| First Author | Spencer NY | Year | 2013 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 305 |
| Issue | 1 | Pages | G84-94 |
| PubMed ID | 23639811 | Mgi Jnum | J:202785 |
| Mgi Id | MGI:5521445 | Doi | 10.1152/ajpgi.00430.2012 |
| Citation | Spencer NY, et al. (2013) Hepatocytes produce TNF-alpha following hypoxia-reoxygenation and liver ischemia-reperfusion in a NADPH oxidase- and c-Src-dependent manner. Am J Physiol Gastrointest Liver Physiol 305(1):G84-94 |
| abstractText | 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-kappaB. We now extend these studies into mouse models to evaluate the contribution of hepatocytes to the NOX- and c-Src-dependent TNF-alpha 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-alpha following H/R compared with controls. In vivo, c-Src-KO mice also had impaired TNF-alpha and NF-kappaB 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-alpha production. To further investigate the involvement of NADPH oxidases in the production of TNF-alpha 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-alpha by the liver following I/R. Interestingly, in the absence of Kupffer cells and NOX2, NOX1 played a dominant role in TNF-alpha production following hepatic I/R. However, NOX1 deletion alone had little effect on I/R-induced TNF-alpha. Thus Kupffer cell-derived factors and NOX2 act to suppress hepatic NOX1-dependent TNF-alpha production. We conclude that c-Src and NADPH oxidase components are necessary for redox-mediated production of TNF-alpha following liver I/R and that hepatocytes play an important role in this process. |
