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IRAK4 kinase Activity is Required for Th17 Differentiation and Th17-mediated Disease
Journal article   Peer reviewed

IRAK4 kinase Activity is Required for Th17 Differentiation and Th17-mediated Disease

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, …
The Journal of immunology (1950), Vol.183(1), pp.568-577
07/01/2009
DOI: 10.4049/jimmunol.0802361
PMCID: PMC3638260
PMID: 19542468

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Abstract

Both IL-23- and IL-1-mediated signaling pathways play important roles in Th17 cell differentiation, cytokine production, and autoimmune diseases. The IL-1 receptor 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 (EAE) due to a reduction in infiltrating inflammatory cells into the CNS and reduced antigen-specific CD4 + T cell-mediated IL-17 production. Adoptive transfer of MOG 35-55 -specific IRAK4 KI Th17 cells failed to induce EAE 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-23 receptor 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-23 receptor expression, Th17 differentiation, and autoimmune disease.
 EAE IL-23 receptor IRAK4 Th17 cells

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