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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing* / genetics
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Adaptor Proteins, Signal Transducing* / immunology
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Adaptor Proteins, Signal Transducing* / metabolism
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Animals
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Chemokine CXCL1 / genetics
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Chemokine CXCL1 / immunology*
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Chemokine CXCL1 / metabolism
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Epithelial Cells / immunology
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Epithelial Cells / metabolism
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Gene Expression Regulation
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I-kappa B Kinase* / deficiency
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I-kappa B Kinase* / genetics
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I-kappa B Kinase* / immunology
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Interleukin-17 / immunology
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Interleukin-17 / metabolism
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Interleukin-17 / pharmacology
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Lung
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinases / immunology
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Mitogen-Activated Protein Kinases / metabolism
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Neutrophils / immunology*
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Neutrophils / metabolism
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Phosphorylation
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Pneumonia / genetics
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Pneumonia / immunology*
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Pneumonia / metabolism
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RNA Stability / drug effects
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RNA, Messenger
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Receptors, Interleukin-17 / immunology
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Signal Transduction / immunology*
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TNF Receptor-Associated Factor 5 / immunology
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TNF Receptor-Associated Factor 5 / metabolism
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Th17 Cells / immunology*
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Th17 Cells / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Chemokine CXCL1
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Interleukin-17
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RNA, Messenger
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Receptors, Interleukin-17
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T2bp protein, mouse
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TNF Receptor-Associated Factor 5
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Traf3ip2 protein, mouse
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I-kappa B Kinase
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Mitogen-Activated Protein Kinases