The peptidyl-prolyl isomerase, Pin1, facilitates NF-κB binding in hepatocytes and protects against hepatic ischemia/reperfusion injury

JOURNAL OF HEPATOLOGY

卷:51

Article

Kuboki, Satoshi¹  Sakai, Nozomu¹  Clarke, Callisia¹  Schuster, Rebecca¹  Blanchard, John¹  Edwards, Michael J.¹  Lentsch, Alex B.¹ 

[1] Univ Cincinnati, Dept Surg, Lab Trauma Sepsis & Inflammat Res, Cincinnati, OH 45267 USA

关键词: Liver;    Hepatocytes;    Ischemia/reperfusion;    Pin1;    NF-kappa B;   

DOI  :  10.1016/j.jhep.2009.04.016

来源: Elsevier

【 摘 要 】

Background/Aims: Our previous work suggested an important role for the peptidyl-prolyl isomerase, Pint, in hepatic NF-kappa B activation and liver injury during ischemia/reperfusion (I/R). In this study, we sought to determine the function of Pint in the injury response to hepatic I/R. Methods: Wild-type and Pin1-/- mice were subjected to partial hepatic I/R. In addition, hepatocytes and Kupffer cells were isolated from these mice. Results: Pin1-/- mice had reduced hepatic NF-kappa B activation and more liver injury after I/R than wild-type mice. The increased injury was not a result of enhanced inflammation as Pin1-/- mice had the same level of proinflammatory cytokine production and less neutrophil accumulation in the liver. The reduced NF-kappa B activation was not a result of a defect in nuclear translocation of NF-kappa B. In fact, hepatic nuclear p65 protein expression was higher in Pin1-/- mice than wild-type mice. This suggests that Pint is important for NF-kappa B-DNA binding. This effect was specific to hepatocytes as isolated Kupffer cells from wild-type and Pin1 -/- mice were identical in their activation of NF-kappa B and production of cytokines after stimulation. In contrast, hepatocytes stimulated with TNF alpha had greatly reduced NF-kappa B activation, reduced production of the CXC chemokine, MIP-2, and increased cell death. Conclusions: These data suggest that Pin1 is a critical regulator of NF-kappa B activation in hepatocytes and its role in these cells appears to confer direct protective effects. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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