Hepatocytes produce TNF-α following hypoxia-reoxygenation and liver ischemia-reperfusion in a NADPH oxidase- and c-Src-dependent manner
| Autor: | Weihong Zhou, Botond Banfi, Qiang Li, Duane Abbott, John F. Engelhardt, Yulong Zhang, Meihui Luo, Thomas J. Lynch, Netanya Y. Spencer, Ziying Yan |
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| Rok vydání: | 2013 |
| Předmět: |
Physiology
Blotting Western Gadolinium Gene Expression Regulation Enzymologic CSK Tyrosine-Protein Kinase Mice Physiology (medical) medicine Animals chemistry.chemical_classification Mice Knockout Reactive oxygen species NADPH oxidase Hepatology biology Tumor Necrosis Factor-alpha Gastroenterology NF-kappa B NADPH Oxidase 1 NADPH Oxidases NFKB1 Molecular biology Liver and Biliary Tract medicine.anatomical_structure src-Family Kinases chemistry Biochemistry Liver Hepatocyte NOX1 Reperfusion Injury Knockout mouse biology.protein cardiovascular system Hepatocytes Tumor necrosis factor alpha Reactive Oxygen Species |
| Zdroj: | American journal of physiology. Gastrointestinal and liver physiology. 305(1) |
| ISSN: | 1522-1547 |
| Popis: | Cell line studies have previously demonstrated that hypoxia-reoxygenation (H/R) leads to the production of NADPH oxidase 1 and 2 (NOX1 and NOX2)-dependent reactive oxygen species (ROS) required for the activation of c-Src and NF-κB. We now extend these studies into mouse models to evaluate the contribution of hepatocytes to the NOX- and c-Src-dependent TNF-α production that follows H/R in primary hepatocytes and liver ischemia-reperfusion (I/R). In vitro, c-Src-deficient primary hepatocytes produced less ROS and TNF-α following H/R compared with controls. In vivo, c-Src-KO mice also had impaired TNF-α and NF-κB responses following partial lobar liver I/R. Studies in NOX1 and p47phox knockout primary hepatocytes demonstrated that both NOX1 and p47phox are partially required for H/R-mediated TNF-α production. To further investigate the involvement of NADPH oxidases in the production of TNF-α following liver I/R, we performed additional in vivo experiments in knockout mice deficient for NOX1, NOX2, p47phox, Rac1, and/or Rac2. Cumulatively, these results demonstrate that NOX2 and its activator subunits (p47phox and Rac) control the secretion of TNF-α by the liver following I/R. Interestingly, in the absence of Kupffer cells and NOX2, NOX1 played a dominant role in TNF-α production following hepatic I/R. However, NOX1 deletion alone had little effect on I/R-induced TNF-α. Thus Kupffer cell-derived factors and NOX2 act to suppress hepatic NOX1-dependent TNF-α production. We conclude that c-Src and NADPH oxidase components are necessary for redox-mediated production of TNF-α following liver I/R and that hepatocytes play an important role in this process. |
| Databáze: | OpenAIRE |
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