The type I interleukin-1 receptor (IL-1RI) mediates the biological effects of interleukin-1, a pro-inflammatory cytokine (Sims et al., Science 241:585–589, 1988; Curtis et al., Proc. Natl. Acad. Sci. USA 86:3045–3049, 1989). A second interleukin-1 receptor (designated type II IL-1R or IL-1RII) binds IL-1, but does not appear to mediate signal transduction (McMahan et al., EMBO J. 10:2821, 1991; Sims et al., Proc. Natl. Acad. Sci. USA 90:6155–6159, 1993). IL-1RI and IL-1RII each bind IL-1α and IL-1β.
IL-1RI and IL-1RII belong to a family of proteins that exhibit significant sequence homology. One such protein is IL-1R accessory protein (IL-1R AcP), described in Greenfeder et al. (J. Biol. Chem. 270: 13757–13765, 1995). This protein, by itself, is not capable of binding IL-1, but does form a complex with IL-1RI and either IL-1α and IL-1β. When co-expressed with IL-1-RI, recombinant IL-1R AcP increases the binding affinity of IL-1RI for IL-1β (Greenfeder et al., supra).
The protein variously known as ST2, ST2L, T1, or Fit-1 also is a member of the IL-1R family, but does not bind IL-1. Cloning of mouse and rat cDNAs encoding membrane-bound and secreted forms of this protein has been reported (Klemenz et al., Proc. Natl. Acad. Sci. USA 86:5708, 1989; Tominaga, FEBS LETTERS 258:301, 1989; Yanagisawa et al., FEBS LETTERS 318:83, 1993; Bergers et al., EMBO J. 13:1176, 1994). Human ST2 cDNA and genomic clones have been isolated as well (Tominaga et al. Biochimica et Biophysica Acta 1171:215, 1992).
Other proteins exhibiting significant sequence homology with IL-1RI are murine MyD88 (Lord et al., Oncogene 5: 1095–1097, 1990), human rsc786 (Nomura et al., DNA Res. 1:27–35, 1994), and a number of Drosophila proteins, the best characterized of which is Toll (Hashimoto et al., Cell 52, 269–279, 1988). The tobacco N gene (Whitham et al., Cell 78:1101–1115, 1994) is among the additional IL-1R family members.
MyD88, rsc786, Toll, and the tobacco N gene product contain domains exhibiting significant homology to the cytoplasmic domain of the IL-1RI. The IL-1R AcP and ST2 proteins exhibit sequence similarity to IL-1RI in both their extracellular and cytoplasmic portions. The B16R protein of vaccinia virus (Goebel et al., Virology 179:247, 1990) appears to be a viral homolog of IL-1RII.
Identification of additional receptors of this family is desirable. Such receptor proteins can be studied to determine whether or not they bind IL-1, and, if so, whether the receptors play a role in mediating signal transduction. The possible existence of additional affinity-converting subunits for receptors of this family can be explored, as well.
USPTO Backgrounds
USPTO Backgrounds