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.
Copyright © 2014 by The American Association of Immunologists, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Animals
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Concanavalin A
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Gene Expression Regulation
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / immunology
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Glycogen Synthase Kinase 3 beta
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Hepatitis, Animal / chemically induced
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Hepatitis, Animal / immunology*
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Hepatitis, Animal / mortality
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Hepatitis, Animal / pathology
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Hepatocytes / immunology*
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Hepatocytes / pathology
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Humans
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Inflammation / chemically induced
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Inflammation / immunology
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Inflammation / mortality
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Inflammation / pathology
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Killer Cells, Natural / immunology
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Killer Cells, Natural / pathology
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Liver / immunology*
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Liver / pathology
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Male
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Mice
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Mice, Knockout
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NF-kappa B / agonists
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NF-kappa B / genetics
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NF-kappa B / immunology*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / immunology
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / immunology
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Receptor-Like Protein Tyrosine Phosphatases, Class 3 / deficiency
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Receptor-Like Protein Tyrosine Phosphatases, Class 3 / genetics
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Receptor-Like Protein Tyrosine Phosphatases, Class 3 / immunology*
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Severity of Illness Index
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Signal Transduction
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Survival Analysis
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T-Lymphocytes / immunology
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T-Lymphocytes / pathology
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beta Catenin / genetics
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beta Catenin / immunology*
Substances
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NF-kappa B
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beta Catenin
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Concanavalin A
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Interferon-gamma
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Erbb2 protein, mouse
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Receptor, ErbB-2
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
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Ptpro protein, mouse
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Receptor-Like Protein Tyrosine Phosphatases, Class 3