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Cell Signal. 2013 Nov;25(11):2176-84. doi: 10.1016/j.cellsig.2013.07.013. Epub 2013 Jul 18.

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

Author information

1
Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX 78229, USA.

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.

KEYWORDS:

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

PMID:
23872479
PMCID:
PMC3793247
DOI:
10.1016/j.cellsig.2013.07.013
[Indexed for MEDLINE]
Free PMC Article
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