title: PTPRO plays a dual role in hepatic ischemia reperfusion injury through feedback activation of NF-κB.
abstract: OBJECTIVE
  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.
authors.affiliation: State Key Laboratory of Reproductive Medicine and Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing, PR China.
authors.forename: Jiajie
authors.initials: J
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Reproductive Medicine and Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing, PR China.
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Reproductive Medicine and Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing, PR China.
authors.forename: Runqiu
authors.initials: R
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Reproductive Medicine and Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing, PR China.
authors.forename: Dianyu
authors.initials: D
authors.lastname: Chen
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Reproductive Medicine and Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Deng
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, PR China.
authors.forename: Xingxu
authors.initials: X
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Reproductive Medicine and Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing, PR China.
authors.forename: Xuehao
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Medicine and Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing, PR China. Electronic address: sunbc@njmu.edu.cn.
authors.forename: Beicheng
authors.initials: B
authors.lastname: Sun
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D015870:Gene Expression; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000293:injuries* / Q000473:pathology; D008264:Macrophages / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C516888:PTPRO protein, human; C516890:Ptpro protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3
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