATE IMMUNITY Interleukin 1(IL-1) Monocytes, macrophages, Vasculature(inflammation); hypothalamus(fever) I iver(induction of acute phase proteins) Tumor necrosis Macrophages asculature(inflammation); liver(induction of acute phase Factor-a(TNF-a) proteins); loss of muscle, body fat (cachexia); induction of death in many cell types; neutrophil activation 12(L-12) Macrophages, dendritic cells NK cells; influences adaptive immunity (promotes TH1 subset) Interleukin 6(IL-6) Macrophages, endothelial cells Liver(induces acute phase proteins); influences adapt Interferon a(IFN-a) Macrophages Induces an antiviral state in most nucleated cells, increases mHc (This is a family of molecules class I expression; activates NK cells interferonβ(FNB) Fibroblasts Induces an antiviral state in most nucleated cells increases mHc class I expression; activates NK cells SOME CYTOKINES OF ADAPTIVE IMMUNITY Interleukin 2(IL-2) T cells AICD. NK cell activation and Interleukin 4 (IL-4) TH2 cells; mast cells Promotes TH2 differentiation; isotype switch to IgE Interleukin 25(IL-25) Unknown Induces secretion of TH2 cytokine profile Inhibits T-cell proliferation and effector functions; inhibits tor other cell type B-cell proliferation; promotes isotype switch to igE: Interferon y(IFN-y) THI cells; CD8 cells; NK cells Activates macrophages; increases expression MHC class I Many cytokines play roles in more than one functional category. Only the major cell types providing cytokines for the indicated activity are listed; other cell types may also have the capacity to synthesize the given cytokine. Also note that activated cells generally secrete greater amounts of cytokine than unactivated cells. the effects of recombinant cytokines, often at nonphysiologic antigen-activated lymphocytes. Another means of maintain concentrations, added individually to in vitro systems. In ing specificity may be a requirement for direct interaction vivo, however, cytokines rarely, if ever, act alone. Instead target cell is exposed to a milieu containing a mixture of trigger cytokine secretion, thus ensuring that effective concen- cytokines, whose combined synergistic or antagonistic ef- trations of the cytokine are released only in the vicinity of the fects can have very different consequences. In addition, intended target. In the case of the TH cell, a major producer of cytokines often induce the synthesis of other cytokines, re- cytokines, close cellular interaction occurs when the T-cell sulting in cascades of activity receptor recognizes an antigen-MHC complex on an appro- The nonspecificity of cytokines seemingly conflicts with priate antigen-presenting cell, such as a macrophage, den- the established specificity of the immune system. What keeps dritic cell, or B lymphocyte Cytokines secreted at the junction the nonspecific cytokines from activating cells in a nonspe- of these interacting cells reach high enough local concentra cific fashion during the immune response? One way in which tions to affect the target APC but not more distant cells. In specificity is maintained is by careful regulation of the ex- addition, the half-life of cytokines in the bloodstream or other pression of cytokine receptors on cells Often cytokine recep- extracellular fluids into wh ley are secreted is usually very tors are expressed on a cell only after that cell has interacted short, ensuring that they act for only a limited period of time with antigen. In this way cytokine activation is limited to and thus over a short distancethe effects of recombinant cytokines, often at nonphysiologic concentrations, added individually to in vitro systems. In vivo, however, cytokines rarely, if ever, act alone. Instead, a target cell is exposed to a milieu containing a mixture of cytokines, whose combined synergistic or antagonistic ef￾fects can have very different consequences. In addition, cytokines often induce the synthesis of other cytokines, re￾sulting in cascades of activity. The nonspecificity of cytokines seemingly conflicts with the established specificity of the immune system. What keeps the nonspecific cytokines from activating cells in a nonspe￾cific fashion during the immune response? One way in which specificity is maintained is by careful regulation of the ex￾pression of cytokine receptors on cells. Often cytokine recep￾tors are expressed on a cell only after that cell has interacted with antigen. In this way cytokine activation is limited to antigen-activated lymphocytes. Another means of maintain￾ing specificity may be a requirement for direct interaction between the cytokine-producing cell and the target cell to trigger cytokine secretion, thus ensuring that effective concen￾trations of the cytokine are released only in the vicinity of the intended target. In the case of the TH cell, a major producer of cytokines, close cellular interaction occurs when the T-cell receptor recognizes an antigen-MHC complex on an appro￾priate antigen-presenting cell, such as a macrophage, den￾dritic cell, or B lymphocyte. Cytokines secreted at the junction of these interacting cells reach high enough local concentra￾tions to affect the target APC but not more distant cells. In addition, the half-life of cytokines in the bloodstream or other extracellular fluids into which they are secreted is usually very short, ensuring that they act for only a limited period of time and thus over a short distance. Cytokines CHAPTER 12 281 TABLE 12-1 Functional groups of selected cytokines1 Cytokine* Secreted by** Targets and effects SOME CYTOKINES OF INNATE IMMUNITY Interleukin 1 (IL-1) Monocytes, macrophages, Vasculature (inflammation); hypothalamus (fever); endothelial cells, epithelial cells l iver (induction of acute phase proteins) Tumor Necrosis Macrophages Vasculature (inflammation); liver (induction of acute phase Factor- (TNF-) proteins); loss of muscle, body fat (cachexia); induction of death in many cell types; neutrophil activation Interleukin 12 (IL-12) Macrophages, dendritic cells NK cells; influences adaptive immunity (promotes TH1 subset) Interleukin 6 (IL-6) Macrophages, endothelial cells Liver (induces acute phase proteins); influences adaptive immunity (proliferation and antibody secretion of B cell lineage) Interferon (IFN-) Macrophages Induces an antiviral state in most nucleated cells; increases MHC (This is a family of molecules) class I expression; activates NK cells Interferon (IFN-) Fibroblasts Induces an antiviral state in most nucleated cells; increases MHC class I expression; activates NK cells SOME CYTOKINES OF ADAPTIVE IMMUNITY Interleukin 2 (IL-2) T cells T-cell proliferation; can promote AICD. NK cell activation and proliferation; B-cell proliferation Interleukin 4 (IL-4) TH2 cells; mast cells Promotes TH2 differentiation; isotype switch to IgE Interleukin 5 (IL-5) TH2 cells Eosinophil activation and generation Interleukin 25 (IL-25) Unknown Induces secretion of TH2 cytokine profile Transforming growth T cells, macrophages, Inhibits T-cell proliferation and effector functions; inhibits factor (TGF-) other cell types B-cell proliferation; promotes isotype switch to IgE; inhibits macrophages Interferon  (IFN-) TH1 cells; CD8+ cells; NK cells Activates macrophages; increases expression MHC class I and class II molecules; increases antigen presentation 1 Many cytokines play roles in more than one functional category. *Only the major cell types providing cytokines for the indicated activity are listed; other cell types may also have the capacity to synthesize the given cytokine. **Also note that activated cells generally secrete greater amounts of cytokine than unactivated cells.