BACKGROUND/AIMS: 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. 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-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. CONCLUSIONS: 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.
BACKGROUND/AIMS: 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. 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-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. CONCLUSIONS: 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.
Authors: Stephane Esnault; Louis A Rosenthal; Zhong-Jian Shen; Julie B Sedgwick; Renee J Szakaly; Ronald L Sorkness; James S Malter Journal: J Allergy Clin Immunol Date: 2007-08-27 Impact factor: 10.793
Authors: Nozomu Sakai; Heather L Van Sweringen; Rebecca Schuster; John Blanchard; Justin M Burns; Amit D Tevar; Michael J Edwards; Alex B Lentsch Journal: Hepatology Date: 2012-01-13 Impact factor: 17.425
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Authors: Nozomu Sakai; Heather L Van Sweringen; R Cutler Quillin; Rebecca Schuster; John Blanchard; Justin M Burns; Amit D Tevar; Michael J Edwards; Alex B Lentsch Journal: Hepatology Date: 2012-10 Impact factor: 17.425