[PDF][PDF] PTEN‐mediated akt/β‐Catenin/foxo1 signaling regulates innate immune responses in mouse liver ischemia/reperfusion injury

N Kamo, B Ke, RW Busuttil, JW Kupiec‐Weglinski - Hepatology, 2013 - Wiley Online Library
N Kamo, B Ke, RW Busuttil, JW Kupiec‐Weglinski
Hepatology, 2013Wiley Online Library
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/β‐catenin/Foxo1 signaling in the
regulation of in vivo and in vitro innate immune responses in a mouse model of hepatic …
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/β‐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/β‐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/β‐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 β‐catenin activity, which in turn provided a negative regulatory feedback to the Foxo1 function, leading to the inhibition of TLR4 and NF‐κB, with ultimate depression of proinflammatory cytokine programs in vitro. Conclusion: Our novel findings identify the PTEN‐mediated Akt/β‐catenin/Foxo1 axis as a key regulator of innate inflammatory response in the mouse liver. By identifying molecular mechanisms of PTEN‐mediated Akt/β‐catenin/Foxo1 signaling in TLR4 innate immune regulation, our study provides a rationale for therapeutic approaches to manage inflammation injury in IR‐stressed liver. (HEPATOLOGY 2013)
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