Journal article
Hepatocytes produce TNF-α following hypoxia-reoxygenation and liver ischemia-reperfusion in a NADPH oxidase- and c-Src-dependent manner
American journal of physiology: Gastrointestinal and liver physiology, Vol.305(1), pp.G84-G94
07/01/2013
DOI: 10.1152/ajpgi.00430.2012
PMCID: PMC3725690
PMID: 23639811
Abstract
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.
Details
- Title: Subtitle
- Hepatocytes produce TNF-α following hypoxia-reoxygenation and liver ischemia-reperfusion in a NADPH oxidase- and c-Src-dependent manner
- Creators
- Netanya Y Spencer - Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IowaWeihong Zhou - Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IowaQiang Li - Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IowaYulong Zhang - Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IowaMeihui Luo - Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IowaZiying Yan - Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IowaThomas J Lynch - Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IowaDuane Abbott - Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IowaBotond Banfi - Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IowaJohn F Engelhardt - Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- American journal of physiology: Gastrointestinal and liver physiology, Vol.305(1), pp.G84-G94
- DOI
- 10.1152/ajpgi.00430.2012
- PMID
- 23639811
- PMCID
- PMC3725690
- NLM abbreviation
- Am J Physiol Gastrointest Liver Physiol
- ISSN
- 0193-1857
- eISSN
- 1522-1547
- Language
- English
- Date published
- 07/01/2013
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Surgery; Radiation Oncology; Cardiothoracic Surgery; Otolaryngology; Internal Medicine
- Record Identifier
- 9984025473802771
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