《免疫学》（英文版） Chapter 12 Cytokines

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 distance

the 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.

PaRt I Immune Effector Mechanisms RECEPTOR FAMILY LIGANDS Cytokine Receptors (a)Immunoglobulin superfamil As noted already, to exert their biological effects, cytokines receptors must first bind to specific receptors expressed on the mem- IL- brane of responsive target cells. Because these receptors are M-CSF expressed by many types of cells, the cytokines can affect a diverse array of cells. Biochemical characterization of cyto- kine receptors initially progressed at a very slow pace because their levels on the membrane of responsive cells is quite low. As with the cytokines themselves, cloning of the genes encod- ing cytokine receptors has led to rapid advances in the iden tification and characterization of these receptors (b) Class I Cytokine Receptors Fall Within Five Families (hematopoietin) Receptors for the various cytokines are quite diverse struc IL-2 IL- turally, but almost all belong to one of five families of recep- IL-3 IL-4 GM-CSF tor proteins( Figure 12-6) 自自> Conser -5 G-CSF Immunoglobulin superfamily receptors IL-6 IL-7 LIF Class I cytokine nown as the IL-9 CNTF hematopoietin IL-11 I L-12 Prolactin Class ll cytokine receptor family (also known as the interferon receptor family (c)Class Il cytokine receptors Many of the cytokine-binding receptors that function in nd hematopoietic systems belong to the cla eceptor family. The members of this receptor fami have conserved amino acid sequence motifs in the extracellu lar domain consisting of four positionally conserved cysteine residues(CCCC)and a conserved sequence of tryptophan- serine-(any amino acid)-tryptophan-serine(wSXWS, where X is the nonconserved amino acid). The receptors for all the (d)TNF receptors cytokines classified as hematopoietins belong to the class I TNFα cytokine receptor family, which also is called the hematopoi- CD40 etin receptor family. The class ll cytokine receptors possess Nerve growth factor (NGF) the conserved CCCC motifs, but lack the wSXWS motif pre- sent in class I cytokine receptors. Initially only the three interferons, a, B, and y, were thought to be ligands for these receptors. However, recent work has shown that the IL-10 receptor is also a member of this group Another feature common to most of the hematopoietin (class I cytokine) and the class lI cytokine receptor families is (e)Chemokine receptors ANTES PF4 MCAF FIGURE 12. Schematic diagrams showing the structural features NAP-2 that define the five types of receptor proteins to which most cytokines bind. The receptors for most of the interleukins belong to the clas tokine receptor family. C refers to conserved cysteine

Cytokine Receptors As noted already, to exert their biological effects, cytokines must first bind to specific receptors expressed on the mem￾brane of responsive target cells. Because these receptors are expressed by many types of cells, the cytokines can affect a diverse array of cells. Biochemical characterization of cyto￾kine receptors initially progressed at a very slow pace because their levels on the membrane of responsive cells is quite low. As with the cytokines themselves, cloning of the genes encod￾ing cytokine receptors has led to rapid advances in the iden￾tification and characterization of these receptors. Cytokine Receptors Fall Within Five Families Receptors for the various cytokines are quite diverse struc￾turally, but almost all belong to one of five families of recep￾tor proteins (Figure 12-6): ■ Immunoglobulin superfamily receptors ■ Class I cytokine receptor family (also known as the hematopoietin receptor family) ■ Class II cytokine receptor family (also known as the interferon receptor family) ■ TNF receptor family ■ Chemokine receptor family Many of the cytokine-binding receptors that function in the immune and hematopoietic systems belong to the class I cytokine receptor family. The members of this receptor family have conserved amino acid sequence motifs in the extracellu￾lar domain consisting of four positionally conserved cysteine residues (CCCC) and a conserved sequence of tryptophan￾serine-(any amino acid)-tryptophan-serine (WSXWS, where X is the nonconserved amino acid). The receptors for all the cytokines classified as hematopoietins belong to the class I cytokine receptor family, which also is called the hematopoi￾etin receptor family. The class II cytokine receptors possess the conserved CCCC motifs, but lack the WSXWS motif pre￾sent in class I cytokine receptors. Initially only the three interferons, , , and , were thought to be ligands for these receptors. However, recent work has shown that the IL-10 receptor is also a member of this group. Another feature common to most of the hematopoietin (class I cytokine) and the class II cytokine receptor families is 282 PART III Immune Effector Mechanisms RECEPTOR FAMILY LIGANDS (a) Immunoglobulin superfamily receptors IL-1 M-CSF C-Kit S S S S S S (b) Class I cytokine receptors (hematopoietin) IL-2 IL-3 IL-4 IL-5 IL-6 IL-7 IL-9 IL-11 IL-12 IL-13 IL-15 GM-CSF G-CSF OSM LIF CNTF Growth hormone Prolactin Conserved cysteines WSXWS (c) Class II cytokine receptors (interferon) IFN-α IFN-β IFN-γ IL-10 C C C C (d) TNF receptors C1 C3 C2 C1 C3 C2 C1 C3 C2 C1 C3 C2 TNF-α TNF-β CD40 Nerve growth factor (NGF) FAS (e) Chemokine receptors IL-8 RANTES MIP-1 PF4 MCAF NAP-2 G-protein FIGURE 12-6 Schematic diagrams showing the structural features that define the five types of receptor proteins to which most cytokines bind. The receptors for most of the interleukins belong to the class I cytokine receptor family. C refers to conserved cysteine.

Cytokines CHAPTER 12 283 multiple subunits, often including one subunit that binds a)GM-CSF receptor subfamily(common p subunit) specific cytokine molecules and another that mediates signal transduction Note however that these two functions are not GM-CSF always confined to one subunit or the other. Engagement of all of the class I and class ll cytokine receptors studied to date has been shown to induce tyrosine phosphorylation of the receptor through the activity of protein tyrosine kinases closely associated with the cytosolic domain of the receptors Subfamilies of Class I Cytokine Receptors Have Signaling Subunits in Common GM-CSFRo IL-3R Several subfamilies of class i cytokine receptors have beer identified, with all the receptors in a subfamily having identical signal-transducing subunit Figure 12-7 schemati cally illustrates the members of three receptor subfamilies, named after GM-cSe. IL-2 and IL-6 The sharing of signal-transducing subunits among recep- tors explains the redundancy and antagonism exhibited by (b)IL-6 Receptor subfamily(common gp130 subunit) some cytokines. Consider the GM-CSF receptor subfamily. which includes the receptors for IL-3, IL-5, and GM-CSF(see CNTF LIF/OSM Figure 12-7a) Each of these cytokines binds to a unique low affinity, cytokine-specific receptor consisting of an a subunit only. All three low-affinity subunits can associate noncova- IL-11 ntly with a common signal-transducing B subunit. The re- sulting dimeric receptor not only exhibits increased affinity for the cytokine but also can transduce a signal across the membrane after binding the cytokine(Figure 12-8a) Inter- estingly, IL-3, IL-5, and GM-CSF exhibit considerable redun- dancy. IL-3 and GM-CSF both ac cells and progenitor cells, activate monocytes, and induce megakaryocyte differentiation. All three of these cytokines induce eosinophil proliferation and basophil degranulation with release of histamine Since the receptors for IL-3, IL-5, and GM-CSF share a CNTFR common signal-transducing B subunit, each of these cyto- kines would be expected to transduce a similar activation nal, accounting for the redundancy among their biological effects(Figure 12-8b). In fact, all three cytokines induce the same patterns of protein phosphorylation. Furthermore, IL-3 and GM-CSF exhibit antagonism; IL-3 binding has been p130 0130 shown to be inhibited by GM-CSE, and conversely, binding IL-2 receptor subfamily(common y subunit IL-15 FIGURE 12-7 Schematic diagrams of the three subfamilies of class I cytokine receptors. All members of a subfamily have a common sig nal-transducing subunit(blue), but a unique cytokine-specific subunit IL-15Ro In addition to the conserved cysteines(double black lines)and WSXWS motifs(red lines) that characterize class I cytokine receptors, immu- noglobulin-like domains are present in some of these receptors. CNTF ciliary neurotrophic factor: LIF/OSM= leukemia-inhibitory factor/ IL2BB正7R9R oncostatin /Adapted from K. Sugamura et al, 1996, Annu. Rev. Im- munol. 14: 179 IL-4R

multiple subunits, often including one subunit that binds specific cytokine molecules and another that mediates signal transduction. Note, however, that these two functions are not always confined to one subunit or the other. Engagement of all of the class I and class II cytokine receptors studied to date has been shown to induce tyrosine phosphorylation of the receptor through the activity of protein tyrosine kinases closely associated with the cytosolic domain of the receptors. Subfamilies of Class I Cytokine Receptors Have Signaling Subunits in Common Several subfamilies of class I cytokine receptors have been identified, with all the receptors in a subfamily having an identical signal-transducing subunit. Figure 12-7 schemati￾cally illustrates the members of three receptor subfamilies, named after GM-CSF, IL-2, and IL-6. The sharing of signal-transducing subunits among recep￾tors explains the redundancy and antagonism exhibited by some cytokines. Consider the GM-CSF receptor subfamily, which includes the receptors for IL-3, IL-5, and GM-CSF (see Figure 12-7a). Each of these cytokines binds to a unique low￾affinity, cytokine-specific receptor consisting of an subunit only. All three low-affinity subunits can associate noncova￾lently with a common signal-transducing subunit. The re￾sulting dimeric receptor not only exhibits increased affinity for the cytokine but also can transduce a signal across the membrane after binding the cytokine (Figure 12-8a). Inter￾estingly, IL-3, IL-5, and GM-CSF exhibit considerable redun￾dancy. IL-3 and GM-CSF both act upon hematopoietic stem cells and progenitor cells, activate monocytes, and induce megakaryocyte differentiation. All three of these cytokines induce eosinophil proliferation and basophil degranulation with release of histamine. Since the receptors for IL-3, IL-5, and GM-CSF share a common signal-transducing subunit, each of these cyto￾kines would be expected to transduce a similar activation sig￾nal, accounting for the redundancy among their biological effects (Figure 12-8b). In fact, all three cytokines induce the same patterns of protein phosphorylation. Furthermore, IL-3 and GM-CSF exhibit antagonism; IL-3 binding has been shown to be inhibited by GM-CSF, and conversely, binding Cytokines CHAPTER 12 283 GM-CSF IL-3 IL-5 ββ β (a) GM-CSF receptor subfamily (common β subunit) (c) IL-2 receptor subfamily (common γ subunit) IL-6 CNTF IL-11 (b) IL-6 Receptor subfamily (common gp130 subunit) CNTFR IL-2Rβ IL-2Rβ IL-2Rα IL-15Rα IL-7R IL-9R γ γγ γ IL-15 IL-9 IL-7 IL-4R γ IL-2 IL-4 GM-CSFRα IL-3R IL-5R LIF/OSM gp130 gp130 gp130 gp130 FIGURE 12-7 Schematic diagrams of the three subfamilies of class I cytokine receptors. All members of a subfamily have a common sig￾nal-transducing subunit (blue), but a unique cytokine-specific subunit. In addition to the conserved cysteines (double black lines) and WSXWS motifs (red lines) that characterize class I cytokine receptors, immu￾noglobulin-like domains are present in some of these receptors. CNTF = ciliary neurotrophic factor; LIF/OSM = leukemia-inhibitory factor/ oncostatin. [Adapted from K. Sugamura et al., 1996, Annu. Rev. Im￾munol. 14:179.]