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

doi:10.1016/j.cellsig.2013.07.013

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

Medicine

Research output: Contribution to journal › Article › peer-review

26 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 language	English (US)
Pages (from-to)	2176-2184
Number of pages	9
Journal	Cellular Signalling
Volume	25
Issue number	11
DOIs	https://doi.org/10.1016/j.cellsig.2013.07.013
State	Published - Nov 2013

Keywords

Cardiac fibroblasts
Cardiac fibrosis
Migration
RNA interference
Remodeling
TRAF3IP2

ASJC Scopus subject areas

Cell Biology

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TRAF3IP2 mediates interleukin-18-induced cardiac fibroblast migration and differentiation. / Valente, Anthony J.; Sakamuri, Siva S.V.P.; Siddesha, Jalahalli M.; Yoshida, Tadashi; Gardner, Jason D.; Prabhu, Ramesh; Siebenlist, Ulrich; Chandrasekar, Bysani.

In: Cellular Signalling, Vol. 25, No. 11, 11.2013, p. 2176-2184.

Research output: Contribution to journal › Article › peer-review

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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.",

keywords = "Cardiac fibroblasts, Cardiac fibrosis, Migration, RNA interference, Remodeling, TRAF3IP2",

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

note = "Funding Information: BC is a recipient of the Department of Veterans Affairs Research Career Scientist award, and is supported by VA Office of Research and Development Biomedical Laboratory Research and Development Service Award 1IO1BX000246 and the NIH/NHLBI grant HL-86787 . The contents of this report do not represent the views of the Department of Veterans Affairs or the United States Government.",

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AU - Valente, Anthony J.

AU - Sakamuri, Siva S.V.P.

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AU - Yoshida, Tadashi

AU - Gardner, Jason D.

AU - Prabhu, Ramesh

AU - Siebenlist, Ulrich

AU - Chandrasekar, Bysani

N1 - Funding Information: BC is a recipient of the Department of Veterans Affairs Research Career Scientist award, and is supported by VA Office of Research and Development Biomedical Laboratory Research and Development Service Award 1IO1BX000246 and the NIH/NHLBI grant HL-86787 . The contents of this report do not represent the views of the Department of Veterans Affairs or the United States Government.

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N2 - 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.

AB - 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.

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