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Interleukin 18

Interleukin 18 Commentary Interleukin 18: Tipping the Balance Towards a T Helper Cell 1 Response Susan L. Swain The Trudeau Institute, Saranac Lake, NY 12983 IL-18 was identified as a factor promoting IFN- produc- studies reenforce the concept of IL-18 as a highly pleio- tion (1) and it was originally called IFN-–inducing factor tropic, but decidedly pro-Th1 cytokine, that dramatically (IGIF). Further study indicated IL-18 had a structure related enhances both innate and acquired immune responses. to IL-1 (2) and later it was found that the IL-18 receptor re- IL-18 induces macrophages to produce IFN-, but the sembles that for IL-1 (3–4). IL-18, like IL-1 and agents in- results of Neighbors and colleagues indicate that it also teracting with Toll receptors, signals via MyD88 which acti- stimulates macrophages to produce of TNF- and nitric vates TNF receptor–associated factor and ultimately nuclear oxide (NO), and that both of these are critical in IL-18’s factor B (5). Like IL-1, IL-18 is made as an inactive pre- important role in protection against Listeria (23). This is cursor that is cleaved by caspase-1 (interleukin-1–converting likely to prove to be a key aspect of IL-18 action because enzyme) to produce active cytokine (6). Many cell types such a mechanism could explain the procytotoxic activities have been reported to produce IL-18, including macro- of IL-18 (18, 19). Neighbors and colleagues have shown phages and dendritic cells (7); IL-18 mRNA or protein is also convincingly, using both cytokine knockout and blocking seen in Kupffer cells (8), astrocytes and microglia (9), intesti- antibody studies, that the action of IL-18 is dominant over nal and airway epithelial cells (10), and in kerotinocytes (11) those of IL-12 and IFN- in promoting resistance to Liste- and osteoblasts (12). What induces IL-18 has not been ex- ria, and that the effect is largely independent of those cy- tensively studied, but IL-18 is found after bacterial (13) and tokines, but dependent on TNF-. They also directly viral (14) infection and, by inference, in many other infec- demonstrate the ability of IL-18 to induce macrophages to tious diseases. IL-18 production from many cells is constitu- produce TNF- and NO (23). These results begin to ex- tive or prolonged after induction (15). An important, but plain the observations in the literature that IL-18 seems to not well-explored, role for IL-18 can also be inferred from be required for protection against a broad range of patho- the fact that poxviruses make a homologue of IL-18–bind- gens including Mycobacteria (25), Salmonella (26), Shigella ing protein, a natural suppressor of IL-18 (16) and also an in- (26), Leishmania (27), Staphylococci (28), and Cryptococci (29). hibitor of interleukin-1–converting enzyme (17). IL-18 and Cytokine Polarization. Early studies of IL-18 Targets and Roles of IL-18. Major targets of IL-18 in- stressed its IFN-–inducing abilities and promoted its role as clude macrophages, NK cells (18), T cells (19), and perhaps an inducer of Th1 responses (1, 19, 20), but more recently a B cells (20). A major effect of IL-18 is the induction of cy- number of studies and reviews have suggested IL-18 can tokine synthesis. IL-18 induces IFN- production from T also enhance production of Th2 cytokines and promote IgE cells (1, 21), and IL-13 from NK cells and T cells (22), es- synthesis (30, 31). The papers in this issue indicate that the pecially in concert with other signals (21). major in vivo role is likely to be weighted towards IL-18 in- Two papers in this issue (23, 24) provide compelling ev- ducing a Th1 response. Not only did IL-18 mediate protec- idence that IL-18 plays a key role in protection against in- tion against Listeria, but in the Trichuris model, the absence fectious disease and shed further light on the nature of that of IL-18–converted B6 mice which were susceptible to low role as well as the mechanism by which it occurs. Papers doses of the helminth, to a highly resistant state that is more from Neighbors et al. studying the role of IL-18 in protec- profound than that seen in IL-12–deficient mice (24). In tion against Listeria monocytogenes (Listeria), and from contrast Balb/c mice, which are normally resistant to Tri- Helmby et al. in protection against the helminth, Trichuris churis via a mechanism dependent on IL-13– and IL-4– muris (Trichuris), both indicate that IL-18 promotes Th1 mediated expulsion of the nematode, become susceptible after polarization of the immune response even when IFN- is IL-18 treatment. In both cases susceptibility correlates with not involved, suggesting a broader range of IL-18 targets low IL-13 (not IL-4) levels. The authors conclude that IL- and actions than was described previously. Together these 18 plays a key role in gastrointestinal nematode infections via downregulation of IL-13 (24). The authors also were able to visualize very early production of IL-18 after infec- Address correspondence to Susan Swain, Trudeau Institute, Inc., 100 tion in the intestine by macrophages and dendritic cells, Algonquin Ave., P.O. Box 59, Saranac Lake, NY 12983. Phone: 518- 891-3080; Fax: 518-891-5126; E-mail: [email protected] which correlates with the susceptible phenotype (24). F11 J. Exp. Med.  The Rockefeller University Press • 0022-1007/2001/08/F11/04 $5.00 Volume 194, Number 3, August 6, 2001 F11–F14 http://www.jem.org/cgi/content/full/194/3/F11 Figure 1. The reason that IL-18 induces Th2 cytokines under mine if the other cytokines produced in response to IL-18 some circumstances remains unexplained, but these new also show prolonged induction. studies tip the balance in favor of a predominantly pro-Th1 The regulation of IL-18 production also deserves further action of IL-18. A cartoon summarizing the action of IL-18 exploration. Some cells have been reported to make IL-18 in protection against infectious disease, derived from the constitutively (15), but certain infections apparently lead to recent and earlier studies, is in Fig. 1. upregulation of production. The consensus seems to be Perspectives and Questions One of the most novel activi- that macrophages and related cells are the major producers, ties of IL-18 is its ability to induce Th1 effectors to produce but what cells make IL-18 in different circumstances and IFN- in the absence of TCR signaling (21). IL-18 and IL-2 what conditions favor IL-18 production, processing, and alone can induce prolonged IFN- protein synthesis and, subsequent blocking by IL-18–binding protein deserve fur- together with TCR triggering, there is a marked synergy ther study. resulting in high levels of IFN- secreted for at least 5 d Conclusions. IL-18 is emerging as a powerful, pleiotropic (21). This is in marked contrast to the effects of TCR trig- cytokine involved in determining the polarization of T cell gering alone which results in only transient cytokine syn- responses and whether the responses to infectious organ- thesis. The prolonged presence of IFN- at sites of inflam- isms are protective or not. IL-18 is made by macrophages, mation is liable to result in very dramatic biological effects dendritic cells, perhaps lymphocytes, and by nonimmune both in the effector phase of the response but also in its cells; and like IL-1, its actions are regulated by the require- subsequent downregulation (32, 33). Thus prolonged IFN- ment for proteinase cleavage and by blocking proteins, as production could provide a source of IFN- that would be well as by the expression of its receptor by the variety of available late in the immune response to help downregulate potential targets. It has potent actions on macrophages, in- excessive CD4 T cell expansion. ducing TNF production and its consequences as well as Finally, as IL-18 shares a common signaling pathway NO production, on T cells and B cells inducing IFN- es- with IL-1 and other Toll receptor interacting compo- pecially in synergy with other cytokine inducers including nents, IL-1 and agents signaling via toll receptors might IL-12 and Ag/APC. We are sure to hear much more about be expected to induce prolonged rather than transient IL-18 as a critical multipotent inducer of innate and ac- IFN- production. It would also be of interest to deter- quired immune responses. F12 Commentary Submitted: 20 June 2001 Matikainen. 1999. Virus infection activates IL-I and IL-18 Accepted: 9 July 2001 production in human macrophages by a caspase-I-dependent pathway. J. Immunol. 162:7322–7329. 15. Okamura, H., H. Tsutsui, S. Kashiwamura, T. Yoshimoto, References and K. Nakanishi. 1998. Interleukin-18: a novel cytokine 1. Okamura, H., H. Tsutsui, T. Komatsu, M. Yutsudo, A. that augments both innate and acquired immunity. Adv. Im- Hakura, T. Tanimoto, K. Torigoe, T. Okura, Y. Nukada, K. munol. 70:281–312. Hattori, et al. 1995. Cloning of a new cytokine that induces 16. Yiang, Y., and B. Moss. 1999. IL-18 binding and inhibition IFN- production by T cells. Nature. 378:88–91. of interferon  induction by human poxvirus-encoded pro- 2. Bazan, J.F., J.C. Timans, and R.A. Kastelein. 1996. A newly teins. Proc. Natl. Acad. Sci. USA. 96:11537–11542. defined interleukin-1? Nature. 379:591. 17. Smith, V.P., N.A. Bryant, and A. Alcami. 2000. Ectromelia, 3. Hoshino, K., H. Tsutsui, T. Kawai, K. Takeda, K. Nakanishi, vaccinia and cowpox viruses encode secreted interleukin-18- Y. Takeda, and S. Akira. 1999. Generation of IL-18 recep- binding proteins. J. Gen. Virol. 5:1223–1230. tor-deficient mice: evidence for IL-1 receptor-related protein 18. Dao, T., W.Z. Mehal, and I.N. Crispe. 1998. IL-18 aug- as an essential IL-18 binding receptor. J. Immunol. 162:5041– ments perforin-dependent cytotoxicity of liver NK-T cells. J. 5044. Immunol. 161:2217–2222. 4. Born, T.L., E. Thomassen, T.A. Bird, and J.E. Sims. 1998. 19. Kanakaraj, P., K. Ngo, Y. Wu, A. Angulo, P. Ghazal, C.A. Cloning of a novel receptor subunit, ACPL, required for in- Harris, J.J. Siekierka, P.A. Peterson, and L.W. Fung. 1999. terleukin-18 signaling. J. Biol. Chem. 273:29445–29450. Defective interleukin (IL)-18-mediated natural killer and T 5. Adachi, O., T. Kawai, K. Takeda, M. Matsumoto, H. Tsut- helper cell type I responses in IL-1 receptor-associated kinase sui, M. Sakagami, K. Nakanishi, and S. Akira. 1998. Targeted (IRAK)-deficient mice. J. Exp. Med. 189:1129–1138. disruption of the MyD88 gene results in loss of IL-1- and IL- 20. Yoshimoto, T., H. Okamura, Y. Tagawa, Y. Iwakura, and K. 18-mediated function. Immunity. 9:143–150. Nakanishi. 1997. lnterleukin 18 together with interleukin 12 6. Gu, Y., K. Kuida, H. Tsutsui, G. Ku, K. Hsiao, M.A. Fieffi- inhibits IgE production by induction of interferon- produc- ing, N. Hayashi, K. Higashino, H. Okainura, K. Nakanishi, tion from activated B cells. Proc. Natl. Acad. Sci. USA. 94: et al. 1997. Activation of interferon- inducing factor medi- 3948–3953. ated by interleukin-1 converting enzyme. Science. 275:206– 21. Yang, J., H. Zhu, T.L. Murphy, W. Ouyang, and K.M. 209. Murphy. 2001. IL-18-stimulated GADD45b required in cy- 7. Stoll, S., H. Jonuleit, E. Schmitt, G. Muller, H. Yarnauchi, tokine-induced, but not TcR-induced IFN- production. M. Kurimoto, J. Knop, and A.H. Enk. 1998. Production of Nat. Immunol. 2:157–164. functional IL-18 by different subtypes of murine and human 22. Hoshino T., R.H. Wiltrout, and H.A. Young 1999. IL-18 is dendritic cells (DC): DC-derived IL-18 enhances IL-inde- a potent co-inducer of IL-13 in NK and T cells: a new po- pendent Th I development. Eur. J. Immunol. 28:3231–3239. tential role for IL-18 in modulating the immune response. J. 8. Matsui, K., T. Yoshimoto, H. Tsutsui, Y. Hyodo, N. Ha- Immunol. 162:5070–5077. yashi, K. Hiroishi, N. Kawada, H. Okamura, K. Nakanishi, 23. Neighbors, M., X. Xu, F.J. Barrat, S.R. Ruuls, T. Chura- and K. Ifigashino. 1997. Propionibacterium acnes treatment di- kova, R. Debets, J.F. Bazan, R.A Kastelein, J.S. Abrams, and minishes CD4 NKI.I T cells but induces type I T cells in A. O’Garra. 2001. A critical role for IL-18 in primary and the liver by induction of IL-12 and IL-18 production from memory responses to Listeria monocytogenes that extends be- Kupffer cells. J. Immunol. 159:97–106. yond its effects on interferon  production. J. Exp. Med. 194: 9. Prinz, M., and U.K. Hanisch. 1999. Murine micrioglial pro- 343–354. duce and respond to interleukin-18. J. Neurochem. 72:2215– 24. Helmby, H., K. Takeda, S. Akira, and R.K. Grencis. 2001. 2218. Interleukin-18 promotes the development of chronic gas- 10. Takeuchi, M., Y. Nishizaki, O. Sano, T. Ohta, M. Ikeda, trointestinal helminth infection by downregulating IL-13. J. and M. Kurimoto. 1997. Immunohistochemical and immu- Exp. Med. 194:355–364. noelectron microscopic detection of interferon--inducing 25. Kobayashi, K, M. Kai, M. Gidoh, N. Nakata, M. Endoh, factor (interleukin-18) in mouse intestinal epithelial cells. Cell R.P. Singh, T. Kasaina, and H. Saito. 1998. The possible role Tissue Res. 289:499–507. of interleukin (IL)-12 and interferon--inducing factor/IL-18 11. Stoll, S., G. Muller, M. Kurimoto, J. Saloga, T. Tanimoto, in protection against experimental Mycobacterium leprae infec- H. Yamauchi, H. Okamura, J. Knop, and A.H. Enk. 1997. tion in mice. Clin. Immunol. lmmunopathol. 88:223–231. Production of IL-18 (IFN--inducing factor) messenger 26. Garcia, V.E., K. Uyemura, P.A. Sieling, M.T. Ochoa, C.T. RNA and functional protein by murine keratinocytes. J. Im- Morita, H. Okamura, M. Kurimoto, T.H. Rea, and R.L. munol. 159:298–302. Modlin. 1999. IL-18 promotes type I cytokine production 12. Udagawa, N., N.J. Horwood, J. Elliott, A. Mackay, J. from NK cells and T cells in human intracellular infection. J. Owens, H. Okamura, M. Kurimoto, T.J. Chambers, T.J. Immunol. 162:6114–6121. Martin, and M.T. Gillespie. 1997. Interleukin-18 (interferon- 27. Sansonetti, P.J., A. Phalipon, J. Arondel, K. Thirumalai, S. -inducing factor) is produced by osteoblasts and acts via Banerjee, S. Akira, K. Takeda, and A. Zychlinsky. 2000. granulocyte/macrophage colony-stimulating factor and not Caspase-I activation of IL-I and IL-18 are essential for Shi- via interferon- to inhibit osteoclast formation. J. Exp. Med. gella flexneri-induced inflammation. Immunity. 12:581–590. 185:1005–1012. 28. Wei, X.Q., B.P. Leung, W. Niedbala, D. Piedrafita, G.J. 13. Yankayalapati, R., B. Wizel, S.E. Weis, B. Samten, W.M. Feng, M. Sweet, L. Dobbie, A.J. Smith, and F.Y. Liew. Girard, and P.F. Bames. 2000. Production of interleukin-18 1999. Altered immune responses and susceptibility to Leish- in human tuberculosis. J. Infect. Dis. 182:234–239. mania major and Staphylococcus aureus infection in IL-18-defi- 14. Pirhonen, I., T. Sareneve, M. Kurimoto, I. Julkunen, and S. cient mice. J. Immunol. 163:2821–2828. F13 Swain 29. Kawakami, K., Y. Koguchi, M.H. Qureshi, A. Miyazato, S. 31. Nakanishi, K., T. Yoshimoto, H. Tsutsui, and H. Okamura. Yara, Y. Kinjo, Y. Iwakura, K. Takeda, S. Akira, M. Kuri- 2001. Interleukin-18 regulates both Th1 and Th2 responses. moto, and A. Saito. 2000. IL-18 contributes to host resistance Annu. Rev. Immunol. 19:423–474. against infection with Cryptococcus neoformans in mice with de- 32. Cauley, L.S., E. Miller, M. Yen, and S.L. Swain. 2000. Su- fective IL-12 synthesis through induction of IFN- produc- perantigen-induced CD4 T cell tolerance mediated by my- tion by NK cells. J. Immunol. 165:941–947. eloid cells and IFN-. J. Immunol. 165:6056–6066. 30. Yoshimoto, T., H. Mizutani, H. Tsutsui, N. Noben-Trauth, 33. Dalton, D.K., L. Haynes, C. Chu, S.L. Swain, and S. Witt- K. Yamanaka, M. Tanaka, S. Izumi, H. Okainura, W.E. Paul, mer. 2000. Interferon  eliminates responding CD4 T cells and K. Nakanishi. 2000. IL-18 induction of IgE: dependence during Mycobacterial infection by inducing apoptosis of acti- on CD4 T cells, IL-4 and STAT6. Nat. Immunol. 1:132–137. vated CD4 T cells. J. Exp. Med. 192:117–212. F14 Commentary http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Pubmed Central

Interleukin 18

Swain, Susan L.
The Journal of Experimental Medicine , Volume 194 (3) – Aug 6, 2001
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Commentary Interleukin 18: Tipping the Balance Towards a T Helper Cell 1 Response Susan L. Swain The Trudeau Institute, Saranac Lake, NY 12983 IL-18 was identified as a factor promoting IFN- produc- studies reenforce the concept of IL-18 as a highly pleio- tion (1) and it was originally called IFN-–inducing factor tropic, but decidedly pro-Th1 cytokine, that dramatically (IGIF). Further study indicated IL-18 had a structure related enhances both innate and acquired immune responses. to IL-1 (2) and later it was found that the IL-18 receptor re- IL-18 induces macrophages to produce IFN-, but the sembles that for IL-1 (3–4). IL-18, like IL-1 and agents in- results of Neighbors and colleagues indicate that it also teracting with Toll receptors, signals via MyD88 which acti- stimulates macrophages to produce of TNF- and nitric vates TNF receptor–associated factor and ultimately nuclear oxide (NO), and that both of these are critical in IL-18’s factor B (5). Like IL-1, IL-18 is made as an inactive pre- important role in protection against Listeria (23). This is cursor that is cleaved by caspase-1 (interleukin-1–converting likely to prove to be a key aspect of IL-18 action because enzyme) to produce active cytokine (6). Many cell types such a mechanism could explain the procytotoxic activities have been reported to produce IL-18, including macro- of IL-18 (18, 19). Neighbors and colleagues have shown phages and dendritic cells (7); IL-18 mRNA or protein is also convincingly, using both cytokine knockout and blocking seen in Kupffer cells (8), astrocytes and microglia (9), intesti- antibody studies, that the action of IL-18 is dominant over nal and airway epithelial cells (10), and in kerotinocytes (11) those of IL-12 and IFN- in promoting resistance to Liste- and osteoblasts (12). What induces IL-18 has not been ex- ria, and that the effect is largely independent of those cy- tensively studied, but IL-18 is found after bacterial (13) and tokines, but dependent on TNF-. They also directly viral (14) infection and, by inference, in many other infec- demonstrate the ability of IL-18 to induce macrophages to tious diseases. IL-18 production from many cells is constitu- produce TNF- and NO (23). These results begin to ex- tive or prolonged after induction (15). An important, but plain the observations in the literature that IL-18 seems to not well-explored, role for IL-18 can also be inferred from be required for protection against a broad range of patho- the fact that poxviruses make a homologue of IL-18–bind- gens including Mycobacteria (25), Salmonella (26), Shigella ing protein, a natural suppressor of IL-18 (16) and also an in- (26), Leishmania (27), Staphylococci (28), and Cryptococci (29). hibitor of interleukin-1–converting enzyme (17). IL-18 and Cytokine Polarization. Early studies of IL-18 Targets and Roles of IL-18. Major targets of IL-18 in- stressed its IFN-–inducing abilities and promoted its role as clude macrophages, NK cells (18), T cells (19), and perhaps an inducer of Th1 responses (1, 19, 20), but more recently a B cells (20). A major effect of IL-18 is the induction of cy- number of studies and reviews have suggested IL-18 can tokine synthesis. IL-18 induces IFN- production from T also enhance production of Th2 cytokines and promote IgE cells (1, 21), and IL-13 from NK cells and T cells (22), es- synthesis (30, 31). The papers in this issue indicate that the pecially in concert with other signals (21). major in vivo role is likely to be weighted towards IL-18 in- Two papers in this issue (23, 24) provide compelling ev- ducing a Th1 response. Not only did IL-18 mediate protec- idence that IL-18 plays a key role in protection against in- tion against Listeria, but in the Trichuris model, the absence fectious disease and shed further light on the nature of that of IL-18–converted B6 mice which were susceptible to low role as well as the mechanism by which it occurs. Papers doses of the helminth, to a highly resistant state that is more from Neighbors et al. studying the role of IL-18 in protec- profound than that seen in IL-12–deficient mice (24). In tion against Listeria monocytogenes (Listeria), and from contrast Balb/c mice, which are normally resistant to Tri- Helmby et al. in protection against the helminth, Trichuris churis via a mechanism dependent on IL-13– and IL-4– muris (Trichuris), both indicate that IL-18 promotes Th1 mediated expulsion of the nematode, become susceptible after polarization of the immune response even when IFN- is IL-18 treatment. In both cases susceptibility correlates with not involved, suggesting a broader range of IL-18 targets low IL-13 (not IL-4) levels. The authors conclude that IL- and actions than was described previously. Together these 18 plays a key role in gastrointestinal nematode infections via downregulation of IL-13 (24). The authors also were able to visualize very early production of IL-18 after infec- Address correspondence to Susan Swain, Trudeau Institute, Inc., 100 tion in the intestine by macrophages and dendritic cells, Algonquin Ave., P.O. Box 59, Saranac Lake, NY 12983. Phone: 518- 891-3080; Fax: 518-891-5126; E-mail: [email protected] which correlates with the susceptible phenotype (24). F11 J. Exp. Med.  The Rockefeller University Press • 0022-1007/2001/08/F11/04 $5.00 Volume 194, Number 3, August 6, 2001 F11–F14 http://www.jem.org/cgi/content/full/194/3/F11 Figure 1. The reason that IL-18 induces Th2 cytokines under mine if the other cytokines produced in response to IL-18 some circumstances remains unexplained, but these new also show prolonged induction. studies tip the balance in favor of a predominantly pro-Th1 The regulation of IL-18 production also deserves further action of IL-18. A cartoon summarizing the action of IL-18 exploration. Some cells have been reported to make IL-18 in protection against infectious disease, derived from the constitutively (15), but certain infections apparently lead to recent and earlier studies, is in Fig. 1. upregulation of production. The consensus seems to be Perspectives and Questions One of the most novel activi- that macrophages and related cells are the major producers, ties of IL-18 is its ability to induce Th1 effectors to produce but what cells make IL-18 in different circumstances and IFN- in the absence of TCR signaling (21). IL-18 and IL-2 what conditions favor IL-18 production, processing, and alone can induce prolonged IFN- protein synthesis and, subsequent blocking by IL-18–binding protein deserve fur- together with TCR triggering, there is a marked synergy ther study. resulting in high levels of IFN- secreted for at least 5 d Conclusions. IL-18 is emerging as a powerful, pleiotropic (21). This is in marked contrast to the effects of TCR trig- cytokine involved in determining the polarization of T cell gering alone which results in only transient cytokine syn- responses and whether the responses to infectious organ- thesis. The prolonged presence of IFN- at sites of inflam- isms are protective or not. IL-18 is made by macrophages, mation is liable to result in very dramatic biological effects dendritic cells, perhaps lymphocytes, and by nonimmune both in the effector phase of the response but also in its cells; and like IL-1, its actions are regulated by the require- subsequent downregulation (32, 33). Thus prolonged IFN- ment for proteinase cleavage and by blocking proteins, as production could provide a source of IFN- that would be well as by the expression of its receptor by the variety of available late in the immune response to help downregulate potential targets. It has potent actions on macrophages, in- excessive CD4 T cell expansion. ducing TNF production and its consequences as well as Finally, as IL-18 shares a common signaling pathway NO production, on T cells and B cells inducing IFN- es- with IL-1 and other Toll receptor interacting compo- pecially in synergy with other cytokine inducers including nents, IL-1 and agents signaling via toll receptors might IL-12 and Ag/APC. We are sure to hear much more about be expected to induce prolonged rather than transient IL-18 as a critical multipotent inducer of innate and ac- IFN- production. It would also be of interest to deter- quired immune responses. F12 Commentary Submitted: 20 June 2001 Matikainen. 1999. Virus infection activates IL-I and IL-18 Accepted: 9 July 2001 production in human macrophages by a caspase-I-dependent pathway. J. Immunol. 162:7322–7329. 15. Okamura, H., H. Tsutsui, S. Kashiwamura, T. Yoshimoto, References and K. Nakanishi. 1998. Interleukin-18: a novel cytokine 1. Okamura, H., H. Tsutsui, T. Komatsu, M. Yutsudo, A. that augments both innate and acquired immunity. Adv. Im- Hakura, T. Tanimoto, K. Torigoe, T. Okura, Y. Nukada, K. munol. 70:281–312. Hattori, et al. 1995. Cloning of a new cytokine that induces 16. Yiang, Y., and B. Moss. 1999. IL-18 binding and inhibition IFN- production by T cells. Nature. 378:88–91. of interferon  induction by human poxvirus-encoded pro- 2. Bazan, J.F., J.C. Timans, and R.A. Kastelein. 1996. A newly teins. Proc. Natl. Acad. Sci. USA. 96:11537–11542. defined interleukin-1? Nature. 379:591. 17. Smith, V.P., N.A. Bryant, and A. Alcami. 2000. Ectromelia, 3. Hoshino, K., H. Tsutsui, T. Kawai, K. Takeda, K. Nakanishi, vaccinia and cowpox viruses encode secreted interleukin-18- Y. Takeda, and S. Akira. 1999. Generation of IL-18 recep- binding proteins. J. Gen. Virol. 5:1223–1230. tor-deficient mice: evidence for IL-1 receptor-related protein 18. Dao, T., W.Z. Mehal, and I.N. Crispe. 1998. IL-18 aug- as an essential IL-18 binding receptor. J. Immunol. 162:5041– ments perforin-dependent cytotoxicity of liver NK-T cells. J. 5044. Immunol. 161:2217–2222. 4. Born, T.L., E. Thomassen, T.A. Bird, and J.E. Sims. 1998. 19. Kanakaraj, P., K. Ngo, Y. Wu, A. Angulo, P. Ghazal, C.A. Cloning of a novel receptor subunit, ACPL, required for in- Harris, J.J. Siekierka, P.A. Peterson, and L.W. Fung. 1999. terleukin-18 signaling. J. Biol. Chem. 273:29445–29450. Defective interleukin (IL)-18-mediated natural killer and T 5. Adachi, O., T. Kawai, K. Takeda, M. Matsumoto, H. Tsut- helper cell type I responses in IL-1 receptor-associated kinase sui, M. Sakagami, K. Nakanishi, and S. Akira. 1998. Targeted (IRAK)-deficient mice. J. Exp. Med. 189:1129–1138. disruption of the MyD88 gene results in loss of IL-1- and IL- 20. Yoshimoto, T., H. Okamura, Y. Tagawa, Y. Iwakura, and K. 18-mediated function. Immunity. 9:143–150. Nakanishi. 1997. lnterleukin 18 together with interleukin 12 6. Gu, Y., K. Kuida, H. Tsutsui, G. Ku, K. Hsiao, M.A. Fieffi- inhibits IgE production by induction of interferon- produc- ing, N. Hayashi, K. Higashino, H. Okainura, K. Nakanishi, tion from activated B cells. Proc. Natl. Acad. Sci. USA. 94: et al. 1997. Activation of interferon- inducing factor medi- 3948–3953. ated by interleukin-1 converting enzyme. Science. 275:206– 21. Yang, J., H. Zhu, T.L. Murphy, W. Ouyang, and K.M. 209. Murphy. 2001. IL-18-stimulated GADD45b required in cy- 7. Stoll, S., H. Jonuleit, E. Schmitt, G. Muller, H. Yarnauchi, tokine-induced, but not TcR-induced IFN- production. M. Kurimoto, J. Knop, and A.H. Enk. 1998. Production of Nat. 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The Journal of Experimental Medicine – Pubmed Central

Published: Aug 6, 2001

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