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The Essential Role of Single Ig IL-1 Receptor-Related Molecule/Toll IL-1R8 in Regulation of Th2 Immune Response¹

Katarzyna Bulek^*,, Shadi Swaidani^,¶, Jinzhong Qin^*, Yi Lu^*, Muhammet F. Gulen^*, Tomasz Herjan^*, Booki Min^*, Robert A. Kastelein, Mark Aronica, Magdalena Kosz-Vnenchak and Xiaoxia Li^2,*

^* Immunology Department, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Laboratory of Molecular Genetics and Virology, Department of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow, Poland; Pathobiology Department, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Schering-Plough Biopharma (formerly DNAX Research), Palo Alto, CA 94304; and ^¶ Department of Molecular Medicine, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195

A novel cytokine IL-33, an IL-1 family member, signals via ST2 receptor and promotes Th2 responses, through the activation of NF-B and MAP kinases. Previous studies reported that single Ig IL-1R-related molecule (SIGIRR)/Toll IL-1R8 acts as negative regulator for TLR-IL-1R-mediated signaling. We now found that SIGIRR formed a complex with ST2 upon IL-33 stimulation and specifically inhibited IL-33/ST2-mediated signaling in cell culture model. Furthermore, IL-33-induced Th2 response was enhanced in SIGIRR-deficient mice compared with that in wild-type control mice, suggesting a negative regulatory role of SIGIRR in IL-33/ST2 signaling in vivo. Similar to ST2, SIGIRR was highly expressed in in vitro polarized Th2 cells, but not Th1 cells. SIGIRR-deficient Th2 cells produce higher levels of Th2 cytokines, including IL-5, IL-4, and IL-13, than that in wild-type cells. Moreover, SIGIRR-deficient mice developed stronger Th2 immune response in OVA-challenged asthma model. Taken together, our results suggest that SIGIRR plays an important role in the regulation of Th2 response in vivo, possibly through its impact on IL-33-ST2-mediated signaling.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant RO1 AI060632.

² Address correspondence and reprint requests to Dr. Xiaoxia Li, Immunology Department, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail address: lix{at}ccf.org

³ Abbreviations used in this paper: TIR, Toll IL-1R; BAL, bronchoalveolar lavage; hSIGIRR, human single Ig IL-1R-related molecule; hST2, human ST2; IP-10, IFN--inducible protein-10; SIGIRR, single Ig IL-1R-related molecule; WT, wild type.

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