Cytokines CHAPTER 12 287 STAT and JAK interaction with released in chronic t-cell activation is the best characterized TABLE 12.2 selected cytokine receptors during a segment containing the amino-terminal 192 amino acids signal transduction of the a subunit is released by proteolytic cleavage, forming a 45-kDa soluble IL-2 receptor. The shed receptor can bind Cytokine receptor JAK TAI L-2 and prevent its interaction with the membrane-bound L-2 receptor. The presence of sIL-2R has been used as a clin IFN-y JAKl and jaK2 Stat1 ical marker of chronic t-cell activation and is observed in a JAKI and Tyk-2 Stat2 number of diseases, including autoimmunity, transplant re- JAK1 and JAK3 Stat5 Some viruses also produce cytokine-binding proteins or JAKl and JAK3 cytokine mimics. The evolution of such anti-cytokine strate- JAK1(and sometimes others) Stat3 gies by microbial pathogens is good biological evidence of JAKI and Tyk-2 the importance of cytokines in organizing and promoting ef- fective anti-microbial immune responses. The poxviruses, for JAK2 and Tyk-2 Stat4 examp ple, have been shown to encode a soluble TNF-binding protein and a soluble IL-l-binding protein Since both TNF Despite its name, Tyk-2 is also a Janus kinase. and IL-1 exhibit a broad spectrum of activities in the inflam- SOURCE: Adapted from E. A. Bach, M. Aguet, and R D. Schreiber, 1997. matory response, these soluble cytokine-binding proteins Annu. Rev Immun. 15: 563 may prohibit or diminish the inflammatory effects of the cytokines, thereby conferring upon the virus a selective ad vantage. Epstein-Barr virus produces an IL-10-like molecule (viral IL-10 or vIL-10) that binds to the IL-10 receptor and like cellular IL-10, suppresses THl-type cell-mediated is specific because a particular STAT homodimer or het- sponses(see the next section), which are effective against erodimer will only recognize certain sequence motifs and many intracellular parasites such as viruses. Molecules pro- thus can interact only with the promoters of certain genes. duced by viruses that mimic cytokines allow the virus to Third, only those target genes whose expression is permitted manipulate the immune response in ways that aid the sur- by a particular cell type can be activated within that variety vival of the pathogen. This is an interesting and powerful of cell. That is, in any given cell type only a subset of the modification some viruses have undergone in their continu potential target genes of a particular STAT may be permitted ing struggle to overcome the formidable barrier of host expression. For example, IL-4 induces one set of genes in immunity. Table 12-3 lists a number of viral products that Tcells, another in B cells, and yet a third in eosinophils mimic cytokines or their receptors. Cytokine Antagonists A number of proteins that inhibit the biological activity of cytokines have been reported. These proteins act in one of two ways: either they bind directly to a cytokine receptor but TABLE 12-3 Viral mimics of cytokine and cytokine receptors fail to activate the cell, or they bind directly to a cytokine, inhibiting its activity. The best-characterized inhibitor is the Virus Product IL-l receptor antagonist(IL-1Ra), which binds to the IL-1 receptor but has no activity. Binding of IL-1Ra to the IL ViRu oluble IFN-Y receptor receptor blocks binding of both IL-la and IL-1B, thus Soluble IFN-y receptor accounting for its antagonistic properties. Production of IL-1Ra has been thought by some to play a role in regulating oluble IL-1β receptor the intensity of the inflammatory response. It has been Epstein-Barr L-10 homolog cloned and is currently being investigated as a potential treat- Human herpesvirus-8 IL-6 homolog: also homologs ment for chronic inflammatory diseases. of the chemokines mip-I and Cytokine inhibitors are found in the bloodstream and xtracellular fluid. These soluble antagonists arise from enzy matic cleavage of the extracellular domain of cytokine rece which binds three different tors. among the soluble cytokine receptors that have been de- soluble chemokines(RANtES tected are those for IL-2, -4, -6, and-7, IFN-y and-c, TNF-B, MCP-1, and MIP-1a) and LiF. Of these, the soluble IL-2 receptor (sIL-2R), which isis specific because a particular STAT homodimer or het￾erodimer will only recognize certain sequence motifs and thus can interact only with the promoters of certain genes. Third, only those target genes whose expression is permitted by a particular cell type can be activated within that variety of cell. That is, in any given cell type only a subset of the potential target genes of a particular STAT may be permitted expression. For example, IL-4 induces one set of genes in T cells, another in B cells, and yet a third in eosinophils. Cytokine Antagonists A number of proteins that inhibit the biological activity of cytokines have been reported. These proteins act in one of two ways: either they bind directly to a cytokine receptor but fail to activate the cell, or they bind directly to a cytokine, inhibiting its activity. The best-characterized inhibitor is the IL-1 receptor antagonist (IL-1Ra), which binds to the IL-1 receptor but has no activity. Binding of IL-1Ra to the IL-1 receptor blocks binding of both IL-1 and IL-1, thus accounting for its antagonistic properties. Production of IL-1Ra has been thought by some to play a role in regulating the intensity of the inflammatory response. It has been cloned and is currently being investigated as a potential treat￾ment for chronic inflammatory diseases. Cytokine inhibitors are found in the bloodstream and extracellular fluid. These soluble antagonists arise from enzy￾matic cleavage of the extracellular domain of cytokine recep￾tors. Among the soluble cytokine receptors that have been de￾tected are those for IL-2, -4, -6, and -7, IFN- and -, TNF-, and LIF. Of these, the soluble IL-2 receptor (sIL-2R), which is released in chronic T-cell activation, is the best characterized. A segment containing the amino-terminal 192 amino acids of the subunit is released by proteolytic cleavage, forming a 45-kDa soluble IL-2 receptor. The shed receptor can bind IL-2 and prevent its interaction with the membrane-bound IL-2 receptor. The presence of sIL-2R has been used as a clin￾ical marker of chronic T-cell activation and is observed in a number of diseases, including autoimmunity, transplant re￾jection, and AIDS. Some viruses also produce cytokine-binding proteins or cytokine mimics. The evolution of such anti-cytokine strate￾gies by microbial pathogens is good biological evidence of the importance of cytokines in organizing and promoting ef￾fective anti-microbial immune responses. The poxviruses, for example, have been shown to encode a soluble TNF-binding protein and a soluble IL-1–binding protein. Since both TNF and IL-1 exhibit a broad spectrum of activities in the inflam￾matory response, these soluble cytokine-binding proteins may prohibit or diminish the inflammatory effects of the cytokines, thereby conferring upon the virus a selective ad￾vantage. Epstein-Barr virus produces an IL-10–like molecule (viral IL-10 or vIL-10) that binds to the IL-10 receptor and, like cellular IL-10, suppresses TH1-type cell-mediated re￾sponses (see the next section), which are effective against many intracellular parasites such as viruses. Molecules pro￾duced by viruses that mimic cytokines allow the virus to manipulate the immune response in ways that aid the sur￾vival of the pathogen. This is an interesting and powerful modification some viruses have undergone in their continu￾ing struggle to overcome the formidable barrier of host immunity. Table 12-3 lists a number of viral products that mimic cytokines or their receptors. Cytokines CHAPTER 12 287 TABLE 12-2 STAT and JAK interaction with selected cytokine receptors during signal transduction Cytokine receptor JAK STAT IFN- JAK1 and JAK2 Stat1 IFN-/ JAK1 and Tyk-2 Stat2 IL-2 JAK1 and JAK3 Stat5 IL-3 JAK2 Stat5 IL-4 JAK1 and JAK3 Stat6 IL-6 JAK1 (and sometimes others) Stat3 IL-10 JAK1 and Tyk-2* Stat3 IL-12 JAK2 and Tyk-2* Stat4 *Despite its name, Tyk-2 is also a Janus kinase. SOURCE: Adapted from E. A. Bach, M. Aguet, and R. D. Schreiber, 1997, Annu. Rev. Immun. 15:563. TABLE 12-3 Viral mimics of cytokine and cytokine receptors Virus Product Leporipoxvirus Soluble IFN- receptor (a myxoma virus) Several poxviruses Soluble IFN- receptor Vaccinia, smallpox virus Soluble IL-1 receptor Epstein-Barr IL-10 homolog Human herpesvirus-8 IL-6 homolog; also homologs of the chemokines MIP-I and MIP-II Cytomegalovirus Three different chemokine receptor homologs, one of which binds three different soluble chemokines (RANTES, MCP-1, and MIP-1)