Cloning of a Novel Receptor Subunit, AcPL, Required for Interleukin-18 Signaling

We have identified a novel member of the interleukin-1 (IL-1) receptor family, which we have termed AcPL. In transient transfection assays, we were unable to demonstrate a role for AcPL in IL-1-induced activation of NFκB. Interleukin-18 (interferon-γ-inducing factor) is another member of the IL-1 family of cytokines, and it has recently been shown that IL-18 has a weak affinity for IL-1R-rp1. We examined whether AcPL might function alone or in concert with IL-1R-rp1 to mediate IL-18 signaling. We found that both IL-1R-rp1 and AcPL expression were required for induction of NFκB activity and for activation of c-Jun N-terminal kinase in response to IL-18. Furthermore, a dominant negative version of AcPL specifically inhibited IL-18 signaling. In vitroimmunoprecipitation assays demonstrated that AcPL alone was unable to bind IL-18 with any appreciable affinity. We propose that although IL-1R-rp1 binds the cytokine, IL-1R-rp1 and AcPL proteins are both required for IL-18 signaling, analogous to the requirement for both IL-1R and IL-1RAcP in IL-1-mediated responses. We have identified a novel member of the interleukin-1 (IL-1) receptor family, which we have termed AcPL. In transient transfection assays, we were unable to demonstrate a role for AcPL in IL-1-induced activation of NFκB. Interleukin-18 (interferon-γ-inducing factor) is another member of the IL-1 family of cytokines, and it has recently been shown that IL-18 has a weak affinity for IL-1R-rp1. We examined whether AcPL might function alone or in concert with IL-1R-rp1 to mediate IL-18 signaling. We found that both IL-1R-rp1 and AcPL expression were required for induction of NFκB activity and for activation of c-Jun N-terminal kinase in response to IL-18. Furthermore, a dominant negative version of AcPL specifically inhibited IL-18 signaling. In vitroimmunoprecipitation assays demonstrated that AcPL alone was unable to bind IL-18 with any appreciable affinity. We propose that although IL-1R-rp1 binds the cytokine, IL-1R-rp1 and AcPL proteins are both required for IL-18 signaling, analogous to the requirement for both IL-1R and IL-1RAcP in IL-1-mediated responses. interleukin murine IL c-Jun N-terminal kinase IL-1 receptor IL-1R-activated kinase polymerase chain reaction natural killer. Interleukin-18 (interferon-γ-inducing factor/IL-1γ)1 has a wide range of immunoregulatory functions, including stimulation of interferon-γ production, induction of natural killer (NK) cell cytotoxicity, potentiation of Th1 differentiation, and inhibition of osteoclast proliferation (1Ushio S. Namba M. Okura T. Hattori K. Nukada Y. Akita K. Tanabe F. Konishi K. Fukuda S. Ikeda M. Okamura H. Kurimoto M. J. Immunol. 1996; 156: 4274-4279PubMed Google Scholar, 2Okamura H. Tsutsui H.H. Komatsu T. Yutsudo M. Hakura A. Tanimoto T. Torigoe K. Okura T. Nukada Y. Hattori K. Akita K. Namba M. Tanabe F. Konishi K. Fukuda S. Kurimoto M. Nature. 1995; 378: 88-91Crossref PubMed Scopus (2384) Google Scholar, 3Robinson D. Shibuya K. Mui A. Zonin F. Murphy E. Sana T. Hartley S.B. Menon S. Kastelein R. Bazan F. O'Garra A. Immunity. 1997; 7: 571-581Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar, 4Udagawa N. Horwood N.J. Elliott J. Mackay A. Owens J. Okamura H. Kurimoto M. Chambers T.J. Martin T.J. Gillespie M.T. J. Exp. Med. 1997; 185: 1005-1012Crossref PubMed Scopus (358) Google Scholar). IL-18-deficient mice display a phenotype largely similar to that of IL-12 knockout mice, exhibiting reductions in interferon-γ production, NK cell activity, and Th1 response. Interestingly, IL-18 and IL-12 double-deficient mice displayed an even greater perturbation of NK cell activity and Th1 cell response than that seen in either of the single knockouts (5Takeda K. Tsutsui H. Yoshimoto T. Adachi O. Yoshida N. Kishimoto T. Okamura H. Nakanishi K. Akira S. Immunity. 1998; 8: 383-390Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar). In terms of its biological effects, IL-18 is thus closely related to and acts synergistically with IL-12. Analysis of amino acid sequence and structural motifs, however, classify IL-18 as a member of the IL-1 family of cytokines (6Bazan J.F. Timans J.C. Kastelein R.A. Nature. 1996; 379: 591Crossref PubMed Scopus (260) Google Scholar). In agreement with this classification, IL-18 has been shown to be processed by the interleukin-1β-converting enzyme, which also processes IL-1β (7Gu Y. Kuida K. Tsutsui H. Ku G. Hsiao K. Fleming M.A. Hayashi N. Higashino K. Okamura H. Nakanishi K. Kurimoto-M M. Tanimoto T. Flavell R.A. Sato V. Harding M.W. Livingston D.J. Su M.S. Science. 1997; 275: 206-209Crossref PubMed Scopus (1010) Google Scholar, 8Ghayur T. Banerjee S. Hugunin M. Butler D. Herzog L. Carter A. Quintal L. Sekut L. Talanian R. Paskind M. Wong W. Kamen R. Tracey D. Allen H. Nature. 1997; 386: 619-623Crossref PubMed Scopus (1032) Google Scholar). Furthermore, IL-18 signaling was shown to be mediated by a member of the IL-1R family, IL-1R-rp1 (9Torigoe K. Ushio S. Okura T. Kobayashi S. Taniai M. Kunikata T. Murakami T. Sanou O. Kojima H. Fujii M. Ohta T. Ikeda M. Ikegami H. Kurimoto M. J. Biol. Chem. 1997; 272: 25737-25742Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar). 2Thomassen, E., Bird, T. A., Renshaw, B. R., Kennedy, M. K., and Sims, J. E. (1998) J. Interferon Cytokine Res., in press.2Thomassen, E., Bird, T. A., Renshaw, B. R., Kennedy, M. K., and Sims, J. E. (1998) J. Interferon Cytokine Res., in press. It was also recently shown that IL-18 can activate IRAK, recruit TRAF6, and induce translocation of NFκB (3Robinson D. Shibuya K. Mui A. Zonin F. Murphy E. Sana T. Hartley S.B. Menon S. Kastelein R. Bazan F. O'Garra A. Immunity. 1997; 7: 571-581Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar, 11Kojima H. Takeuchi M. Ohta T. Nishida Y. Arai N. Ikeda M. Ikegami H. Kurimoto M. Biochem. Biophys. Res. Commun. 1998; 244: 183-186Crossref PubMed Scopus (123) Google Scholar),2 which are all involved in IL-1 signaling (12Cao Z. Xiong J. Takeuchi M. Kurama T. Goeddel D.V. Nature. 1996; 383: 443-446Crossref PubMed Scopus (1113) Google Scholar, 13Cao Z. Henzel W.J. Gao X. Science. 1996; 271: 1128-1131Crossref PubMed Scopus (766) Google Scholar, 14Dinarello C.A. Blood. 1996; 87: 2095-2147Crossref PubMed Google Scholar).There are several members of the IL-1R family, many of which are currently orphan receptors. The type I and type II IL-1 receptors bind IL-1-α, IL-1β, and IL-1ra. The type II IL-1 receptor lacks a cytoplasmic domain, thus rendering it a decoy receptor that has been shown to down-modulate IL-1 responses (15Colotta F. Dower S.K. Sims J.E. Mantovani A. Immunol. Today. 1994; 15: 562-566Abstract Full Text PDF PubMed Scopus (328) Google Scholar). Signaling by IL-1 is dependent not only on expression of IL-1R type I but also on expression of the IL-1RAcP (16Greenfeder S.A. Nunes P. Kwee L. Labow M. Chizzonite R.A. Ju G. J. Biol. Chem. 1995; 270: 13757-13765Abstract Full Text Full Text PDF PubMed Scopus (557) Google Scholar, 17Wesche H. Neumann D. Resch K. Martin M.U. FEBS Lett. 1996; 391: 104-108Crossref PubMed Scopus (47) Google Scholar). Although IL-1RAcP does not bind IL-1 directly, it does increase the affinity of IL-1R for cytokine binding. Furthermore, the IL-1RAcP in the active receptor complex is responsible for recruitment of the IL-1R-activated kinase (IRAK) (18Huang J. Gao X. Li S. Cao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 12829-12832Crossref PubMed Scopus (194) Google Scholar). Two other members of the family, IL-1R-rp1 and T1/ST2, are unable to bind IL-1 but do respond to IL-1 stimulation in reporter assays when expressed in chimeric form with IL-1R extracellular and transmembrane regions fused to the cytoplasmic domains of these receptors (19Tominaga S. FEBS Lett. 1989; 318: 83-87Google Scholar, 20Klemenz R. Hoffmann S. Werenskiold A.K. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 5708-5712Crossref PubMed Scopus (150) Google Scholar, 21Mitcham J. Parnet P. Bonnert T.P. Garka K.E. Gerhart M.J. Slack J.L. Gayle M.A. Dower S.K. Sims J.E. J. Biol. Chem. 1996; 271: 5777-5783Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 22Parnet P. Garka K.E. Bonnert T.P. Dower S.K. Sims J.E. J. Biol. Chem. 1996; 271: 3967-3970Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). IL-1R-rp2 is another orphan family member, incapable of IL-1 binding (23Lovenberg T.W. Crowe P.D. Liu C. Chalmers D.T. Liu X.J. Liaw C. Clevenger W. Oltersdorf T. De Souza E.B. Maki R.A. J. Neuroimmunol. 1996; 70: 113-122Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Interestingly, IL-1R type I, IL-1R type II, IL-1R-rp1, and T1/ST2 all map to the same region of chromosome 2, indicating that perhaps these receptors arise from a common ancestral gene (22Parnet P. Garka K.E. Bonnert T.P. Dower S.K. Sims J.E. J. Biol. Chem. 1996; 271: 3967-3970Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 24Sims J.E. Painter S.L. Gow I.R. Cytokine. 1995; 7: 483-490Crossref PubMed Scopus Google of the expressed sequence a sequence with to that this might be a member of the IL-1R family, we the to a to Analysis of the that this is a novel member of the IL-1R family, with the IL-1R domains on its to IL-1RAcP we have termed this AcPL AcPL was unable to mediate signaling by IL-1 but a role in signaling the related cytokine IL-18. Although AcPL not bind IL-18 in of IL-1R-rp1 and AcPL was required for IL-18 in terms of NFκB induction and Furthermore, a version of AcPL the cytoplasmic inhibited IL-18 signaling. We propose that both the identified IL-1R-rp1 and the novel AcPL are involved in signaling by have a novel member of the IL-1R family which we is of cell signaling in response to IL-18. AcPL is of the IL-18 receptor complex is not that IL-18 is related to IL-1 and be to a receptor with a related to IL-1R and IL-18 has been shown to bind another member of this receptor family, IL-1R-rp1 (9Torigoe K. Ushio S. Okura T. Kobayashi S. Taniai M. Kunikata T. Murakami T. Sanou O. Kojima H. Fujii M. Ohta T. Ikeda M. Ikegami H. Kurimoto M. J. Biol. Chem. 1997; 272: 25737-25742Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar). that the only other member of this family receptor for signaling, it be that receptor be required for IL-18 signaling. In of we have that or with IL-1R-rp1 alone were not to IL-18 in terms of NFκB that another was required to form an active IL-18 receptor The in this that the other required for IL-18 is have shown that AcPL is expressed in and as as cell and NK was not in or expression closely that of IL-1R-rp1 (22Parnet P. Garka K.E. Bonnert T.P. Dower S.K. Sims J.E. J. Biol. Chem. 1996; 271: 3967-3970Abstract Full Text Full Text PDF PubMed Scopus (217) Google although as and IL-1R-rp1 but not AcPL. The of AcPL expression also with the cell that have been to be to IL-18. have shown that IL-18 interferon-γ from and NK of IL-18 have also been in and K. Kurimoto M. Immunol. 1998; 86: PubMed Scopus Google we have also that IL-1R-rp1 and AcPL are of activity in response to IL-18 not The is by IL-1 N. Y. K. J. Biol. Chem. Full Text PDF PubMed Google but it has not been shown to be by IL-18 to It was recently demonstrated that was in IL-18 and NK but this induction was dependent on the induction of G. Y. Su M.S. C.A. J. 1998; PubMed Scopus Google Scholar). that in to activation of an AcPL and IL-1R-rp1 are to mediate IL-18 signaling to a complex AcPL alone was unable to bind we propose that it is analogous to the which is required for IL-1 signaling but does not bind IL-1 of this it be of to whether IL-1R-rp1 and AcPL display a affinity IL-18 than do IL-1R-rp1 We have to this by binding on either or to IL-1R-rp1, or both receptors We have been unable to demonstrate binding of in these assays, that perhaps the has with cytokine binding. We are currently to this of IL-18 signaling to be related to involved in IL-1 signaling. and have recently shown that stimulation of or with IL-18 in the recruitment of and to IL-1R-rp1 H. Takeuchi M. Ohta T. Nishida Y. Arai N. Ikeda M. Ikegami H. Kurimoto M. Biochem. Biophys. Res. Commun. 1998; 244: 183-186Crossref PubMed Scopus (123) Google In IL-1 signaling, it is IL-1RAcP that is responsible for recruitment of to the active receptor IL-1R M. J. P. Science. 1997; PubMed Scopus Google Scholar, J. Gao X. Li S. Cao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 12829-12832Crossref PubMed Scopus (194) Google Scholar). It be to whether AcPL is to with these signaling that IL-1R-rp1 with do not the that IL-1R-rp1 is of a IL-18 binding than involved in binding these Interleukin-18 (interferon-γ-inducing factor/IL-1γ)1 has a wide range of immunoregulatory functions, including stimulation of interferon-γ production, induction of natural killer (NK) cell cytotoxicity, potentiation of Th1 differentiation, and inhibition of osteoclast proliferation (1Ushio S. Namba M. Okura T. Hattori K. Nukada Y. Akita K. Tanabe F. Konishi K. Fukuda S. Ikeda M. Okamura H. Kurimoto M. J. Immunol. 1996; 156: 4274-4279PubMed Google Scholar, 2Okamura H. Tsutsui H.H. Komatsu T. Yutsudo M. Hakura A. Tanimoto T. Torigoe K. Okura T. Nukada Y. Hattori K. Akita K. Namba M. Tanabe F. Konishi K. Fukuda S. Kurimoto M. Nature. 1995; 378: 88-91Crossref PubMed Scopus (2384) Google Scholar, 3Robinson D. Shibuya K. Mui A. Zonin F. Murphy E. Sana T. Hartley S.B. Menon S. Kastelein R. Bazan F. O'Garra A. Immunity. 1997; 7: 571-581Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar, 4Udagawa N. Horwood N.J. Elliott J. Mackay A. Owens J. Okamura H. Kurimoto M. Chambers T.J. Martin T.J. Gillespie M.T. J. Exp. Med. 1997; 185: 1005-1012Crossref PubMed Scopus (358) Google Scholar). IL-18-deficient mice display a phenotype largely similar to that of IL-12 knockout mice, exhibiting reductions in interferon-γ production, NK cell activity, and Th1 response. Interestingly, IL-18 and IL-12 double-deficient mice displayed an even greater perturbation of NK cell activity and Th1 cell response than that seen in either of the single knockouts (5Takeda K. Tsutsui H. Yoshimoto T. Adachi O. Yoshida N. Kishimoto T. Okamura H. Nakanishi K. Akira S. Immunity. 1998; 8: 383-390Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar). In terms of its biological effects, IL-18 is thus closely related to and acts synergistically with IL-12. Analysis of amino acid sequence and structural motifs, however, classify IL-18 as a member of the IL-1 family of cytokines (6Bazan J.F. Timans J.C. Kastelein R.A. Nature. 1996; 379: 591Crossref PubMed Scopus (260) Google Scholar). In agreement with this classification, IL-18 has been shown to be processed by the interleukin-1β-converting enzyme, which also processes IL-1β (7Gu Y. Kuida K. Tsutsui H. Ku G. Hsiao K. Fleming M.A. Hayashi N. Higashino K. Okamura H. Nakanishi K. Kurimoto-M M. Tanimoto T. Flavell R.A. Sato V. Harding M.W. Livingston D.J. Su M.S. Science. 1997; 275: 206-209Crossref PubMed Scopus (1010) Google Scholar, 8Ghayur T. Banerjee S. Hugunin M. Butler D. Herzog L. Carter A. Quintal L. Sekut L. Talanian R. Paskind M. Wong W. Kamen R. Tracey D. Allen H. Nature. 1997; 386: 619-623Crossref PubMed Scopus (1032) Google Scholar). Furthermore, IL-18 signaling was shown to be mediated by a member of the IL-1R family, IL-1R-rp1 (9Torigoe K. Ushio S. Okura T. Kobayashi S. Taniai M. Kunikata T. Murakami T. Sanou O. Kojima H. Fujii M. Ohta T. Ikeda M. Ikegami H. Kurimoto M. J. Biol. Chem. 1997; 272: 25737-25742Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar). 2Thomassen, E., Bird, T. A., Renshaw, B. R., Kennedy, M. K., and Sims, J. E. (1998) J. Interferon Cytokine Res., in press.2Thomassen, E., Bird, T. A., Renshaw, B. R., Kennedy, M. K., and Sims, J. E. (1998) J. Interferon Cytokine Res., in press. It was also recently shown that IL-18 can activate IRAK, recruit TRAF6, and induce translocation of NFκB (3Robinson D. Shibuya K. Mui A. Zonin F. Murphy E. Sana T. Hartley S.B. Menon S. Kastelein R. Bazan F. O'Garra A. Immunity. 1997; 7: 571-581Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar, 11Kojima H. Takeuchi M. Ohta T. Nishida Y. Arai N. Ikeda M. Ikegami H. Kurimoto M. Biochem. Biophys. Res. Commun. 1998; 244: 183-186Crossref PubMed Scopus (123) Google Scholar),2 which are all involved in IL-1 signaling (12Cao Z. Xiong J. Takeuchi M. Kurama T. Goeddel D.V. Nature. 1996; 383: 443-446Crossref PubMed Scopus (1113) Google Scholar, 13Cao Z. Henzel W.J. Gao X. Science. 1996; 271: 1128-1131Crossref PubMed Scopus (766) Google Scholar, 14Dinarello C.A. Blood. 1996; 87: 2095-2147Crossref PubMed Google Scholar). are several members of the IL-1R family, many of which are currently orphan receptors. The type I and type II IL-1 receptors bind IL-1-α, IL-1β, and IL-1ra. The type II IL-1 receptor lacks a cytoplasmic domain, thus rendering it a decoy receptor that has been shown to down-modulate IL-1 responses (15Colotta F. Dower S.K. Sims J.E. Mantovani A. Immunol. Today. 1994; 15: 562-566Abstract Full Text PDF PubMed Scopus (328) Google Scholar). Signaling by IL-1 is dependent not only on expression of IL-1R type I but also on expression of the IL-1RAcP (16Greenfeder S.A. Nunes P. Kwee L. Labow M. Chizzonite R.A. Ju G. J. Biol. Chem. 1995; 270: 13757-13765Abstract Full Text Full Text PDF PubMed Scopus (557) Google Scholar, 17Wesche H. Neumann D. Resch K. Martin M.U. FEBS Lett. 1996; 391: 104-108Crossref PubMed Scopus (47) Google Scholar). Although IL-1RAcP does not bind IL-1 directly, it does increase the affinity of IL-1R for cytokine binding. Furthermore, the IL-1RAcP in the active receptor complex is responsible for recruitment of the IL-1R-activated kinase (IRAK) (18Huang J. Gao X. Li S. Cao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 12829-12832Crossref PubMed Scopus (194) Google Scholar). Two other members of the family, IL-1R-rp1 and T1/ST2, are unable to bind IL-1 but do respond to IL-1 stimulation in reporter assays when expressed in chimeric form with IL-1R extracellular and transmembrane regions fused to the cytoplasmic domains of these receptors (19Tominaga S. FEBS Lett. 1989; 318: 83-87Google Scholar, 20Klemenz R. Hoffmann S. Werenskiold A.K. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 5708-5712Crossref PubMed Scopus (150) Google Scholar, 21Mitcham J. Parnet P. Bonnert T.P. Garka K.E. Gerhart M.J. Slack J.L. Gayle M.A. Dower S.K. Sims J.E. J. Biol. Chem. 1996; 271: 5777-5783Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 22Parnet P. Garka K.E. Bonnert T.P. Dower S.K. Sims J.E. J. Biol. Chem. 1996; 271: 3967-3970Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). IL-1R-rp2 is another orphan family member, incapable of IL-1 binding (23Lovenberg T.W. Crowe P.D. Liu C. Chalmers D.T. Liu X.J. Liaw C. Clevenger W. Oltersdorf T. De Souza E.B. Maki R.A. J. Neuroimmunol. 1996; 70: 113-122Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Interestingly, IL-1R type I, IL-1R type II, IL-1R-rp1, and T1/ST2 all map to the same region of chromosome 2, indicating that perhaps these receptors arise from a common ancestral gene (22Parnet P. Garka K.E. Bonnert T.P. Dower S.K. Sims J.E. J. Biol. Chem. 1996; 271: 3967-3970Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 24Sims J.E. Painter S.L. Gow I.R. Cytokine. 1995; 7: 483-490Crossref PubMed Scopus Google Scholar). of the expressed sequence a sequence with to that this might be a member of the IL-1R family, we the to a to Analysis of the that this is a novel member of the IL-1R family, with the IL-1R domains on its to IL-1RAcP we have termed this AcPL AcPL was unable to mediate signaling by IL-1 but a role in signaling the related cytokine IL-18. Although AcPL not bind IL-18 in of IL-1R-rp1 and AcPL was required for IL-18 in terms of NFκB induction and Furthermore, a version of AcPL the cytoplasmic inhibited IL-18 signaling. We propose that both the identified IL-1R-rp1 and the novel AcPL are involved in signaling by IL-18. have a novel member of the IL-1R family which we is of cell signaling in response to IL-18. AcPL is of the IL-18 receptor complex is not that IL-18 is related to IL-1 and be to a receptor with a related to IL-1R and IL-18 has been shown to bind another member of this receptor family, IL-1R-rp1 (9Torigoe K. Ushio S. Okura T. Kobayashi S. Taniai M. Kunikata T. Murakami T. Sanou O. Kojima H. Fujii M. Ohta T. Ikeda M. Ikegami H. Kurimoto M. J. Biol. Chem. 1997; 272: 25737-25742Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar). that the only other member of this family receptor for signaling, it be that receptor be required for IL-18 signaling. In of we have that or with IL-1R-rp1 alone were not to IL-18 in terms of NFκB that another was required to form an active IL-18 receptor The in this that the other required for IL-18 is have shown that AcPL is expressed in and as as cell and NK was not in or expression closely that of IL-1R-rp1 (22Parnet P. Garka K.E. Bonnert T.P. Dower S.K. Sims J.E. J. Biol. Chem. 1996; 271: 3967-3970Abstract Full Text Full Text PDF PubMed Scopus (217) Google although as and IL-1R-rp1 but not AcPL. The of AcPL expression also with the cell that have been to be to IL-18. have shown that IL-18 interferon-γ from and NK of IL-18 have also been in and K. Kurimoto M. Immunol. 1998; 86: PubMed Scopus Google we have also that IL-1R-rp1 and AcPL are of activity in response to IL-18 not The is by IL-1 N. Y. K. J. Biol. Chem. Full Text PDF PubMed Google but it has not been shown to be by IL-18 to It was recently demonstrated that was in IL-18 and NK but this induction was dependent on the induction of G. Y. Su M.S. C.A. J. 1998; PubMed Scopus Google Scholar). that in to activation of an AcPL and IL-1R-rp1 are to mediate IL-18 signaling to a complex AcPL alone was unable to bind we propose that it is analogous to the which is required for IL-1 signaling but does not bind IL-1 of this it be of to whether IL-1R-rp1 and AcPL display a affinity IL-18 than do IL-1R-rp1 We have to this by binding on either or to IL-1R-rp1, or both receptors We have been unable to demonstrate binding of in these assays, that perhaps the has with cytokine binding. We are currently to this of IL-18 signaling to be related to involved in IL-1 signaling. and have recently shown that stimulation of or with IL-18 in the recruitment of and to IL-1R-rp1 H. Takeuchi M. Ohta T. Nishida Y. Arai N. Ikeda M. Ikegami H. Kurimoto M. Biochem. Biophys. Res. Commun. 1998; 244: 183-186Crossref PubMed Scopus (123) Google In IL-1 signaling, it is IL-1RAcP that is responsible for recruitment of to the active receptor IL-1R M. J. P. Science. 1997; PubMed Scopus Google Scholar, J. Gao X. Li S. Cao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 12829-12832Crossref PubMed Scopus (194) Google Scholar). It be to whether AcPL is to with these signaling that IL-1R-rp1 with do not the that IL-1R-rp1 is of a IL-18 binding than involved in binding these We have a novel member of the IL-1R family which we is of cell signaling in response to IL-18. AcPL is of the IL-18 receptor complex is not that IL-18 is related to IL-1 and be to a receptor with a related to IL-1R and IL-18 has been shown to bind another member of this receptor family, IL-1R-rp1 (9Torigoe K. Ushio S. Okura T. Kobayashi S. Taniai M. Kunikata T. Murakami T. Sanou O. Kojima H. Fujii M. Ohta T. Ikeda M. Ikegami H. Kurimoto M. J. Biol. Chem. 1997; 272: 25737-25742Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar). that the only other member of this family receptor for signaling, it be that receptor be required for IL-18 signaling. In of we have that or with IL-1R-rp1 alone were not to IL-18 in terms of NFκB that another was required to form an active IL-18 receptor The in this that the other required for IL-18 is AcPL. We have shown that AcPL is expressed in and as as cell and NK was not in or expression closely that of IL-1R-rp1 (22Parnet P. Garka K.E. Bonnert T.P. Dower S.K. Sims J.E. J. Biol. Chem. 1996; 271: 3967-3970Abstract Full Text Full Text PDF PubMed Scopus (217) Google although as and IL-1R-rp1 but not AcPL. The of AcPL expression also with the cell that have been to be to IL-18. have shown that IL-18 interferon-γ from and NK of IL-18 have also been in and K. Kurimoto M. Immunol. 1998; 86: PubMed Scopus Google Scholar). Interestingly, we have also that IL-1R-rp1 and AcPL are of activity in response to IL-18 not The is by IL-1 N. Y. K. J. Biol. Chem. Full Text PDF PubMed Google but it has not been shown to be by IL-18 to It was recently demonstrated that was in IL-18 and NK but this induction was dependent on the induction of G. Y. Su M.S. C.A. J. 1998; PubMed Scopus Google Scholar). that in to activation of an AcPL and IL-1R-rp1 are to mediate IL-18 signaling to a complex AcPL alone was unable to bind we propose that it is analogous to the which is required for IL-1 signaling but does not bind IL-1 of this it be of to whether IL-1R-rp1 and AcPL display a affinity IL-18 than do IL-1R-rp1 We have to this by binding on either or to IL-1R-rp1, or both receptors We have been unable to demonstrate binding of in these assays, that perhaps the has with cytokine binding. We are currently to this The of IL-18 signaling to be related to involved in IL-1 signaling. and have recently shown that stimulation of or with IL-18 in the recruitment of and to IL-1R-rp1 H. Takeuchi M. Ohta T. Nishida Y. Arai N. Ikeda M. Ikegami H. Kurimoto M. Biochem. Biophys. Res. Commun. 1998; 244: 183-186Crossref PubMed Scopus (123) Google In IL-1 signaling, it is IL-1RAcP that is responsible for recruitment of to the active receptor IL-1R M. J. P. Science. 1997; PubMed Scopus Google Scholar, J. Gao X. Li S. Cao Z. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 12829-12832Crossref PubMed Scopus (194) Google Scholar). It be to whether AcPL is to with these signaling that IL-1R-rp1 with do not the that IL-1R-rp1 is of a IL-18 binding than involved in binding these We for for of the and for the expression We also for the and and for the NK We also and for of