- 作者：Bibo Ke ; Xiu-Da Shen ; Haofeng Ji ; Naoko Kamo ; Feng Gao ; Maria Cecilia S. Freitas ; Ronald W. Busuttil ; Jerzy W. Kupiec-Weglinski ; jkupiec@mednet.ucla.edu
- 关键词：Ad-HO-1 ; recombinant adenovirus encoding hemeoxygenase-1 ; Ad-¦Â-gal ; recombinant adenovirus ¦Â-galactosidase reporter gene ; BMMs ; bone marrow derived-macrophages ; IRI ; ischemia/reperfusion injury ; MPO ; myeloperoxidase ; PI3K ; phosphoinositide 3-kinase ; PTE
- 刊名：Journal of Hepatology
- 出版年：2012
- 出版时间：February 2012
- 年：2012
- 卷：56
- 期：2
- 页码：359-366
- 全文大小：1482 K
Background & Aims
Signal transducer and activator of transcription 3 (STAT3), a key mediator of anti-inflammatory cytokine signaling, is essential for heme oxygenase-1 (HO-1)-induced cytoprotection. The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog delete on chromosome 10 (PTEN) pathways regulate diverse innate immune responses. This study was designed to investigate the role of STAT3 in the regulation of PI3K/PTEN cascade after HO-1 induction in a mouse model of innate immune-dominated liver ischemia/reperfusion injury (IRI).Methods
Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90 min, followed by 6 h of reperfusion.
Results
Mice subjected to Ad-HO-1 transfer were resistant to liver IRI, and this cytoprotective effect correlated with increased intrahepatic PI3K/Akt and diminished PTEN expression. In contrast, mice undergoing adjunctive Ad-HO-1 treatment and STAT3 knockdown (siRNA) remained susceptible to IR-mediated local inflammatory response and hepatocellular damage. Consistent with decreased cell apoptosis and inhibited TLR4 expression after PI3K/Akt activation, treatment with specific PI3k inhibitor increased local inflammation and recreated liver IRI despite Ad-HO-1 gene transfer. Parallel in vitro studies with bone marrow derived-macrophages have confirmed that HO-1-STAT3 axis-induced PI3K/Akt negatively regulated PTEN expression in TLR4-dependent fashion.
Conclusions
These findings underscore the role of HO-1 induced STAT3 in modulating PI3K/PTEN in liver IRI cascade. Activating PI3K/Akt provides negative feedback mechanism for TLR4-driven inflammation. Identifying molecular pathways of STAT3 modulation in the innate immune system provides the rationale for novel therapeutic approaches for the management of liver inflammation and IRI in transplant patients.