IL-25 prevents and cures fulminant hepatitis in mice through a myeloid-derived suppressor cell-dependent mechanism

Sarra, Massimiliano; Cupi, Maria Laura; Bernardini, Roberta; Ronchetti, G; Monteleone, Ivan; Ranalli, Marco; Franzè, Eleonora; Rizzo, Angelamaria; Colantoni, Alfredo; Caprioli, Flavio; Maggioni, Marco; Gambacurta, Alessandra; Mattei, Maurizio; MacDonald, Thomas T.; Pallone, Francesco; Monteleone, Giovanni

doi:10.1002/hep.26446

Cited by 45 publications

(49 citation statements)

References 36 publications

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“…Among several pro-inflammatory cytokines involved, TNF-α and IFN-γ play a critical role in protecting mice from Con A-induced liver injury (Gantner et al, 1995;Kusters et al, 1996). Earlier reports demonstrated that cytokines TNF-α (Schumann et al, 2000) and IFN-γ (Sarra et al, 2013) were essential to trigger liver injury in Con A model, and we found that Con A stimulation triggers higher TNF-α and IFN-γ expression in serum. These variations of cytokine expression were in accordance with the observed changes in aminopherase activity and histopathology.…”

Section: Discussionsupporting

confidence: 62%

Dexmedetomidine premedication attenuates concanavalin A-induced hepatitis in mice

Wang

Zou

et al. 2014

J. Toxicol. Sci.

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-Activated T cells selectively induced by concanavalin A (Con A) in liver are subsequent efficient resolution of inflammation. Activated T cells infiltrating in liver combined with pro-inflammatory cytokines are the major causes in Con A-induced liver injury. In our study, C57/BL mice were injected with Con A combined with dexmedetomidine or not. ALT and AST in blood and histopathology of liver were measured. T cell infiltration in liver was examined by flow cytometry and pro-inflammatory cytokines including IL-6, IL-10, TNF-α, and IFN-γ in blood were measured by ELISA. The mRNA level of CXCL10 was detected by RT-PCR and the protein level of NF-κB was measured by Western-blot. We found that dexmedetomidine alleviated Con A-induced liver injury by down-regulating levels of ALT and AST in blood and the severity of histopathology, which reflect the severity of hepatitis induced by Con A. In addition, pro-inflammatory cytokines in blood were attenuated by dexmedetomidine. Dexmedetomidine restrained the phosphorylation of NF-κB IκBα and P-65 dramatically which may participate in the regulation of cytokines secretion. Moreover, CXCL10 mRNA attenuated by dexmedetomidine in liver may result in the lower level of CD4 + T cells infiltration in liver. These results suggested that dexmedetomidine might be a potential compound in treating T cell-mediated liver injury.

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Section: Discussionsupporting

confidence: 62%

Dexmedetomidine premedication attenuates concanavalin A-induced hepatitis in mice

Wang

Zou

et al. 2014

J. Toxicol. Sci.

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“…Hepatocytes are capable of producing IL-25 and decreased hepatic IL-25 expression has been reported in humans or mice with hepatitis (14). We established a HFD-induced model of hepatic steatosis in mice and evaluated a role of IL-25 in NAFLD.…”

Section: Resultsmentioning

confidence: 99%

“…The highest levels of IL-25 are found in the gastrointestinal tract and lung, where it is expressed primarily by epithelial cells and certain types of immune cells (8, 9, 11–13). More recently, a study showed that hepatocytes were capable of producing IL-25 and decreased hepatic IL-25 was observed in animals or humans with hepatitis (14). Whether IL-25 is involved in regulation of lipid metabolism and associated hepatic steatosis is not known.…”

Section: Introductionmentioning

confidence: 99%

IL-25 or IL-17E Protects against High-Fat Diet–Induced Hepatic Steatosis in Mice Dependent upon IL-13 Activation of STAT6

Wang

Yang

Grinchuk

et al. 2015

The Journal of Immunology

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Interleukin-25 or IL-17E is a member of IL-17 cytokine family and has immune-modulating activities. The role of IL-25 in maintaining lipid metabolic homeostasis remains unknown. We investigated the effects of exogenous IL-25 or deficiency of IL-25 on hepatic lipid accumulation. IL-25 expression was examined in paraffin-embedded tissue sections of liver from patients or in the livers from mice. Mouse model of steatosis was induced by feeding a high-fat diet (HFD). Extent of steatosis as well as expression of cytokines, key enzymes for lipid metabolic pathways, markers for Kupffer cells/macrophages, and lipid droplet proteins were analyzed. Our results show that hepatic steatosis in mice was accompanied by increased lipid droplet proteins, but decreased IL-25 in the liver. Decreased hepatic IL-25 was also observed in patients with fatty liver. Administration of IL-25 to HFD-fed wild-type mice led to a significant improvement in hepatic steatosis. This effect was associated with increased expression of IL-13, development of alternatively-activated Kupffer cells/macrophages, and decreased expression of lipid droplet proteins in the liver. In contrast, administration of IL-25 to HFD-fed mice deficient in STAT6 or IL-13 had no effects. In addition, stimulation of primary hepatocytes with IL-13, but not IL-25, resulted in down-regulation of lipid droplet proteins. Finally, mice deficient in IL-25 had exacerbated hepatic lipid accumulation when fed the HFD. These data demonstrate that dysregulated IL-25 expression contributes to lipid accumulation, while exogenous IL-25 protects against hepatic steatosis through IL-13 activation of STAT6. IL-25 and IL-13 are potential therapeutic agents for hepatic steatosis and associated pathologies.

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“…Later studies using dexamethasone show that its positive effect is specifically due to an increased MDSC induction [20]. Next to this, cannabidiol, a non-psychoactive cannabinoid and IL-25 treatment can reduce ConA induced inflammation and protect mice from liver injury by triggering the induction of MDSCs, opening a new window for therapeutic strategies [66,67].…”

Section: Therapeutic Interventionsmentioning

confidence: 99%

“…Different therapeutic interventions have been shown to be associated with the induction and/or expansion of MDSCs during ConA-induced liver inflammation [20,66,67]. For example, treatment with glucocorticoids, which are strong anti-inflammatory molecules working through the GC receptor GR, led to accumulation of MDSCs and protected against liver injury [20,166].…”

Section: Myeloid-derived Suppressor Cellsmentioning

confidence: 99%

Different Cell Types Involved in Mediating Concanavalin A Induced Liver Injury: A Comprehensive Overview

2016

GHR

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• Concanavalin A (ConA) induced T cell infiltration and liver injury is a model for acute hepatitis• Important cell types include most white blood cells as well as stromal cells• The ConA model has successfully been used to discover new pathways in hepatitis research• New therapeutic interventions for hepatitis were discovered using the ConA model Introduction Autoimmune hepatitisAutoimmune Hepatitis (AIH) is a chronic liver disease associated with raised plasma liver enzymes like transaminases and the presence of autoantibodies [1,2]. The initial trigger of the disease is unknown but different genetic risk factors have been identified [3,4]. In general, it is believed that multiple perturbations, unidentified environmental factors or drugs and the loss of self-tolerance are needed for the onset and development of AIH. The mechanisms for loss of self-tolerance leading to auto reactivity remain unclear but major contributors such as impaired thymic negative selection and expansion of promiscuous T cell clones are suggested [5]. In AIH, presentation of a self-antigen peptide within a Major Histocompatibility (MHC) II molecule by professional Antigen Presenting Cells (APCs) initiates liver damage. This antigen presentation, in combination with exposure to various cytokines, drives the differentiation of uncommitted CD4 helper T cells and immune reaction that is skewed to a Th1 and Th17 response. However, the Th2 response cannot be ignored because it is important in the production of auto-antibodies, which trigger cellular cytotoxicity and complement activation [6,7]. The current standard treatment of AIH patients consists of non-specific immune suppressing drugs such as corticosteroids in combination with azathioprine, which leads to a decrease in serum aminotransferase levels [8]. AIH animal modelsDespite extensive research on the pathogenesis of AIH, the details of the mechanism remain elusive and the current treatments are non-specific and insufficient. The need for faithful and reliable animal models is therefore high. However, finding a suitable animal model is difficult due to the fact that AIH lacks a precise time of onset, etiological agent and the clinical phenotype is variable. According to Czaja et al., the current AIH models can be divided in two categories: the pathogenic and therapeutic models [1]. Pathogenic models focus on characterization of individual mechanisms contributing to occurrence and severity of the disease. In these perturbed models, individual pathways can be isolated and manipulated in a genetic homogenous background. Next to transgenic models in which target antigens are expressed under the control of liver-specific promoters, several inducible models such as the D Galactosamine (GalN) in com HSOA Journal of Gastroenterology & Hepatology Research Review Article AbstractAutoimmune Hepatitis (AIH) is a chronic liver disease where presentation of a self-antigen peptide by professional antigen presenting cells initiates liver damage and drives the differentiation of uncommitted CD4 helpe...

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IL-25 prevents and cures fulminant hepatitis in mice through a myeloid-derived suppressor cell-dependent mechanism

Cited by 45 publications

References 36 publications

Dexmedetomidine premedication attenuates concanavalin A-induced hepatitis in mice

Dexmedetomidine premedication attenuates concanavalin A-induced hepatitis in mice

IL-25 or IL-17E Protects against High-Fat Diet–Induced Hepatic Steatosis in Mice Dependent upon IL-13 Activation of STAT6

Different Cell Types Involved in Mediating Concanavalin A Induced Liver Injury: A Comprehensive Overview

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