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

Abstract

Background & aims: Nuclear factor-κB (NF-κB) activation in hepatocytes and macrophages appeared as a double-edged-sword 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-κB 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 TNFα 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-κB up-regulated PTPRO transcription. Using ptpro(-/-) mice and primary cells, we found that PTPRO deficiency resulted in reduction of NF-κB 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-κB in a positive feedback manner, and plays a dual role in hepatic IR injury.

Keywords: HCC; Hepatic ischemia reperfusion injury; IKK; IL-1β; IR; IκB; IκB kinase; JNK; Jun N-terminal kinase; KCs; NF-κB; Nuclear factor-κB; PTP; PTPRO; Protein tyrosine phosphatase receptor type O; ROS; SHP2; STAT; Src homology domain-containing phosphatase-2; TNFα; c-Src; hepatocellular carcinoma; inhibitor of NF-κB; interleukin-1β; ischemia reperfusion; kupffer cells; phosphotyrosine phosphatase; reactive oxygen species; signal transducers and activators of transcription; tumor necrosis factor α.