title: The IL-1 receptor accessory protein (AcP) is required for IL-33 signaling and soluble AcP enhances the ability of soluble ST2 to inhibit IL-33.
abstract: Interleukin (IL)-33 (or IL-1F11) was recently identified as a ligand for the orphan IL-1 receptor family member T1/ST2 (ST2). IL-33 belongs to the IL-1 cytokine family and, upon binding to ST2, induces intracellular signals similar to those utilized by IL-1. The effects of other IL-1 family cytokines are mediated by their binding to a specific receptor and the recruitment of a co-receptor required for elicitation of signaling. The aim of this study was to characterize the co-receptor involved in IL-33 signaling. Immunoprecipitation confirmed that IL-33 specifically binds ST2 and revealed that cellular IL-1 receptor accessory protein (AcP) associates with ST2 in a ligand-dependent manner. Receptor binding measurements demonstrated that the affinity of mouse (m)IL-33 for ST2 is increased by 4-fold in presence of AcP. IL-33 dose-dependently stimulated IL-6 secretion from wild-type (WT) mast cells, while no effect of IL-33 was observed with mast cells derived from AcP-deficient mice. Finally, soluble (s)ST2-Fc and sAcP-Fc acted synergistically to inhibit IL-33 activity. These observations identify AcP as a shared co-receptor within the IL-1 family that is essential for IL-33 signaling and suggest a novel role for sAcP in modulating the activity of IL-33.
authors.affiliation: Division of Rheumatology, University Hospital of Geneva, 26 Avenue Beau-Séjour, 1211 Geneva 14, Switzerland.
authors.forename: Gaby
authors.initials: G
authors.lastname: Palmer
authors.forename: Brian P
authors.initials: BP
authors.lastname: Lipsky
authors.forename: Molly D
authors.initials: MD
authors.lastname: Smithgall
authors.forename: David
authors.initials: D
authors.lastname: Meininger
authors.forename: Sophia
authors.initials: S
authors.lastname: Siu
authors.forename: Dominique
authors.initials: D
authors.lastname: Talabot-Ayer
authors.forename: Cem
authors.initials: C
authors.lastname: Gabay
authors.forename: Dirk E
authors.initials: DE
authors.lastname: Smith
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism; D053577:Interleukin-1 Receptor Accessory Protein / Q000378:metabolism*; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D018123:Receptors, Interleukin; D015398:Signal Transduction; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance
chemical_list: C506536:IL33 protein, human; C507767:Il1rap protein, mouse; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D007141:Immunoglobulin Fc Fragments; D053577:Interleukin-1 Receptor Accessory Protein; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D015850:Interleukin-6; D007378:Interleukins; D008565:Membrane Proteins; D018123:Receptors, Interleukin