The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation

Abstract

Interleukin 17 (IL-17) is critical in the pathogenesis of inflammatory and autoimmune diseases. Here we report that Act1, the key adaptor for the IL-17 receptor (IL-7R), formed a complex with the inducible kinase IKKi after stimulation with IL-17. Through the use of IKKi-deficient mice, we found that IKKi was required for IL-17-induced expression of genes encoding inflammatory molecules in primary airway epithelial cells, neutrophilia and pulmonary inflammation. IKKi deficiency abolished IL-17-induced formation of the complex of Act1 and the adaptors TRAF2 and TRAF5, activation of mitogen-activated protein kinases (MAPKs) and mRNA stability, whereas the Act1-TRAF6-transcription factor NF-κB axis was retained. IKKi was required for IL-17-induced phosphorylation of Act1 on Ser311, adjacent to a putative TRAF-binding motif. Substitution of the serine at position 311 with alanine impaired the IL-17-mediated Act1-TRAF2-TRAF5 interaction and gene expression. Thus, IKKi is a kinase newly identified as modulating IL-17 signaling through its effect on Act1 phosphorylation and consequent function. PMID: 21822257 Funding information This work was supported by: NCI NIH HHS, United States Grant ID: R01 CA039621 NHLBI NIH HHS, United States Grant ID: P01 HL103453 NINDS NIH HHS, United States Grant ID: R01 NS071996-02 NIGMS NIH HHS, United States Grant ID: R01 GM080271 NIGMS NIH HHS, United States Grant ID: R01 GM080271-04 NINDS NIH HHS, United States Grant ID: R01 NS071996 NHLBI NIH HHS, United States Grant ID: R01 HL098935 NHLBI NIH HHS, United States Grant ID: R01HL098935-01A1 More Less keyboard_arrow_down

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