CD40 Is Essential in the Upregulation of TRAF Proteins and NF-KappaB-Dependent Proinflammatory Gene Expression after Arterial Injury

Despite extensive investigations, restenosis, which is characterized primarily by neointima formation, remains an unsolved clinical problem after vascular interventions. A recent study has shown that CD40 signaling through TNF receptor associated factor 6 (TRAF6) plays a key role in neointima format...

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Main Authors:	Song, Zifang, Jin, Rong, Yu, Shiyong, Rivet, Joshua J., Smyth, Susan S., Nanda, Anil, Granger, D. Neil, Li, Guohong
Format:	Online
Language:	English
Published:	Public Library of Science 2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158063/

id	pubmed-3158063
recordtype	oai_dc
spelling	pubmed-31580632011-08-29 CD40 Is Essential in the Upregulation of TRAF Proteins and NF-KappaB-Dependent Proinflammatory Gene Expression after Arterial Injury Song, Zifang Jin, Rong Yu, Shiyong Rivet, Joshua J. Smyth, Susan S. Nanda, Anil Granger, D. Neil Li, Guohong Research Article Despite extensive investigations, restenosis, which is characterized primarily by neointima formation, remains an unsolved clinical problem after vascular interventions. A recent study has shown that CD40 signaling through TNF receptor associated factor 6 (TRAF6) plays a key role in neointima formation after carotid artery injury; however, underlying mechanisms are not clearly elucidated. Because neointima formation may vary significantly depending on the type of injury, we first assessed the effect of CD40 deficiency on neointima formation in 2 injury models, carotid artery ligation and femoral artery denudation injury. Compared with wild-type mice, CD40 deficiency significantly reduced neointima formation and lumen stenosis in two different models. Further, we investigated the mechanism by which CD40 signaling affects neointima formation after arterial injury. In wild-type mice, the expression levels of CD40, several TRAF proteins, including TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6, as well as total NF-kB p65 and phospho-NF-kB p65, in the carotid artery were markedly upregulated within 3–7 days after carotid ligation. Deficiency of CD40 abolished the injury-induced upregulation of TRAFs including TRAF6 and NF-kB-p65 in the injured vessel wall. Further, CD40−/− mice showed a significant decrease in the recruitment of neutrophils (at 3, 7d) and macrophages (at 7, 21d) into injured artery; this effect was most likely attributed to inhibition of NF-kB activation and marked downregulation of NF-kB-related gene expression, including cytokines (TNFα, IL-1β, IL-6), chemokines (MCP-1), and adhesion molecules (ICAM-1, VCAM-1). Moreover, neutrophil recruitment in a model of thioglycollate-induced peritonitis is impaired in CD40-deficient mice. In vitro data revealed that CD40 deficiency blocked CD40L-induced NF-kB p65 nuclear translocation in leukocytes. Altogether, our data identified for the first time that CD40 is essential in the upregulation of TRAF6, NF-kB activation, and NF-kB-dependent proinflammatory genes in vivo. Our findings firmly established the role for CD40 in neointima formation in 2 distinct injury models. Public Library of Science 2011-08-18 /pmc/articles/PMC3158063/ /pubmed/21876738 http://dx.doi.org/10.1371/journal.pone.0023239 Text en Song et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Song, Zifang Jin, Rong Yu, Shiyong Rivet, Joshua J. Smyth, Susan S. Nanda, Anil Granger, D. Neil Li, Guohong
spellingShingle	Song, Zifang Jin, Rong Yu, Shiyong Rivet, Joshua J. Smyth, Susan S. Nanda, Anil Granger, D. Neil Li, Guohong CD40 Is Essential in the Upregulation of TRAF Proteins and NF-KappaB-Dependent Proinflammatory Gene Expression after Arterial Injury
author_facet	Song, Zifang Jin, Rong Yu, Shiyong Rivet, Joshua J. Smyth, Susan S. Nanda, Anil Granger, D. Neil Li, Guohong
author_sort	Song, Zifang
title	CD40 Is Essential in the Upregulation of TRAF Proteins and NF-KappaB-Dependent Proinflammatory Gene Expression after Arterial Injury
title_short	CD40 Is Essential in the Upregulation of TRAF Proteins and NF-KappaB-Dependent Proinflammatory Gene Expression after Arterial Injury
title_full	CD40 Is Essential in the Upregulation of TRAF Proteins and NF-KappaB-Dependent Proinflammatory Gene Expression after Arterial Injury
title_fullStr	CD40 Is Essential in the Upregulation of TRAF Proteins and NF-KappaB-Dependent Proinflammatory Gene Expression after Arterial Injury
title_full_unstemmed	CD40 Is Essential in the Upregulation of TRAF Proteins and NF-KappaB-Dependent Proinflammatory Gene Expression after Arterial Injury
title_sort	cd40 is essential in the upregulation of traf proteins and nf-kappab-dependent proinflammatory gene expression after arterial injury
description	Despite extensive investigations, restenosis, which is characterized primarily by neointima formation, remains an unsolved clinical problem after vascular interventions. A recent study has shown that CD40 signaling through TNF receptor associated factor 6 (TRAF6) plays a key role in neointima formation after carotid artery injury; however, underlying mechanisms are not clearly elucidated. Because neointima formation may vary significantly depending on the type of injury, we first assessed the effect of CD40 deficiency on neointima formation in 2 injury models, carotid artery ligation and femoral artery denudation injury. Compared with wild-type mice, CD40 deficiency significantly reduced neointima formation and lumen stenosis in two different models. Further, we investigated the mechanism by which CD40 signaling affects neointima formation after arterial injury. In wild-type mice, the expression levels of CD40, several TRAF proteins, including TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6, as well as total NF-kB p65 and phospho-NF-kB p65, in the carotid artery were markedly upregulated within 3–7 days after carotid ligation. Deficiency of CD40 abolished the injury-induced upregulation of TRAFs including TRAF6 and NF-kB-p65 in the injured vessel wall. Further, CD40−/− mice showed a significant decrease in the recruitment of neutrophils (at 3, 7d) and macrophages (at 7, 21d) into injured artery; this effect was most likely attributed to inhibition of NF-kB activation and marked downregulation of NF-kB-related gene expression, including cytokines (TNFα, IL-1β, IL-6), chemokines (MCP-1), and adhesion molecules (ICAM-1, VCAM-1). Moreover, neutrophil recruitment in a model of thioglycollate-induced peritonitis is impaired in CD40-deficient mice. In vitro data revealed that CD40 deficiency blocked CD40L-induced NF-kB p65 nuclear translocation in leukocytes. Altogether, our data identified for the first time that CD40 is essential in the upregulation of TRAF6, NF-kB activation, and NF-kB-dependent proinflammatory genes in vivo. Our findings firmly established the role for CD40 in neointima formation in 2 distinct injury models.
publisher	Public Library of Science
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158063/
_version_	1611471396047683584

CD40 Is Essential in the Upregulation of TRAF Proteins and NF-KappaB-Dependent Proinflammatory Gene Expression after Arterial Injury

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