IL-22-Dependent Attenuation of T Cell-Dependent (ConA) Hepatitis in Herpes Virus Entry Mediator Deficiency

Wahl, Christian; Wegenka, Ursula; Leithäuser, Frank; Schirmbeck, Reinhold; Reimann, Jörg

doi:10.4049/jimmunol.0802810

Cited by 44 publications

(29 citation statements)

References 28 publications

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“…1A). As reported previously [32], serum AST and ALT activities in WT mice peaked at around 12 h after Con A injection, and p19-deficient mice showed similar time kinetics but with enhanced activities compared with WT mice (Fig. 1B).…”

Section: Resultssupporting

confidence: 86%

“…Increased susceptibility of IL-23p19-deficient mice to Con A-induced hepatitis Since NKT cells play a critical role in Con A-induced hepatitis and are the main producer of the hepatoprotective cytokine IL-22 [32], we first examined T-and NKT-cell populations in liver mononuclear cells (MNCs) of WT-and IL-23p19-deficient mice. Consistent with a previous report that p19-deficient mice have no overt phenotype in thymocytes, splenocytes or peripheral blood leukocytes [33], the populations of NKT, NK and T cells were not impaired in liver MNCs as observed in the splenocytes of p19-deficient mice compared with those of WT mice without any treatment and 5 h after Con A injection (Supporting Information Table 1).…”

Section: Resultsmentioning

confidence: 99%

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Regulation of the development of acute hepatitis by IL‐23 through IL‐22 and IL‐17 production

Morishima

Mizoguchi

et al. 2011

Eur J Immunol

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IL-23 plays a critical role in the expansion of highly proinflammatory Th17 cells secreting . Recently, we demonstrated that Notch signaling drives IL-22 secretion through the aryl hydrocarbon receptor (AHR) and plays a protective role in Con A-induced hepatitis. In this study, we investigated the role of IL-23 in hepatitis using IL-23p19-and IL-17-deficient mice. In WT mice, the injection of Con A induced the upregulation of various cytokines, which included IL-23, IL-22, IL-17, IFN-c and TNF-a. In IL-23p19-deficient mice, exacerbated hepatitis was observed and serum IL-22 and IL-17 levels were greatly reduced, whereas in IL-17-deficient mice, ameliorated hepatitis was observed. The injection of exogenous IL-22 protected p19-deficient mice from hepatitis, whereas the injection of exogenous IL-23 significantly increased the serum levels of not only IL-22 but also IL-17, and less effectively protected against hepatitis in IL-17-dependent and -independent manners. Finally, it was revealed that STAT3, STAT4 and Notch contributed to the production of both the cytokines, and that the AHR was important only for IL-22 production in response to Con A and IL-23 in liver mononuclear cells. These results suggest that IL-23 plays a protective role in hepatitis through IL-22 production and also a pathological role via IL-17-dependent and -independent mechanisms.Key words: Hepatitis . IL-17 . IL-22 . IL-23Supporting Information available online Introduction IL-23 is a heterodimeric cytokine which belongs to the IL-6/IL-12 family and plays a key role in autoimmune and inflammatory disorders [1]. IL-23 acts on memory-type cells [2] and induces the production of . Moreover, IL-23 is an essential factor in the survival and expansion of Th17 cells [5], which produce cytokines including IL-17, IL-17F, . p19-deficient mice are highly resistant to the development of experimental allergic encephalomyelitis (EAE) [7], and it has been shown that the IL-23-dependent production of IL-17, but not , is important for the pathogenesis of autoimmune 2828diseases such as EAE [9]. Recent studies have also revealed that the IL-23-dependent production of IL-22, but not IL-17, plays a critical role in protection against subsequent infection. In infection with an attenuated strain of Salmonella enterica serovar Enteritidis, p19-deficient mice showed reduced survival and exacerbated liver necrosis only in the absence of IL-12 in an IL-17-independent manner [10]. In peroral infection with Toxoplasma gondii, which leads to the development of small intestine inflammation, the IL-23-dependent upregulation of IL-22 is essential for the development of ileitis; on the other hand, IL-17 is downregulated and dispensable [11].IL-22 is a member of the IL-10 cytokine family and plays important roles in inflammation, immune surveillance and tissue homeostasis [12][13][14][15] [10,25,26].Recently, we demonstrated that Notch, which is an evolutionally conserved molecule that controls cell fate decision in a variety of cells [27,28], drives IL-22 secretion by stimu...

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Regulation of the development of acute hepatitis by IL‐23 through IL‐22 and IL‐17 production

Morishima

Mizoguchi

et al. 2011

Eur J Immunol

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“…Because HVEM is expressed by most cells of the immune system (T cells, B cells, NK cells, dendritic cells, and monocytes) and by some nonimmune cells such as hepatocytes, the specific cell subtypes that function as APC in this model were not strictly defined. However, because intrahepatic dendritic cells express HVEM on the surface and NKT maturation in the Con A model requires IL-12, these professional APC are an attractive candidate (54). In addition to professional APC, it is suggested that liver sinusoidal cells could play a role in NKT cell activation.…”

Section: Discussionmentioning

confidence: 99%

“…Liver NKT cells can be locally activated either specifically through the TCR (e.g., by glycolipid-presenting cells) or nonspecifically through cytokines such as IL-12 or IL-18 (54). In vivo, activation of T cells is an APC-dependent process, but the APC type that presents the lectin in the liver in this model is not defined.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo, activation of T cells is an APC-dependent process, but the APC type that presents the lectin in the liver in this model is not defined. Using herpes virus entry mediator (HVEM)-deficient mice, Wahl et al (54) have shown that nonparenchymal APC are essential for activating NKT cells in the Con A model. Because HVEM is expressed by most cells of the immune system (T cells, B cells, NK cells, dendritic cells, and monocytes) and by some nonimmune cells such as hepatocytes, the specific cell subtypes that function as APC in this model were not strictly defined.…”

Section: Discussionmentioning

confidence: 99%

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The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

Mencarelli

Renga²,

Migliorati³

et al. 2009

The Journal of Immunology

143

110

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Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. In this study, we report that activation of the farnesoid X receptor (FXR), a member of the ligand-activated nuclear receptor superfamily and bile sensor highly expressed in the liver, attenuates liver injury in a model of autoimmune hepatitis induced by Con A. We found that FXR gene ablation results in a time-dependent increase of liver expression (up to 20-fold in a 9-mo-old mouse) of osteopontin, a NKT cell-derived extracellular matrix protein and immunoregulatory cytokine. In comparison to wild-type, FXR−/− mice are more susceptible to Con A-induced hepatitis and react to Con A administration by an unregulated production of osteopontin. Administering wild-type mice with a synthetic FXR agonist attenuated Con A-induced liver damage and liver expression of the osteopontin gene. By in vitro studies, we found that FXR is expressed by primarily isolated NKT cells and its ablation favors ostepontin production in response to Con A. Chromatin immunoprecipitation assay and coimmunoprecipitation experiments demonstrate that the short heterodimer partner (SHP), a nuclear receptor and FXR target, was expressed by NKT cell hybridomas and increased in response to FXR activation. FXR activates SHP that interacts with and inhibits c-Jun binding to the osteopontin promoter. These data indicate that in NKT cells, FXR activation causes a SHP-mediated inhibition of osteopontin production. These data support the notion that the bile acid sensor FXR regulates the activation of liver NKT cells.

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A catch‐22: Interleukin‐22 and cancer

2018

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Barrier surfaces of multicellular organisms are in constant contact with the environment and infractions to the integrity of epithelial surfaces is likely a frequent event. Interestingly, components of the immune system, that can be activated by environmental compounds such as the microbiota or nutrients, are interspersed among epithelial cells or directly underlie the epithelium. It is now appreciated that immune cells continuously receive and integrate signals from the environment. Curiously, such continuous reception of stimulation does not normally trigger an inflammatory response but mediators produced by immune cells in response to such signals seem to rather promote barrier integrity and repair. The molecular mediators involved in this process are poorly understood. In recent years, the cytokine interleukin-22, produced mainly by group 3 innate lymphoid cells (ILCs), has been studied as a paradigm for how immune cells can control various aspects of epithelial cell function because expression of its receptor is restricted to non-hematopoietic cells. We will summarize here the diverse roles of IL-22 for the malignant transformation of epithelial cells, for tumor growth, wound healing and tissue repair. Furthermore, we will discuss IL-22 as a potential therapeutic target. Keywords:Aryl hydrocarbon receptor r Cancer r IL-22 r Innate lymphoid cells r RORγt IntroductionBarrier organs like the skin, the gut and lung mucosae are in constant contact with the environment. Their cellular components need to adapt to the continuous and ever changing presence of a large number of microbes (i.e., bacteria, fungi, viruses and parasites collectively referred to as the "microbiome") and their metabolites, including toxins. In addition, the epithelial barrier of the intestine is also subjected to food components, some of which are toxic by being poisonous, noxious or irritating. The skin barrier is exposed to UV irradiation, which is beneficial (e.g., conversion of Vitamin D) but can also be harmful (e.g., direct and Correspondence: Dr. Andreas Diefenbach e-mail: andreas.diefenbach@charite.de indirect DNA damage). Thus, barrier surfaces with the environment are sites where adaptive processes are initiated. Over millions of years of co-evolution of multicellular organisms with their habitat, adaptive signaling networks have been selected that are believed to shield the organism against such continuous threats and, thereby, shape their fitness. A well-studied example of such adaptive processes is microbiota-host relationships [1]. Through contact with microbial communities, epithelial function is being modified as to minimize damage to the barrier. For example, epithelial cells directly receive signals from the microbiota leading to the production of anti-bacterial proteins and to the protection of epithelial cells against TNF-triggered apoptosis [2][3][4]. * These authors contributed equally to this work.C 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 16Pedro Hernandez et al. Eur. J. Immunol. 2018. 48: ...

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IL-22-Dependent Attenuation of T Cell-Dependent (ConA) Hepatitis in Herpes Virus Entry Mediator Deficiency

Cited by 44 publications

References 28 publications

Regulation of the development of acute hepatitis by IL‐23 through IL‐22 and IL‐17 production

Regulation of the development of acute hepatitis by IL‐23 through IL‐22 and IL‐17 production

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

A catch‐22: Interleukin‐22 and cancer

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