title: Survival and inflammation promotion effect of PTPRO in fulminant hepatitis is associated with NF-κB activation.
abstract: Previous investigations demonstrated that protein tyrosine phosphatase, receptor type, O (PTPRO) acts as a tumor suppressor in liver cancer; however, little is known about its role in liver inflammation. Thus, we investigated the role of PTPRO in fulminant hepatitis (FH) using a Con A-induced mouse model. Significantly more severe liver damage, but attenuated inflammation, was detected in PTPRO-knockout (KO) mice, and PTPRO deficiency could confer this phenotype to wild-type mice in bone marrow transplantation. Moreover, hepatocytes with PTPRO depletion were more sensitive to TNF-α-induced apoptosis, and secretion of cytokines was significantly decreased in both T and NK/NKT cells and led to marked impairment of NF-κB activation. Intriguingly, wild-type and PTPRO-KO cells responded equally to TNF-α in activation of IKK, but NF-κB activation was clearly decreased in PTPRO-KO cells. PTPRO associated with ErbB2, and loss of PTPRO potentiated activation of the ErbB2/Akt/GSK-3β/β-catenin cascade. Increased β-catenin formed a complex with NF-κB and attenuated its nuclear translocation and activation. Importantly, in humans, PTPRO was much decreased in FH, and this was associated with enhanced β-catenin accumulation but reduced IFN-γ secretion. Taken together, our study identified a novel PTPRO/ErbB2/Akt/GSK-3β/β-catenin/NF-κB axis in FH, which suggests that PTPRO may have therapeutic potential in this liver disease.
authors.affiliation: Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and.
authors.forename: Runqiu
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and.
authors.forename: Dianyu
authors.initials: D
authors.lastname: Chen
authors.affiliation: Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and.
authors.forename: Jiajie
authors.initials: J
authors.lastname: Hou
authors.affiliation: Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and.
authors.forename: Youjing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, People's Republic of China.
authors.forename: Xingxu
authors.initials: X
authors.lastname: Huang
authors.affiliation: Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and.
authors.forename: Xuehao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, People's Republic of China; Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, People's Republic of China; and sunbc@njmu.edu.cn.
authors.forename: Beicheng
authors.initials: B
authors.lastname: Sun
mesh_terms: D000208:Acute Disease; D000818:Animals; D003208:Concanavalin A; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000276:immunology; D000071679:Glycogen Synthase Kinase 3 beta; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000401:mortality / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012720:Severity of Illness Index; D015398:Signal Transduction; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D051176:beta Catenin / Q000235:genetics / Q000276:immunology*
chemical_list: D003208:Concanavalin A; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007371:Interferon-gamma; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D051176:beta Catenin; C524056:Erbb2 protein, mouse; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C516890:Ptpro protein, mouse