NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease
Copyright policy )NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease
AbstractRecruitment 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 αSMA-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, TNFα, and IL-6 was significantly reduced in NOX4HSCKO 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.
- University of California System United States
- University of California, Davis United States
- Goethe University Frankfurt Germany
- VA Northern California Health Care System United States
- Johann Wolfgang Goethe-Universitaet Germany
Alcohol Drinking, Receptors, CCR2, Cells, Knockout, RNA Stability, Medical Physiology, Chronic Liver Disease and Cirrhosis, 610, Acetaldehyde, Inbred C57BL, Oral and gastrointestinal, Article, ELAV-Like Protein 1, Alcohol Use and Health, Substance Misuse, Mice, Receptors, Hepatic Stellate Cells, 2.1 Biological and endogenous factors, Animals, Humans, Liver Diseases, Alcoholic, Cells, Cultured, Chemokine CCL2, Cell Nucleus, Mice, Knockout, ddc:610, Cultured, Biomedical and Clinical Sciences, Liver Disease, Inflammatory and immune system, Liver Diseases, Alcoholic, Mice, Inbred C57BL, Alcoholism, Protein Transport, NADPH Oxidase 4, CCR2, Inflammation Mediators, Digestive Diseases, ddc: ddc:610
Alcohol Drinking, Receptors, CCR2, Cells, Knockout, RNA Stability, Medical Physiology, Chronic Liver Disease and Cirrhosis, 610, Acetaldehyde, Inbred C57BL, Oral and gastrointestinal, Article, ELAV-Like Protein 1, Alcohol Use and Health, Substance Misuse, Mice, Receptors, Hepatic Stellate Cells, 2.1 Biological and endogenous factors, Animals, Humans, Liver Diseases, Alcoholic, Cells, Cultured, Chemokine CCL2, Cell Nucleus, Mice, Knockout, ddc:610, Cultured, Biomedical and Clinical Sciences, Liver Disease, Inflammatory and immune system, Liver Diseases, Alcoholic, Mice, Inbred C57BL, Alcoholism, Protein Transport, NADPH Oxidase 4, CCR2, Inflammation Mediators, Digestive Diseases, ddc: ddc:610
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