| First Author | Sasaki Y | Year | 2017 |
| Journal | Sci Rep | Volume | 7 |
| Pages | 46144 | PubMed ID | 28383062 |
| Mgi Jnum | J:275264 | Mgi Id | MGI:6296335 |
| Doi | 10.1038/srep46144 | Citation | Sasaki Y, et al. (2017) NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease. Sci Rep 7:46144 |
| abstractText | 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 alphaSMA-expressing activated HSC. We generated HSC-specific NOX4 KO mice and these were pair-fed on alcohol diet. Lipid peroxidation have not changed significantly however, the expression of CCR2, CCL2, Ly6C, TNFalpha, 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. |
