T1/ST2 Signaling Establishes It as a Member of an Expanding Interleukin-1 Receptor Family

Through data base searches, we have discovered new proteins that share homology with the signaling domain of the type I interleukin-1 receptor (IL-1RI): human “randomly sequenced cDNA 786” (rsc786), murine MyD88, and two partial Drosophila open reading frames, MstProx and STSDm2245. Comparisons between these new proteins and known IL-1RI homologous proteins such as Toll, 18-Wheeler, and T1/ST2 revealed six clusters of amino acid similarity. We tested the hypothesis that sequence similarity between the signaling domain of IL-1RI and the three mammalian family members might indicate functional similarity. Chimeric IL-1RI receptors expressing the putative signaling domains of T1/ST2, MyD88, and rsc786 were assayed by three separate IL-1 responsive assays, NF-κB, phosphorylation of an epidermal growth factor receptor peptide, and an interleukin 8 promoter-controlled reporter construct, for their ability to transduce an IL-1-stimulated signal. All three assays were positive in response to the T1/ST2 chimera, while the MyD88 and rsc786 chimeras failed to respond. These data indicate that the sequence homology between IL-1RI and T1/ST2 indicates a functional homology as well. Through data base searches, we have discovered new proteins that share homology with the signaling domain of the type I interleukin-1 receptor (IL-1RI): human “randomly sequenced cDNA 786” (rsc786), murine MyD88, and two partial Drosophila open reading frames, MstProx and STSDm2245. Comparisons between these new proteins and known IL-1RI homologous proteins such as Toll, 18-Wheeler, and T1/ST2 revealed six clusters of amino acid similarity. We tested the hypothesis that sequence similarity between the signaling domain of IL-1RI and the three mammalian family members might indicate functional similarity. Chimeric IL-1RI receptors expressing the putative signaling domains of T1/ST2, MyD88, and rsc786 were assayed by three separate IL-1 responsive assays, NF-κB, phosphorylation of an epidermal growth factor receptor peptide, and an interleukin 8 promoter-controlled reporter construct, for their ability to transduce an IL-1-stimulated signal. All three assays were positive in response to the T1/ST2 chimera, while the MyD88 and rsc786 chimeras failed to respond. These data indicate that the sequence homology between IL-1RI and T1/ST2 indicates a functional homology as well. INTRODUCTIONInterleukin-1 (IL-1) ( 1The abbreviations used are: IL-1interleukin 1IL-1RItype I interleukin 1 receptorrsc786randomly sequenced cDNA 786IL-1R AcPinterleukin 1 receptor accessory proteinORFopen reading frameEGFRepidermal growth factor receptor.) is an important component of the mammalian inflammatory response and is produced by many different types of cells following tissue injury and infection (1.Dinarello C.A. Blood. 1991; 77: 1627-1652Crossref PubMed Google Scholar). The receptors and ligands of the IL-1 pathway have been well defined (for review see (2.Dinarello C.A. FASEB J. 1994; 8: 1314-1325Crossref PubMed Google Scholar) and (3.Sims J.E. Bird T.A. Giri J.G. Dower S.K. Interleukin- 1 signal transduction: Advances in Cell and Molecular Biology of Membranes and Organelles. 3. JAI Press Inc., Greenwich, CT1994: 197-222Google Scholar)). Three ligands, IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1ra) bind three forms of IL-1 receptor, an 80-kDa type I IL-1 receptor (IL-1RI)(4.Sims J.E. March C.J. Cosman D. Widmer M.B. MacDonald H.R. McMahan C.J. Grubin C.E. Wignall J.M. Jackson J.L. Call S.M. Friend D. Alpert A.R. Gillis S. Urdal D.L. Dower S.K. Science. 1988; 241: 585-589Crossref PubMed Scopus (703) Google Scholar), a 68-kDa type II IL-1 receptor (IL-1RII)(5.McMahan C.J. Mosley B. Cosman D. Lupton S.D. Brunton L.L. Grubin C.E. Wignall J.M. Jenkins N.A. Brannan C.I. Copeland N.G. Huebner K. Croce C. Cannizzaro L.A. Benjamin D. Dower S.K. Spriggs M.K. Sims J.E. EMBO J. 1991; 10: 2821-2832Crossref PubMed Scopus (616) Google Scholar), and a soluble form of the type II IL-1R (sIL-1RII)(6.Colotta F. Re F. Muzio M. Bertini R. Polentarutti N. Sironi M. Giri J.G. Dower S.K. Sims J.E. Mantovani A. Science. 1993; 261: 472-475Crossref PubMed Scopus (864) Google Scholar). The cytoplasmic or signaling domain of the human IL-1RI consists of 213 amino acids and has been shown to be essential for cellular responses to IL-1 in vivo(7.Curtis B.M. Gallis B. Overell R.W. McMahan C.J. De Roos P. Ireland R. Eisenman J. Dower S.K. Sims J.E. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 3045-3049Crossref PubMed Scopus (89) Google Scholar), while the type II receptor has a cytoplasmic domain of only 29 residues and does not appear to transduce a signal(8.Sims J.E. Gayle M.A. Slack J.L. Alderson M.R. Bird T.A. Giri J.G. Colotta F. Re F. Mantovani A. Shanebeck K. Grabstein K.H. Dower S.K. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 6155-6159Crossref PubMed Scopus (544) Google Scholar). The interactions between the ligands and receptors play an essential role in the stimulation and regulation of the IL-1-mediated host response to injury and infection. Cells expressing IL-1RI and treated with IL-1α or IL-1β respond in several specific ways, including stimulating nuclear localization of the rel-related transcription factor, NF-κB (for review, see (9.Thanos D. Maniatis T. Cell. 1995; 80: 529-532Abstract Full Text PDF PubMed Scopus (1216) Google Scholar)), activation of protein kinases of the mitogen-activated protein kinase superfamily that phosphorylate residue threonine 669 (Thr-669) of the epidermal growth factor receptor (EGFR)(10.Guy G.R. Cao X. Chua S.P. Tan Y.H. J. Biol. Chem. 1992; 267: 1846-1852Abstract Full Text PDF PubMed Google Scholar, 11.Bird T.A. Sleath P.R. deRoos P.C. Dower S.K. Virca G.D. J. Biol. Chem. 1991; 266: 22661-22670Abstract Full Text PDF PubMed Google Scholar, 12.Bird T.A. Kyriakis J.M. Tyshler L. Gayle M. Milne A. Virca G.D. J. Biol. Chem. 1994; 269: 31836-31844Abstract Full Text PDF PubMed Google Scholar), and stimulation of transcription of the IL-8 gene(13.Mukaida N. Mahe Y. Matsushima K. J. Biol. Chem. 1990; 265: 21128-21133Abstract Full Text PDF PubMed Google Scholar).We explore the possibility of of in IL-1 the of proteins and their role in IL-1 and signal IL-1RI cytoplasmic domain homology to the cytoplasmic of the Drosophila protein C. Cell. 1988; Full Text PDF PubMed Scopus Google Scholar). is a protein in of in the Drosophila and have that the cytoplasmic domain of IL-1RI in residues between IL-1RI and essential for of IL-1-stimulated B.M. Gallis B. Overell R.W. McMahan C.J. De Roos P. Ireland R. Eisenman J. Dower S.K. Sims J.E. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 3045-3049Crossref PubMed Scopus (89) Google Scholar, A. J.L. M. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar, K. L. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google to Toll, have been as homologous to the cytoplasmic domain of the type I IL-1 These R. S. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: PubMed Scopus Google Scholar, S. 1989; PubMed Scopus Google Scholar, K. T. T. T. S. 1993; PubMed Scopus Google Scholar), the IL-1 receptor accessory protein P. L. M. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), the S. S.P. D. R. C. B. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar), and the Drosophila protein S. D. M. P. J. 1994; Google Scholar). T1/ST2 is a protein that has been as a response in The IL-1R is a protein and a that the of IL-1β to IL-1RI a protein the receptor T1/ST2 and IL-1R share homology to IL-1RI and The a protein with an domain that has homology to the cytoplasmic domain of and the to by of a that a inflammatory response to that by IL-1 in mammalian has not been is to a for we data base to with sequence homology to IL-1RI and We the sequence similarity in these proteins and in the T1/ST2 protein indicates a similarity in signaling as receptor and receptor were a of B. March C.J. S.D. T. Friend D. Alpert A. D. Jackson J. Wignall J.M. C. Gallis B. Sims J.E. Urdal D. Widmer M.B. Cosman D. Cell. 1989; Full Text PDF PubMed Scopus Google Scholar). the we a the murine IL-1RI of the a amino acid sequence to is the human IL-1RI sequence The signaling domains of T1/ST2, MyD88, and rsc786 were by and and the the murine IL-1RI for the a in the murine All were by were by the by as D. A. L. March C. Dower S. Gillis S. Urdal D. PubMed Scopus Google Scholar) of the chimeras were by cells were with a to the murine IL-1RI and with were with and and data as All rsc786 receptors tested as well as or to three the murine IL-1RI cells in not 1 in a new of cells were with for for NF-κB the kinase stimulation with for the IL-8 activation cells were 1 with 1 for human IL-1R type to stimulation a were as J. Sims J.E. M.A. Dower S.K. K. J. Biol. Chem. 1991; 266: Full Text PDF PubMed Google Scholar) and IL-1 the the by phosphorylation with were with for and were by in T.A. Sims J.E. B. Dower S.K. 1992; PubMed Scopus Google Scholar) were and of to of a and of were with in of the for the were by of were by and of were with and were by as the of kinase in cells to cells treated with or IL-1 cells cells well in a tissue were with of the receptor and of the reporter 1 the and the cells were with the a and with 1 IL-1α or cells were with and with of for Cells were for with of 1 of the D. A. L. March C. Dower S. Gillis S. Urdal D. PubMed Scopus Google Scholar) with Cells were with and with 1 of of for were with and with were by the of 1 of and were as two of the IL-1RI homologous of Drosophila as and with sequence were as and The and used to of a Drosophila were to The with the sequenced the of the MstProx were data base we have discovered two new mammalian members of the family in a murine B. 1990; Google Scholar), and a human rsc786 sequenced N. N. Y. S. 1994; PubMed Scopus Google Scholar) and MyD88 and as a response of a to that while the receptor in were in two the sequence similarity between MyD88 and D. 1994; PubMed Scopus Google Scholar, M. 1994; PubMed Scopus Google Scholar)). The MyD88 a protein of residues a and a signal The of homology to the IL-1RI cytoplasmic domain is to the residues of The of human rsc786 has not been the sequence a protein with a cytoplasmic domain of residues that homology to The of rsc786 does not IL-1RI to of and family homology of the cytoplasmic domain of the human IL-1 receptor type I with the of homology in murine T1/ST2, murine MyD88, human murine IL-1R accessory and the D. and The the for the and by the for the mammalian members of the family three of members for a specific of members for a functional and for family members of members for a specific six of members for a functional residues shown in residues residues The indicate of sequence and indicate of sequence the sequence indicate the of known human IL-1 J.E. 1995; PubMed Scopus Google open the of A. S. P. M. EMBO J. 1994; PubMed Scopus Google to the mammalian data base two Drosophila IL-1RI These new IL-1RI family members the R. C. D. K.H. U. M. 1991; PubMed Scopus Google Scholar) and and and of these of that homology to the IL-1RI cytoplasmic several proteins in to the partial to the of the to as MstProx for to the a we a Drosophila and and sequenced the MstProx We that MstProx an a receptor protein and to and of the mammalian family to The of MstProx homologous to the cytoplasmic domain of IL-1RI is shown in amino acid sequence of the of the IL-1R family members is shown in of the homologous of these proteins six of in 8 to residues the IL-1RI cytoplasmic domain of 213 residues 1 and the sequence these a functional with to IL-1 we IL-1RI receptors for three of the mammalian IL-1R family members and tested the receptors for their ability to transduce an IL-1-mediated signal in of IL-1RI receptors to for response to a known The of the receptors shown in of the and of the murine IL-1RI have the IL-1RI cytoplasmic domain by the IL-1RI homologous domains of T1/ST2, MyD88, or the T1/ST2 sequence a of homology with the to the between the IL-1RI and T1/ST2 for MyD88 and not the several different were for These the residues to different and between the putative signaling domain and the of the receptor receptors were tested for their ability to transduce an IL-1 signal in in a cells with the were with a to the human IL-1RI to IL-1 to the IL-1R and assayed for IL-1 response the We a different of IL-1RI for the and of is not and to IL-1 by the data of the chimeras were by and The ability of the receptors to activation of NF-κB, or of the IL-8 reporter IL-1 stimulation is in with that of the murine IL-1RI cells in cells with NF-κB protein to the and the of NF-κB assays nuclear cells with murine receptor, or a the the that stimulation by IL-1 in a NF-κB signal that is by with the IL-1RI and Cells with murine with and with IL-1 IL-1α, as positive in the of a NF-κB signal is an IL-1 response the murine IL-1RI and of NF-κB by IL-1 in cells with receptor NF-κB assays nuclear cells with T1/ST2 receptor and and murine IL-1RI and as shown of the a human IL-1R type is by a the is the as of NF-κB as is a nuclear NF-κB assays nuclear cells as shown murine IL-1RI and and different MyD88 receptors and and and and and of see and to of NF-κB as in the in is a nuclear the T1/ST2 receptor cells and with IL-1 in the of a NF-κB response that the T1/ST2 cytoplasmic domain is of NF-κB in response to IL-1 as well as the murine IL-1RI and by functional as well as sequence T1/ST2 is a of the IL-1R tested several for MyD88 and of the in with different MyD88 receptors for MyD88 chimeras appear to NF-κB to a in response to of these were in to by the T1/ST2 or murine IL-1RI were be that the MyD88 receptors were a the IL-1RI and the T1/ST2 chimeras All of the rsc786 receptors shown in were tested for their ability to NF-κB in response to failed to NF-κB not All as well as or the IL-1R positive not of cells to phosphorylation G.R. Cao X. Chua S.P. Tan Y.H. J. Biol. Chem. 1992; 267: 1846-1852Abstract Full Text PDF PubMed Google Scholar). kinase is that residue threonine 669 (Thr-669) of the phosphorylation is by members of the mitogen-activated protein kinase T.A. Sleath P.R. deRoos P.C. Dower S.K. Virca G.D. J. Biol. Chem. 1991; 266: 22661-22670Abstract Full Text PDF PubMed Google Scholar, 12.Bird T.A. Kyriakis J.M. Tyshler L. Gayle M. Milne A. Virca G.D. J. Biol. Chem. 1994; 269: 31836-31844Abstract Full Text PDF PubMed Google Scholar). of kinase by IL-1 has been shown to a different signal pathway that to activation of T.A. Sims J.E. B. Dower S.K. 1992; PubMed Scopus Google the kinase by IL-1 in we the of phosphorylation of a of residues of T.A. Kyriakis J.M. Tyshler L. Gayle M. Milne A. Virca G.D. J. Biol. Chem. 1994; 269: 31836-31844Abstract Full Text PDF PubMed Google Scholar). IL-1-stimulated or cells with murine or receptors were were with as for kinase in the of as the of kinase in cells IL-1 stimulation to the in the of kinase assays cells with murine and the T1/ST2 indicate treated with the and indicate with by a stimulation with IL-1 IL-1α, the of a in the kinase the of with IL-1 in the of a of kinase with by stimulation with IL-1 the kinase in cells to a with that stimulation receptors is that cells with murine IL-1 receptor respond to IL-1 kinase with the of kinase by IL-1 in cells with receptor of cells were in the of the IL-1RI for or were with by of is to cells with murine IL-1RI or the T1/ST2 the of three to assayed in cells with with murine IL-1RI or with different murine MyD88 chimeras of see is the of a assayed in with the T1/ST2 in 3. Cells with chimera, with and with respond to IL-1 with a in kinase of T.A. Sims J.E. B. Dower S.K. 1992; PubMed Scopus Google Scholar), that the T1/ST2 receptor is of the kinase pathway IL-1 type of kinase functional that the T1/ST2 protein is a of the IL-1R we that with by IL-1 stimulation of cells with MyD88 receptor does not kinase the with that the receptors to respond to IL-1 stimulation by activation of of the rsc786 receptors were to the kinase pathway IL-1 stimulation not activation of the IL-8 in cells with a receptor and a reporter The ( in the open reading for the human receptor of a of the human IL-8 that has been shown to be and to IL-1 N. Mahe Y. Matsushima K. J. Biol. Chem. 1990; 265: 21128-21133Abstract Full Text PDF PubMed Google Scholar). 1 the cells were with with IL-1α, assayed for of the in the NF-κB and kinase assays, the IL-8 reporter is in cells expressing the murine IL-1RI and in cells expressing the T1/ST2 receptor not in IL-1 stimulation does not the IL-8 reporter in cells expressing MyD88 and rsc786 receptors data not of IL-8 by IL-1 in cells with receptor 1 cells with the receptor were treated with the IL-1RI by of indicate or IL-1 that signal in not cells were assayed for response to IL-1 with the as as two proteins homology to the cytoplasmic domain of the family murine and human Drosophila and a We have two new mammalian members and two new Drosophila The new mammalian family members a murine protein MyD88 B. 1990; Google Scholar) and a human rsc786 N. N. Y. S. 1994; PubMed Scopus Google Scholar). MyD88 and as a response in of cells to rsc786 is murine T1/ST2, as a response in R. S. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: PubMed Scopus Google Scholar, S. 1989; PubMed Scopus Google Scholar, K. T. T. T. S. 1993; PubMed Scopus Google Scholar). The protein P. L. M. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar) has homology to the type I and type II IL-1R has been shown to the of IL-1RI for IL-1β and be in the IL-1 D. members of the IL-1RI family the protein 1991; PubMed Scopus Google Scholar, 1991; PubMed Scopus Google Scholar). The IL-1RI homologous of has been shown to be for role in the of the Drosophila C. Cell. 1988; Full Text PDF PubMed Scopus Google Scholar, 1991; PubMed Scopus Google Scholar). of by nuclear localization of a Drosophila of NF-κB, and activation of the protein C.A. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar, J. A. P. C. 1994; PubMed Scopus Google Scholar). has been shown that the of with homology to IL-1RI is and for the pathway that in nuclear localization of in J.L. J.L. 1995; PubMed Scopus Google Scholar). the sequence homology between and IL-1RI and the homologous of their signal an functional similarity. we two Drosophila family MstProx and Drosophila that partial of proteins homologous to the signaling domain of and of the MstProx has that is a new of the IL-1R family the mammalian and Drosophila proteins is a of the IL-1RI the The a protein with an domain that has homology to and the cytoplasmic domain of the S. S.P. D. R. C. B. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar). of the of to the ability to a response to the the of infection S. S.P. D. R. C. B. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar) to the inflammatory response pathway by injury and by IL-1 in have the sequence between of the mammalian members of the family indicate functional sequence these were homology of IL-1R family members is shown in of the homologous of these proteins six of in 8 to residues the IL-1RI cytoplasmic domain of 213 The of the homology domains has been defined by and of the IL-1RI to be essential for IL-1-mediated A. J.L. M. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar). ( of the residues in and that were defined as essential in the human IL-1RI by in members of the family The of these is is that sequence in domains indicate that these domains with of the of the signal pathway as the to activation of signal these interactions might such as or of the IL-1 have shown that a receptor of the and of the murine IL-1RI and the cytoplasmic domain of T1/ST2 is of an IL-1-mediated signal to the as assayed by activation of NF-κB, and an IL-8 promoter-controlled reporter of NF-κB and kinase indicates that the T1/ST2 cytoplasmic domain is of two separate signaling that respond to T.A. Sims J.E. B. Dower S.K. 1992; PubMed Scopus Google Scholar). that the sequence homology between the cytoplasmic domain of the IL-1RI and the T1/ST2 protein is is not MyD88 and rsc786 were of a IL-1-mediated signal their IL-1RI receptors as assayed by NF-κB, and IL-8 possibility might be that the in the of the MyD88 and rsc786 were not functional we possibility by several of of these of in assays in is that the MyD88 and rsc786 receptors the in response to IL-1 not the NF-κB, or IL-8 MyD88 and rsc786 with of the proteins that the IL-1RI and the T1/ST2 protein these proteins to signal in different not in or of the for with and signaling the domain of MyD88 and rsc786 not in We these cells IL-1 and is to signaling murine IL-1RI and the murine T1/ST2 possibility is by the of an IL-1 receptor accessory P. L. M. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). a of with the of rsc786 or the domain of MyD88, is for signaling by these an accessory in not be to with the of the and is that the IL-1R might not be to the rsc786 and MyD88 signaling domains for signaling is that MyD88 and rsc786 not in a signaling to IL-1 signaling by with of the IL-1 signaling to or the ability to respond to T1/ST2, the family to the IL-1RI in sequence as well as to the N.G. Jenkins N.A. Cannizzaro L.A. Croce Huebner K. Sims J.E. 1991; PubMed Scopus Google Scholar, S. Jenkins N.A. Copeland N.G. T. 1991; PubMed Scopus Google Scholar), while rsc786 is in does not appear to be as by and to a separate ( J. S. J. and J. for the IL-1RI homologous of T1/ST2 as of a IL-1 is of an IL-1 response to that by the The of signal be of T1/ST2 receptor and that the of IL-1RI and IL-1α and to be shown the by T1/ST2 and by IL-1RI family members such as MyD88 and rsc786 the of IL-1 signal INTRODUCTIONInterleukin-1 (IL-1) ( 1The abbreviations used are: IL-1interleukin 1IL-1RItype I interleukin 1 receptorrsc786randomly sequenced cDNA 786IL-1R AcPinterleukin 1 receptor accessory proteinORFopen reading frameEGFRepidermal growth factor receptor.) is an important component of the mammalian inflammatory response and is produced by many different types of cells following tissue injury and infection (1.Dinarello C.A. Blood. 1991; 77: 1627-1652Crossref PubMed Google Scholar). The receptors and ligands of the IL-1 pathway have been well defined (for review see (2.Dinarello C.A. FASEB J. 1994; 8: 1314-1325Crossref PubMed Google Scholar) and (3.Sims J.E. Bird T.A. Giri J.G. Dower S.K. Interleukin- 1 signal transduction: Advances in Cell and Molecular Biology of Membranes and Organelles. 3. JAI Press Inc., Greenwich, CT1994: 197-222Google Scholar)). Three ligands, IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1ra) bind three forms of IL-1 receptor, an 80-kDa type I IL-1 receptor (IL-1RI)(4.Sims J.E. March C.J. Cosman D. Widmer M.B. MacDonald H.R. McMahan C.J. Grubin C.E. Wignall J.M. Jackson J.L. Call S.M. Friend D. Alpert A.R. Gillis S. Urdal D.L. Dower S.K. Science. 1988; 241: 585-589Crossref PubMed Scopus (703) Google Scholar), a 68-kDa type II IL-1 receptor (IL-1RII)(5.McMahan C.J. Mosley B. Cosman D. Lupton S.D. Brunton L.L. Grubin C.E. Wignall J.M. Jenkins N.A. Brannan C.I. Copeland N.G. Huebner K. Croce C. Cannizzaro L.A. Benjamin D. Dower S.K. Spriggs M.K. Sims J.E. EMBO J. 1991; 10: 2821-2832Crossref PubMed Scopus (616) Google Scholar), and a soluble form of the type II IL-1R (sIL-1RII)(6.Colotta F. Re F. Muzio M. Bertini R. Polentarutti N. Sironi M. Giri J.G. Dower S.K. Sims J.E. Mantovani A. Science. 1993; 261: 472-475Crossref PubMed Scopus (864) Google Scholar). The cytoplasmic or signaling domain of the human IL-1RI consists of 213 amino acids and has been shown to be essential for cellular responses to IL-1 in vivo(7.Curtis B.M. Gallis B. Overell R.W. McMahan C.J. De Roos P. Ireland R. Eisenman J. Dower S.K. Sims J.E. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 3045-3049Crossref PubMed Scopus (89) Google Scholar), while the type II receptor has a cytoplasmic domain of only 29 residues and does not appear to transduce a signal(8.Sims J.E. Gayle M.A. Slack J.L. Alderson M.R. Bird T.A. Giri J.G. Colotta F. Re F. Mantovani A. Shanebeck K. Grabstein K.H. Dower S.K. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 6155-6159Crossref PubMed Scopus (544) Google Scholar). The interactions between the ligands and receptors play an essential role in the stimulation and regulation of the IL-1-mediated host response to injury and infection. Cells expressing IL-1RI and treated with IL-1α or IL-1β respond in several specific ways, including stimulating nuclear localization of the rel-related transcription factor, NF-κB (for review, see (9.Thanos D. Maniatis T. Cell. 1995; 80: 529-532Abstract Full Text PDF PubMed Scopus (1216) Google Scholar)), activation of protein kinases of the mitogen-activated protein kinase superfamily that phosphorylate residue threonine 669 (Thr-669) of the epidermal growth factor receptor (EGFR)(10.Guy G.R. Cao X. Chua S.P. Tan Y.H. J. Biol. Chem. 1992; 267: 1846-1852Abstract Full Text PDF PubMed Google Scholar, 11.Bird T.A. Sleath P.R. deRoos P.C. Dower S.K. Virca G.D. J. Biol. Chem. 1991; 266: 22661-22670Abstract Full Text PDF PubMed Google Scholar, 12.Bird T.A. Kyriakis J.M. Tyshler L. Gayle M. Milne A. Virca G.D. J. Biol. Chem. 1994; 269: 31836-31844Abstract Full Text PDF PubMed Google Scholar), and stimulation of transcription of the IL-8 gene(13.Mukaida N. Mahe Y. Matsushima K. J. Biol. Chem. 1990; 265: 21128-21133Abstract Full Text PDF PubMed Google Scholar).We explore the possibility of of in IL-1 the of proteins and their role in IL-1 and signal IL-1RI cytoplasmic domain homology to the cytoplasmic of the Drosophila protein C. Cell. 1988; Full Text PDF PubMed Scopus Google Scholar). is a protein in of in the Drosophila and have that the cytoplasmic domain of IL-1RI in residues between IL-1RI and essential for of IL-1-stimulated B.M. Gallis B. Overell R.W. McMahan C.J. De Roos P. Ireland R. Eisenman J. Dower S.K. Sims J.E. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 3045-3049Crossref PubMed Scopus (89) Google Scholar, A. J.L. M. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar, K. L. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google to Toll, have been as homologous to the cytoplasmic domain of the type I IL-1 These R. S. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: PubMed Scopus Google Scholar, S. 1989; PubMed Scopus Google Scholar, K. T. T. T. S. 1993; PubMed Scopus Google Scholar), the IL-1 receptor accessory protein P. L. M. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), the S. S.P. D. R. C. B. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar), and the Drosophila protein S. D. M. P. J. 1994; Google Scholar). T1/ST2 is a protein that has been as a response in The IL-1R is a protein and a that the of IL-1β to IL-1RI a protein the receptor T1/ST2 and IL-1R share homology to IL-1RI and The a protein with an domain that has homology to the cytoplasmic domain of and the to by of a that a inflammatory response to that by IL-1 in mammalian has not been is to a for we data base to with sequence homology to IL-1RI and We the sequence similarity in these proteins and in the T1/ST2 protein indicates a similarity in signaling as well.