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J Hepatol. 2009 Aug;51(2):296-306. doi: 10.1016/j.jhep.2009.04.016. Epub 2009 May 24.

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

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  • 1The Laboratory of Trauma, Sepsis & Inflammation Research, Department of Surgery, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0558, USA.



Our previous work suggested an important role for the peptidyl-prolyl isomerase, Pin1, in hepatic NF-kappaB activation and liver injury during ischemia/reperfusion (I/R). In this study, we sought to determine the function of Pin1 in the injury response to hepatic I/R.


Wild-type and Pin1(-/-) mice were subjected to partial hepatic I/R. In addition, hepatocytes and Kupffer cells were isolated from these mice.


Pin1(-/-) mice had reduced hepatic NF-kappaB 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-kappaB activation was not a result of a defect in nuclear translocation of NF-kappaB. In fact, hepatic nuclear p65 protein expression was higher in Pin1(-/-) mice than wild-type mice. This suggests that Pin1 is important for NF-kappaB-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-kappaB and production of cytokines after stimulation. In contrast, hepatocytes stimulated with TNFalpha had greatly reduced NF-kappaB activation, reduced production of the CXC chemokine, MIP-2, and increased cell death.


These data suggest that Pin1 is a critical regulator of NF-kappaB activation in hepatocytes and its role in these cells appears to confer direct protective effects.

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