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IRAK4 Kinase Activity Is Required for Th17 Differentiation and Th17-Mediated Disease¹

Kirk A. Staschke^*, Sucai Dong^*, Joy Saha^*, Jingyong Zhao^*, Nathan A. Brooks^*, Deena L. Hepburn^*, Jinqi Xia^*, Muhammet F. Gulen, Zizhen Kang, Cengiz Z. Altuntas, Vincent K. Tuohy, Raymond Gilmour^*, Xiaoxia Li and Songqing Na^2,*

^* Lilly Research laboratory, Eli Lilly and Co., Indianapolis, IN 46285; and Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195

Both IL-23- and IL-1-mediated signaling pathways play important roles in Th17 cell differentiation, cytokine production, and autoimmune diseases. The IL-1R-associated kinase 4 (IRAK4) is critical for IL-1/TLR signaling. We show here that inactivation of IRAK4 kinase in mice (IRAK4 KI) results in significant resistance to experimental autoimmune encephalomyelitis due to a reduction in infiltrating inflammatory cells into the CNS and reduced Ag-specific CD4⁺ T cell-mediated IL-17 production. Adoptive transfer of myelin oligodendrocyte glycoprotein 35–55-specific IRAK4 KI Th17 cells failed to induce experimental autoimmune encephalomyelitis in either wild-type or IRAK4 KI recipient mice, indicating the lack of autoantigen-specific Th17 cell activities in the absence of IRAK4 kinase activity. Furthermore, the absence of IRAK4 kinase activity blocked induction of IL-23R expression, STAT3 activation by IL-23, and Th17 cytokine expression in differentiated Th17 cells. Importantly, blockade of IL-1 signaling by IL-1RA inhibited Th17 differentiation and IL-23-induced cytokine expression in differentiated Th17 cells. The results of these studies demonstrate that IL-1-mediated IRAK4 kinase activity in T cells is essential for induction of IL-23R expression, Th17 differentiation, and autoimmune disease.

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 study was supported in part by funding from the National Multiple Sclerosis Society awarded to Xiaoxia Li (RG 4056-A-1).

² Address correspondence and reprint requests to Dr. Songqing Na, Lilly Research Laboratory, Eli Lilly and Co., Indianapolis, IN 46285. E-mail address: na_songqing{at}lilly.com

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; IRAK, IL-1R-associated kinase; MOG, myelin oligodendrocyte glycoprotein; PKC, protein kinase C; ROR, retinoid-related orphan receptor; WT, wild type.