Premium
Redox‐Dependent Hepatocyte TNFα Secretion Following Reoxygenation Injury
Author(s) -
Spencer Netanya Y.,
Zhou Weihong,
Li Qiang,
Zhang Yulong,
Abbott Duane,
Banfi Botond,
Engelhardt John F.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.682.12
Subject(s) - nox1 , nadph oxidase , in vivo , chemistry , hepatocyte , tumor necrosis factor alpha , reactive oxygen species , secretion , microbiology and biotechnology , endocrinology , biology , biochemistry , in vitro
Cell line studies have previously shown 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 NFκB. We now extend these studies into mouse models to evaluate the contribution of hepatocytes to the NOX‐ and c‐Src‐dependent TNFα production that follows H/R and liver ischemia/reperfusion (I/R). In vitro , c‐Src‐knockout (KO) primary hepatocytes produced less ROS and TNFα following H/R than controls. In vivo , c‐Src KO mice also had impaired TNFα and NFκB responses following partial liver I/R. We found that NOX1 and p47 phox are partially required for H/R‐mediated TNFα production by primary hepatocytes. In vivo experiments in KO mice deficient for NOX1, NOX2, p47 phox , Rac1, and/or Rac2 showed that compared to controls, all of these KO mice, except NOX1 KO, had significantly decreased serum TNFα after I/R injury. These results demonstrate that NOX2 and its activator subunits p47 phox and Rac control liver secretion of TNFα following I/R. Interestingly, NOX1 played a major role in secretion of TNFα by primary hepatocytes following in vitro H/R, but not following in vivo I/R. Thus, NOX2 can compensate for loss of NOX1 in vivo . We conclude that c‐Src and NADPH oxidase components are necessary for redox‐mediated production of TNFα following liver I/R and that hepatocytes play an important role in this process.