IL-12-independent antitumor effects. J. Immunol. 160:1742– 1749. 4. Zhang, T., K. Kawakami, M.H. Qureshi, H. Okamura, M. Kurimoto, and A. Saito. 1997. Interleukin-12 (IL-12) and IL-18 synergistically induced the fungicidal activity of mu- rine peritoneal exudate cells against Cryptococcus neoformans through production of interferon by natural killer cells. In- fect. Immunity. 65:3594–3599. 5. Tominaga, K., T. Yoshimoto, K. Torigoe, M. Kurimoto, K. Matsui, T. Hada, H. Okamura, and K. Nakanishi. 2000. IL- 12 synergizes with IL-18 or IL-1 for IFN- production from human T cells. Int. Immunol. 12:151–160. 6. Kohno, K., J. Kataoka, T. Ohtsuki, Y. Suemoto, I. Oka- moto, M. Usui, M. Ikeda, and M. Kurimoto. 1997. IFN- -inducing factor (IGIF) is a costimulatory factor on the ac- tivation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J. Immunol. 158:1541–1550. 7. Robinson, D., K. Shibuya, A. Mui, F. Zonin, E. Murphy, T. Sana, S.B. Hartley, S. Menon, R. Kastelein, F. Basan, and A. O’Garra. 1997. IGIF does not drive Th1 development but synergizes with IL-12 for interferon- production and acti- vates IRAK and NF B. Immunity. 7:571–581. 8. Stoll, S., H. Jonuleit, E. Schmitt, G. Muller, H. Yamauchi, M. Kurimoto, J. Knop, and A.H. Enk. 1998. Production of functional IL-18 by different subtypes of murine and human dendritic cells (DC): DC-derived IL-18 enhances IL-12-depen- dent Th1 development. Eur. J. Immunol. 28:3231–3239. 9. Micallef, M.J., T. Ohtsuki, K. Kohno, F. Tanabe, S. Ushio, M. Namba, T. Tanimoto, K. Torigoe, M. Fujii, M. Ikeda, S. Fukuda, and M. Kurimoto. 1996. Interferon- -inducing fac- tor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon- production. Eur. J. Immunol. 26:1647–1651. 10. Takeda, K., H. Tsutsui, T. Yoshimoto, O. Adachi, N. Yoshida, T. Koshimoto, H. Okamura, K. Nakanishi, and S. Akira. 1998. Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity. 8:383–390 11. Yoshimoto, T., H. Tsutsui, K. Tominaga, K. Hoshino, H. Okamura, S. Akira, W.E. Paul, and K. Nakanishi. 1999. IL- 18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils. Proc. Natl. Acad. Sci. USA. 96:13962–13966. 12. Yoshimoto, T., H. Mizutani, H. Tsutsui, N. Noben-Trauth, K. Yamanaka, M. Tanaka, S. Izumi, H. Okamura, W.E. Paul, and K. Nakanishi. 2000. IL-18 induction of IgE: de- pendence on CD4 T cells, IL-4 and STAT6. Nat. Immunol. 2:132–137. 13. Hoshino, T., H. Yagita, J.R. Ortaldo, R.H. Wiltrout, and H.A. Young. 2000. In vivo administration of IL-18 can in- duce IgE production through Th2 cytokine induction and up-regulation of CD40 ligand (CD154) expression on CD4 T cells. Eur. J. Immunol. 30:1998–2006. 14. Hoshino, T., R.H. Wiltrout, and H.A. Young. 1999. IL-18 is a potent coinducer of IL-13 in NK and T cells: a new po- tential role for IL-18 in modulating the immune response. J. Immunol. 162:5070–5077. 15. Torigoe, K., S. Ushio, T. Okura, S. Kobayashi, M. Taniai, T. Kunikata, T. Murakami, O. Sanou, H. Kojima, M. Fujii, et al. 1997. Purification and characterization of the human in- terleukin-18 receptor. J. Biol. Chem. 272:25737–25742. 16. Born, T.L., E. Thomassen, T.A. Bird, and J.E. Sims. 1998. Cloning of a novel receptor subunit, AcPL, required for in- terleukin-18 signaling. J. Biol. Chem. 273:29445–29450. 17. Parnet, P., K.E. Garka, T.P. Bonnert, S.K. Dower, and J.E. Sims. 1996. IL-1Rrp is a novel receptor-like molecular simi- lar to the type I interleukin-1 receptor and its homologues T1/ST2 and IL-1R AcP. J. Biol. Chem. 271:3967–3970. 18. Thomassen, E., T.A. Bird, B.R. Renshaw, M.K. Kennedy, and J.E. Sims. 1998. Binding of interleukin-18 to the inter- leukin-1 receptor homologous receptor IL-1Rrp1 leads to activation of signaling pathways similar to those used by in- terleukin-1. J. Interferon Cytokine Res. 18:1077–1088. 19. O’Neill, L.A.J., and C.A. Dinarello. 2000. The interleukin-1 receptor/toll-like receptor superfamily: signal transduction during inflammation and host defense. Immunol. Today. 21: 206–209. 20. Debets, R., J.C. Timans, T. Churakowa, S. Zurawski, R.W. Malefyt, K. Moore, J. Abrams, A. O’Garra, J. Bazan, and R.A. Kastelein. 2000. IL-18 receptors, their role in ligand binding and function: anti-IL-1RAcPL antibody, a potent antagonist of IL-18. J. Immunol. 165:4950–4956. 21. Hu-Li, J., H. Huang, J. Ryan, and W.E. Paul. 1997. In dif- ferentiated CD4 T cells, interleukin 4 production is cyto- kine-autonomous, whereas interferon production is cyto- kine-dependent. Proc. Natl. Acad. Sci. USA. 94:3189–3194. 22. Xu, D., W.L. Chan, B.P. Leung, D. Hunter, K. Schulz, R.W. Carter, I.B. McInnes, J.H. Robinson, and F.Y. Liew. 1998. Selective expression and functions of interleukin 18 re- ceptor on T helper (Th) type 1 but not Th2 cells. J. Exp. Med. 188:1485–1492. 23. Yoshimoto, T., K. Takeda, T. Tanaka, K. Ohkusu, S. Kashi- wamura, H. Okamura, S. Akira, and K. Nakanishi. 1998. IL- 12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN- produc- tion. J. Immunol. 161:3400–3407. 24. Tomura, M., S. Maruo, J. Mu, Z.Y. Zhou, H.J. Ahn, T. Hamaoka, H. Okamura, K. Nakanishi, S. Clark, M. Kuri- moto, and H. Fujiwara. 1998. Differential capacities of CD4 , CD8 , and CD4 CD8 T cell subsets to express IL-18 receptor and produce IFN- in response to IL-18. J. Immunol. 160:3759–3765. 25. Chang, J.T., B.M. Segal, K. Nakanishi, H. Okamura, and E.M. Shevach. 2000. The costimulatory effect of IL-18 on the induction of antigen-specific IFN- production by rest- ing T cells is IL-12 dependent and is mediated by up-regula- tion of the IL-12 receptor 2 subunit. Eur. J. Immunol. 30: 1113–1119. 26. Kunikata, T., K. Torigoe, S. Ushio, T. Okura, C. Ushio, H. Yamuchi, M. Ikeda, H. Ikegami, and M. Kurimoto. 1998. Constitutive and induced IL-18 receptor expression by vari- ous peripheral blood cell subsets as determined by anti-hIL- 18R monoclonal antibody. Cell. Immunol. 189:135–143. 27. Nakamura, S., T. Otani, R. Okura, Y. Ijiri, R. Motoda, M. Kurimoto, and K. Orita. 2000. Expression and responsiveness of human interleukin-18 receptor (IL-18R) on hematopoi- etic cell lines. Leukemia. 14:1052–1059. 28. Hoshino, K., H. Tsutsui, T. Kawai, K. Takeda, K. Naka- nishi, Y. Takeda, and S. Akira. 1999. Generation of IL-18 receptor-deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 binding receptor. J. Immunol. 162:5041–5044. 29. Sareneva, T., I. Julkunen, and S. Matikainen. 2000. IFN- and IL-12 induce IL-18 receptor gene expression in human NK and T cells. J. Immunol. 165:1933–1938. 30. Ahn, H.J., S. Maruo, M. Tomura, J. Mu, T. Hanaoka, K. Nakanishi, S. Clark, M. Kurimoto, H. Okamura, and H. 152 Regulation of IL-18 Receptor Expression