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

Abstract

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...

ExperimentalPneumocystislung infection promotes M2a alveolar macrophage-derived MMP12 production

“…IL-17A production by CD4 T cells requires IL-23-mediated activation of the transcription factors STAT3 and STAT4 (21,40). Because IL-4 signals through STAT6 (15), we determined the relative contribution of STAT4 and STAT6 in Mmp12 expression during P. murina lung infection.…”

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

“…Moreover, IL-17 secretion by activated T cells upon ConA stimulation promoted TNF-α and IL-6 production by KCs, causing liver damage [100]. Supporting this pro-inflammatory role of IL-17, neutralization or deficiency of IL-17 led to reduced ConA-induced liver damage whereas exogenous IL-17 aggravated it [71,100,102,103]. Nevertheless, the complete role of IL-17 in the pathogenesis of ConA-induced hepatitis remains unclear since an immunosuppressive role was recently described [104].…”

“…Nevertheless, the complete role of IL-17 in the pathogenesis of ConA-induced hepatitis remains unclear since an immunosuppressive role was recently described [104]. By promoting inducible Nitric Oxide Synthase (iNOS) expression in mesenchymal stem cells and induction of cytokine/chemokine gene expression, IL-17 can enhance in vivo immunosuppressive effects in ConA-induced hepatitis [103][104][105][106].…”

“…In ConA-induced hepatitis, the induction of IL-23 expression and Notch activation results in the production of IL-22 which is critical for protection. IL-23 induces the expression of IL-17 as well, which is detrimental in the pathogenesis, showing that IL-23 has both a hepatotoxic and a protective role [103].…”

Interleukin-22 as a molecular adjuvant facilitates IL-17-producing CD8+T cell responses against a HBV DNA vaccine in mice

“…Previous studies showed that IL-22 can upregulate keratinocyte genes for anti-microbial peptides including β-defensins (S100A7, S100A8), CXCL5 and MMP3. [35][36][37] IL-22 can enhance innate immune responses, inducing acute phase proteins in ConA-induced hepatitis, in protecting liver from damage, 38,39 including from fibrosis and chronic hepatitis B infection, 40,41 but little is known about the effect of IL-22 on adaptive immune responses when it is used as a molecular adjuvant.…”