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

作者：Bulek Katarzyna; Liu Caini; Swaidani Shadi; Wang Liwen; Page Richard C; Gulen Muhammet F; Herjan Tomasz; Abbadi Amina; Qian Wen; Sun Dongxu; Lauer Mark; Hascall Vincent; Misra Saurav; Chance Mark; Aronica Mark; Hamilton Thomas; Li Xiaoxia^*

来源：Nature Immunology, 2011, 12(9): 844-U61.

DOI：10.1038/ni.2080

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-kappa B 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.

• 出版日期2011-9