Dataset Information

Resveratrol Pretreatment Attenuates Concanavalin A-induced Hepatitis through Reverse of Aberration in the Immune Response and Regenerative Capacity in Aged Mice.

ABSTRACT: Loss of regenerative capacity plays a critical role in age-related autoimmune hepatitis. Evidence implicates SIRT1 and p66^shc in cell senescence, apoptosis, oxidative stress, and proliferation. This study investigated the effect of resveratrol on concanavalin A (Con A)-induced hepatitis in aged mice and the roles of SIRT1 and p66^shc. Aged mice were administrated resveratrol (30?mg/kg orally) seven times at an interval of 12?h before a single intravenous injection of Con A (20?mg/kg). Results showed that the cytokines, TNF-?, IL-6, IFN-?, and MCP-1, as well as infiltration of macrophages, neutrophils, and T lymphocytes in liver were dramatically enhanced in the mice given only Con A. The aged mouse livers showed markedly raised oxidative stress and cell apoptosis. This oxidative stress further aggravated regenerative dysfunction as indicated by the decreased levels of Ki67, PCNA, Cyclin D1, and Cdk2. Conversely, these phenomena were attenuated by pretreatment with resveratrol. Moreover, resveratrol suppressed the elevation of p66^shc in the liver by reversing Con-A-mediated downregulation of SIRT1. The findings suggest that resveratrol protected against Con A-induced hepatitis in aged mice by attenuating an aberration of immune response and liver regeneration, partially via the mechanism of SIRT1-mediated repression of p66^shc expression.

SUBMITTER: Huang TH

PROVIDER: S-EPMC5457448 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Resveratrol Pretreatment Attenuates Concanavalin A-induced Hepatitis through Reverse of Aberration in the Immune Response and Regenerative Capacity in Aged Mice.

Huang Tse-Hung TH Chen Chin-Chang CC Liu Hsuan-Miao HM Lee Tzung-Yan TY Shieh Sue-Heui SH

Scientific reports 20170602 1

Loss of regenerative capacity plays a critical role in age-related autoimmune hepatitis. Evidence implicates SIRT1 and p66<sup>shc</sup> in cell senescence, apoptosis, oxidative stress, and proliferation. This study investigated the effect of resveratrol on concanavalin A (Con A)-induced hepatitis in aged mice and the roles of SIRT1 and p66<sup>shc</sup>. Aged mice were administrated resveratrol (30 mg/kg orally) seven times at an interval of 12 h before a single intravenous injection of Con A ( ...[more]

PMID: 28578410

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Project description:BackgroundAs a kind of mesenchymal-like stromal cells, endometrial regenerative cells (ERCs) have been demonstrated effective in the treatment of Concanavalin A (Con A)-induced hepatitis. However, the therapeutic mechanism of ERCs is not fully understood. Ecto-5`-nucleotidase (CD73), an enzyme that could convert immune-stimulative adenosine monophosphate (AMP) to immune-suppressive adenosine (ADO), was identified highly expressed on ERCs. The present study was conducted to investigate whether the expression of CD73 on ERCs is critical for its therapeutic effects in Con A-induced hepatitis.MethodsERCs knocking out CD73 were generated with lentivirus-mediated CRISPR-Cas9 technology and identified by flow cytometry, western blot and AMPase activity assay. CD73-mediated immunomodulatory effects of ERCs were investigated by CD4+ T cell co-culture assay in vitro. Besides, Con A-induced hepatitis mice were randomly assigned to the phosphate-buffered saline treated (untreated), ERC-treated, negative lentiviral control ERC (NC-ERC)-treated, and CD73-knockout-ERC (CD73-KO-ERC)-treated groups, and used to assess the CD73-mediated therapeutic efficiency of ERCs. Hepatic histopathological analysis, serum transaminase concentrations, and the proportion of CD4+ T cell subsets in the liver and spleen were performed to assess the progression degree of hepatitis.ResultsExpression of CD73 on ERCs could effectively metabolize AMP to ADO, thereby inhibiting the activation and function of conventional CD4+ T cells was identified in vitro. In addition, ERCs could markedly reduce levels of serum and liver transaminase and attenuate liver damage, while the deletion of CD73 on ERCs dampens these effects. Furthermore, ERC-based treatment achieved less infiltration of CD4+ T and Th1 cells in the liver and reduced the population of systemic Th1 and Th17 cells and the levels of pro-inflammatory cytokines such as IFN-γ and TNF-α, while promoting the generation of Tregs in the liver and spleen, while deletion of CD73 on ERCs significantly impaired their immunomodulatory effects locally and systemically.ConclusionTaken together, it is concluded that CD73 is critical for the therapeutic efficiency of ERCs in the treatment of Con A-induced hepatitis.

Project description:Autoimmune hepatitis (AIH) is an inflammatory liver disease caused by a dysregulated immune response. Although the pathogenesis of AIH remains unclear, impaired regulatory T cells (Tregs) have been considered a driver of AIH development. Unlike autoreactive T cells, Tregs mainly utilize oxidative phosphorylation (OXPHOS) as their energy supply. Elevated glycolysis has been reported to limit the suppressive functions of Tregs. However, whether glucose metabolism reprogramming in Tregs is involved in AIH etiology remains unknown. The aim of this study was to examine alternations in Treg numbers and functions in AIH patients and concanavalin A (Con A)-induced hepatitis, while exploring associations between impaired Tregs and glucose metabolism. The frequency of Tregs was decreased in the peripheral blood but increased in liver biopsies of AIH patients. Moreover, immunosuppressive therapy rescued circulating Tregs in AIH. In Con A-induced immune hepatitis, enhanced intrahepatic Treg accumulation was observed over time, accompanied by reduced splenic Treg numbers. To investigate whether functional impairment of Tregs occurs in AIH, Tregs were isolated from experimental AIH (EAH) model mice and normal controls and the former displayed downregulated mRNA levels of FOXP3, CTLA4, CD103, TIGIT, CD39, and CD73. EAH model-derived Tregs also produced fewer anti-inflammatory mediators (TGF-β and IL-35) than control Tregs. Moreover, enhanced glycolysis and reduced OXPHOS were found in Tregs from EAH model mice, as reflected by elevated levels of key glycolytic enzymes (HK2, PK-M2, and LDH-A) and a decreased ATP concentration. This study revealed a decreased peripheral Treg frequency and abnormal intrahepatic Treg infiltration in AIH. It is first reported that glucose metabolism reprogramming is associated with decreases and functional impairments in the Treg population, promoting AIH development. Targeting glucose metabolism may provide novel insights for the treatment of AIH.

Dataset Information

Resveratrol Pretreatment Attenuates Concanavalin A-induced Hepatitis through Reverse of Aberration in the Immune Response and Regenerative Capacity in Aged Mice.

Publications

Resveratrol Pretreatment Attenuates Concanavalin A-induced Hepatitis through Reverse of Aberration in the Immune Response and Regenerative Capacity in Aged Mice.

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