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

• Published in: Cytokine (Philadelphia, Pa.) Vol. 42; no. 3; pp. 358 - 364
• Main Authors: Palmer, Gaby, Lipsky, Brian P., Smithgall, Molly D., Meininger, David, Siu, Sophia, Talabot-Ayer, Dominique, Gabay, Cem, Smith, Dirk E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2008
• Subjects: Animals; Cell Line, Tumor; Cytokine; Humans; Immunoglobulin Fc Fragments - metabolism; Inflammation; Interleukin-1 family; Interleukin-1 Receptor Accessory Protein - metabolism; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukin-6 - metabolism; Interleukins - metabolism; Mast Cells - metabolism; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Protein Binding; Receptor complex; Receptors, Interleukin; Signal Transduction; Signaling; Substrate Specificity; Surface Plasmon Resonance; Interleukin-1 family; Signaling; Inflammation; Receptor complex; Cytokine
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2008.03.008

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.