PTPRO plays a dual role in hepatic ischemia reperfusion injury through feedback activation of NF-κB

Background & Aims: Nuclear factor-kappa B (NF-kappa B) activation in hepatocytes and macrophages appeared as a double-edgedsword in hepatic ischemia reperfusion (IR) injury. Protein tyrosine phosphatase receptor type O (PTPRO) was recently identified as a potential activator of c-Src, which can in turn activate the NF-kappa B pathway. In this study, we aimed to determine the change and function of PTPRO in hepatocytes and macrophages during IR. Methods: Clinical patients with benign liver condition undergoing liver surgery were recruited in our study. Wild type (WT) and ptpro(-/-) C57BL/6 mice were processed to construct hepatic IR models. Isolated mouse hepatocytes and macrophages were treated with peroxide or TNFa in vitro. Results: In human and mouse IR models, PTPRO level was decreased in the early phase but reversed in the late phase. In vitro studies demonstrated that NF-kappa B up-regulated PTPRO transcription. Using ptpro(-/-) mice and primary cells, we found that PTPRO deficiency resulted in reduction of NF-kappa B activation in both hepatocytes and macrophages and was correlated to c-Src phosphorylation; PTPRO in hepatocytes alleviated, but PTPROt in macrophages exacerbated IR injury. Conclusions: PTPRO activates NF-kappa B in a positive feedback manner, and plays a dual role in hepatic IR injury. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.