title: NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease.
abstract: 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 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 NOX4HSCKOcompared 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.
authors.affiliation: Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA.|VA Northern California Health Care System, Mather, CA, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA.|VA Northern California Health Care System, Mather, CA, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Dehnad
authors.affiliation: Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fish
authors.affiliation: Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA.
authors.forename: Ai
authors.initials: A
authors.lastname: Sato
authors.affiliation: Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA.
authors.forename: Jijing
authors.initials: J
authors.lastname: Tian
authors.affiliation: Wolfgang Goethe University, Frankfurt am Main, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schröder
authors.affiliation: Wolfgang Goethe University, Frankfurt am Main, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Brandes
authors.affiliation: Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA.|VA Northern California Health Care System, Mather, CA, USA.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Török
mesh_terms: D000079:Acetaldehyde / Q000494:pharmacology; D000428:Alcohol Drinking / Q000235:genetics; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D000067780:ELAV-Like Protein 1 / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000235:genetics* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4 / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics*; D054390:Receptors, CCR2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D000067780:ELAV-Like Protein 1; D018836:Inflammation Mediators; D054390:Receptors, CCR2; D000074663:NADPH Oxidase 4; D000079:Acetaldehyde