2017年4月
NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease
SCIENTIFIC REPORTS
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- 巻
- 7
- 号
- 開始ページ
- 46144
- 終了ページ
- 46144
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1038/srep46144
- 出版者・発行元
- NATURE PUBLISHING GROUP
Recruitment of inflammatory cells is a major feature of alcoholic liver injury however; the signals and cellular sources regulating this are not well defined. C-C chemokine receptor type 2 (CCR2) is expressed by active hepatic stellate cells (HSC) and is a key monocyte recruitment signal. Activated HSC are also important sources of hydrogen peroxide resulting from the activation of NADPH oxidase 4 (NOX4). As the role of this NOX in early alcoholic liver injury has not been addressed, we studied NOX4-mediated regulation of CCR2/CCL2 mRNA stability. NOX4 mRNA was significantly induced in patients with alcoholic liver injury, and was co-localized with aSMA-expressing activated HSC. We generated HSCspecific NOX4 KO mice and these were pair-fed on alcohol diet. Lipid peroxidation have not changed significantly however, the expression of CCR2, CCL2, Ly6C, TNF alpha, and IL-6 was significantly reduced in NOX4(HSCKO) compared to fl/fl mice. NOX4 promoter was induced in HSC by acetaldehyde treatment, and NOX4 has significantly increased mRNA half-life of CCR2 and CCL2 in conjunction with Ser221 phosphorylation and cytoplasmic shuttling of HuR. In conclusion, NOX4 is induced in early alcoholic liver injury and regulates CCR2/CCL2 mRNA stability thereby promoting recruitment of inflammatory cells and production of proinflammatory cytokines.
- リンク情報
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- DOI
- https://doi.org/10.1038/srep46144
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/28383062
- PubMed Central
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382722
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000398581700001&DestApp=WOS_CPL
- URL
- http://orcid.org/0000-0002-3939-9480
- ID情報
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- DOI : 10.1038/srep46144
- ISSN : 2045-2322
- ORCIDのPut Code : 35401417
- PubMed ID : 28383062
- PubMed Central 記事ID : PMC5382722
- Web of Science ID : WOS:000398581700001
- ORCIDで取得されたその他外部ID : a:1:{i:0;a:1:{s:0:"";s:0:"";}}