title: TRAF3IP2 mediates interleukin-18-induced cardiac fibroblast migration and differentiation.
abstract: TRAF3IP2 is a cytoplasmic adapter protein and an upstream regulator of IKK/NF-κB and JNK/AP-1. Here we demonstrate for the first time that the proinflammatory cytokine interleukin (IL)-18 induces TRAF3IP2 expression in primary cardiac fibroblasts (CF) in a Nox4/hydrogen peroxide-dependent manner. Silencing TRAF3IP2 using a phosphorothioated, 2'-O-methyl modified, cholesterol-tagged TRAF3IP2 siRNA duplex markedly attenuated IL-18-induced NF-κB and AP-1 activation and CF migration. Using co-IP/IB and co-localization experiments, we show that Nox4 physically associates with IL-18 receptor proteins, and IL-18 enhances their binding. Further, IL-18 promotes fibroblast to myofibroblast transition, as evidenced by enhanced α-smooth muscle actin expression, types 1 and 3 collagen induction, and soluble collagen secretion, via TRAF3IP2. These results indicate that TRAF3IP2 is a critical intermediate in IL-18-induced CF migration and differentiation in vitro. TRAF3IP2 could serve as a potential therapeutic target in cardiac fibrosis and adverse remodeling in vivo.
authors.affiliation: Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.forename: Siva S V P
authors.initials: SS
authors.lastname: Sakamuri
authors.forename: Jalahalli M
authors.initials: JM
authors.lastname: Siddesha
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Jason D
authors.initials: JD
authors.lastname: Gardner
authors.forename: Ramesh
authors.initials: R
authors.lastname: Prabhu
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020382:Interleukin-18 / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D024042:Collagen Type I; D024061:Collagen Type III; D020382:Interleukin-18; D016328:NF-kappa B; D034741:RNA, Small Interfering; C515963:Traf3ip2 protein, mouse; D018808:Transcription Factor AP-1; C544013:alpha-smooth muscle actin, mouse; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse
keywords: Cardiac fibroblasts; Cardiac fibrosis; Migration; RNA interference; Remodeling; TRAF3IP2