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.
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Change history
22 August 2011
In the version of this article initially published, the author Mark R. Chance was incorrectly identified as Mark Chance. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank T. Maniatis (Harvard University) for IKKi-deficient and wild-type C57BL/6 control mice; and the High Performance Computing Resource in the Core Facility for Advanced Research Computing and Center of Proteomics and Bioinformatics at Case Western Reserve University. Supported by the American Asthma Foundation (X.L.), the US National Institutes of Health (R01HL098935-01A1 to X.L.) and the American Heart Association (09POST2010041 to R.C.P.).
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K.B., C.L., S.S., L.W., M.F.G., T.H., W.Q. and D.S., experiments; K.B. and C.L., experimental design, performance and interpretation and writing of the manuscript; L.W. and M.R.C., mass spectrometry study; R.C.P. and S.M., structure modeling; A.A., M.L. and V.H., assistance with the primary mouse airway epithelial cell culture; M.A., assistance with in vivo experiments; X.L. and T.H., design and interpretation of experiments and writing of the manuscript; all authors, review of the final manuscript.
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Bulek, K., Liu, C., Swaidani, S. et al. The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation. Nat Immunol 12, 844–852 (2011). https://doi.org/10.1038/ni.2080
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DOI: https://doi.org/10.1038/ni.2080
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