TRAF3IP2 mediates interleukin-18-induced cardiac fibroblast migration and differentiation

Anthony J. Valente, Siva S.V.P. Sakamuri, Jalahalli M. Siddesha, Tadashi Yoshida, Jason D. Gardner, Ramesh Prabhu, Ulrich Siebenlist, Bysani Chandrasekar

Research output: Contribution to journalArticle

25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2176-2184
Number of pages9
JournalCellular Signalling
Volume25
Issue number11
DOIs
StatePublished - Nov 2013

Keywords

  • Cardiac fibroblasts
  • Cardiac fibrosis
  • Migration
  • RNA interference
  • Remodeling
  • TRAF3IP2

ASJC Scopus subject areas

  • Cell Biology

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