title: 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.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bulek
authors.forename: Caini
authors.initials: C
authors.lastname: Liu
authors.forename: Shadi
authors.initials: S
authors.lastname: Swaidani
authors.forename: Liwen
authors.initials: L
authors.lastname: Wang
authors.forename: Richard C
authors.initials: RC
authors.lastname: Page
authors.forename: Muhammet F
authors.initials: MF
authors.lastname: Gulen
authors.forename: Tomasz
authors.initials: T
authors.lastname: Herjan
authors.forename: Amina
authors.initials: A
authors.lastname: Abbadi
authors.forename: Wen
authors.initials: W
authors.lastname: Qian
authors.forename: Dongxu
authors.initials: D
authors.lastname: Sun
authors.forename: Mark
authors.initials: M
authors.lastname: Lauer
authors.forename: Vincent
authors.initials: V
authors.lastname: Hascall
authors.forename: Saurav
authors.initials: S
authors.lastname: Misra
authors.forename: Mark R
authors.initials: MR
authors.lastname: Chance
authors.forename: Mark
authors.initials: M
authors.lastname: Aronica
authors.forename: Thomas
authors.initials: T
authors.lastname: Hamilton
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008168:Lung; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011014:Pneumonia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger; D053722:Receptors, Interleukin-17 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D048015:TNF Receptor-Associated Factor 5 / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054360:Chemokine CXCL1; D020381:Interleukin-17; D012333:RNA, Messenger; D053722:Receptors, Interleukin-17; C499176:T2bp protein, mouse; D048015:TNF Receptor-Associated Factor 5; C515963:Traf3ip2 protein, mouse; D051550:I-kappa B Kinase; D020928:Mitogen-Activated Protein Kinases