PTEN-mediated Akt/?-catenin/Foxo1 signaling regulates innate immune responses in mouse liver ischemia/reperfusion injury.
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ABSTRACT: The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulates innate immune responses inversely with phosphoinositide 3-kinase (PI3K) and its direct downstream target gene, Akt. The Forkhead box O (Foxo) transcription factors are essential in the regulation of tissue development, immune homeostasis, and cell survival. This study was designed to investigate the role of PTEN-mediated Akt/?-catenin/Foxo1 signaling in the regulation of in vivo and in vitro innate immune responses in a mouse model of hepatic inflammatory injury induced by 90 minutes of liver partial warm ischemia followed by 6 hours of reperfusion. We found that knockdown of PTEN with small interfering RNA (siRNA) promoted Akt/?-catenin/Foxo1 signaling, leading to resistance against liver ischemia/reperfusion (IR) damage, local enhancement of antiapoptotic function, and downregulation of innate Toll-like receptor 4 (TLR4) expression. A specific PI3K blockade inhibited Akt/?-catenin signaling, increased Foxo1-mediated TLR4-driven local inflammation, and recreated cardinal features of liver IR injury. Moreover, knockdown of PTEN in lipopolysaccharide-stimulated mouse bone marrow-derived macrophages enhanced ?-catenin activity, which in turn provided a negative regulatory feedback to the Foxo1 function, leading to the inhibition of TLR4 and NF-?B, with ultimate depression of proinflammatory cytokine programs in vitro.Our novel findings identify the PTEN-mediated Akt/?-catenin/Foxo1 axis as a key regulator of innate inflammatory response in the mouse liver. By identifying molecular mechanisms of PTEN-mediated Akt/?-catenin/Foxo1 signaling in TLR4 innate immune regulation, our study provides a rationale for therapeutic approaches to manage inflammation injury in IR-stressed liver.
SUBMITTER: Kamo N
PROVIDER: S-EPMC3524373 | biostudies-literature | 2013 Jan
REPOSITORIES: biostudies-literature
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