Survival and inflammation promotion effect of PTPRO in fulminant hepatitis is associated with NF-κB activation

J Immunol. 2014 Nov 15;193(10):5161-70. doi: 10.4049/jimmunol.1303354. Epub 2014 Oct 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Concanavalin A
  • Gene Expression Regulation
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / immunology
  • Glycogen Synthase Kinase 3 beta
  • Hepatitis, Animal / chemically induced
  • Hepatitis, Animal / immunology*
  • Hepatitis, Animal / mortality
  • Hepatitis, Animal / pathology
  • Hepatocytes / immunology*
  • Hepatocytes / pathology
  • Humans
  • Inflammation / chemically induced
  • Inflammation / immunology
  • Inflammation / mortality
  • Inflammation / pathology
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / pathology
  • Liver / immunology*
  • Liver / pathology
  • Male
  • Mice
  • Mice, Knockout
  • NF-kappa B / agonists
  • NF-kappa B / genetics
  • NF-kappa B / immunology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / immunology
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / immunology
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / deficiency
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / immunology*
  • Severity of Illness Index
  • Signal Transduction
  • Survival Analysis
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • beta Catenin / genetics
  • beta Catenin / immunology*

Substances

  • NF-kappa B
  • beta Catenin
  • Concanavalin A
  • Interferon-gamma
  • Erbb2 protein, mouse
  • Receptor, ErbB-2
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Ptpro protein, mouse
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3