Myeloid STAT3 Inhibits T Cell-Mediated Hepatitis by Regulating T Helper 1 Cytokine and Interleukin-17 Production

Lafdil, Fouad; Wang, Hua; Park, Ogyi; Zhang, Weici; Moritoki, Yuki; Yin, Shi; Fu, Xin; Gershwin, M. Eric; Lian, Zhe‐Xiong; Gao, Bin

doi:10.1053/j.gastro.2009.08.004

Cited by 106 publications

(108 citation statements)

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“…5). Recently, STAT3 activation in T cells was reported to contribute to IL-17 production and promote Con A-induced hepatitis [42], which is consistent with the present study. Moreover, one of the Notch ligands, delta-like 4 (Dll4), was reported to upregulate the expression of RORgt, which is critical for IL-17 mRNA induction, and also to induce IL-17 production in T cells by the direct binding of RBP-J to both RORgt and IL-17 promoter regions [35].…”

Section: Discussionsupporting

confidence: 93%

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: Discussionsupporting

confidence: 93%

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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“…Conditional deletion of STAT3 in myeloid cells results in enhanced inflammatory response and inflammation in various organs including the liver. 18,25,26 Here, we demonstrate that deletion of IL-10 markedly increased the inflammatory responses in the liver after PHx (Figure 3). Expression of F4/80 (a marker for macrophages) and CCR2 (a marker for monocytes) in the liver was slightly induced after PHx in wild-type mice but was induced up to 60-fold in IL-10 Ϫ/Ϫ mice.…”

Section: Il-10 Plays An Important Role In Tempering Inflammatory Respmentioning

confidence: 56%

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Yin

Wang

Park

et al. 2011

The American Journal of Pathology

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Emerging evidence suggests that proinflammatory cytokines, including tumor necrosis factor-␣ (TNF-␣) and interleukin-6 (IL-6), play a critical role in the initiation and progression of liver regeneration; however, relatively little is known about the role of antiinflammatory cytokine IL-10 in liver regeneration after partial hepatectomy (PHx). Here, we examined the role of IL-10 in liver regeneration using a model of PHx in several strains of genetically modified mice. After PHx, expression of IL-10 mRNA in the liver and spleen was significantly elevated. Such elevation was diminished in TLR4 mutant mice. Compared with wild-type mice, IL-10 ؊/؊ mice had higher levels of expression of proinflammatory cytokines (IL-6, TNF-␣, and IFN-␥) and inflammatory markers (CCR2 and F4/80) in the liver, as well as higher serum levels of proinflammatory cytokines after PHx. The number of neutrophils and macrophages was also higher in the livers of IL-10 ؊/؊ mice than in wild-type mice after PHx. Liver regeneration as determined by BrdU incorporation after PHx was higher in IL-10 ؊/؊ mice than in wild-type mice, which was associated with higher levels of activation of IL-6 downstream signal STAT3 in the liver. An additional deletion of STAT3 in hepatocytes significantly reduced liver regeneration in IL-10 ؊/؊ mice after PHx. Collectively, IL-10 plays an important role in negatively regulating liver regeneration via limiting inflammatory response and subsequently tempering hepatic STAT3 activation.

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“…Betulin reduces serum levels of IFN-γ, TNF-α, and IL-6 in mice with hepatitis Several lines of evidence suggest that IFN-γ [16,17] , TNF-α [18,19] , IL-4 [20] , and IL-17 [21,22] promote hepatic damage, whereas IL-10 [23] protects the liver from injury, and IL-6 [18] has varying effects depending on the stage of Con A-induced hepatitis at which it is present. To ascertain whether betulin interfered with the systemic levels of these cytokines, we examined the serum levels of IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, and IL-17 by using a CBA kit.…”

Section: Resultsmentioning

confidence: 99%

Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

et al. 2016

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Hedyotis hedyotidea has been used in traditional Chinese medicine for the treatment of autoimmune diseases. However, the mechanisms underlying for the effect remain unknown. We previously showed that, among 11 compounds extracted from H hedyotidea, betulin produced the strongest suppressive effect on T cell activation. Here, we examined the hepatoprotective effects of betulin against acute autoimmune hepatitis in mice and the mechanisms underlying the effects. Freshly isolated mouse splenocytes were stimulated with concanavalin A (Con A, 5 μg/mL) in the presence of betulin, the cell proliferation was assessed with CSFE-dilution assay. Mice were injected with betulin (10, 20 mg· kg -1 ·d -1 , ip) for 3 d. One hour after the last injection, the mice were injected with Con A (15 mg/kg, iv) to induce acute hepatitis. Blood samples and liver tissues were harvested at 10 h after Con A injection, and serum transaminase levels and liver histopathology were detected; serum levels of proinflammatory cytokines, hepatic T lymphocyte ratios, and functional statuses of conventional T and NKT cells were also analyzed. Betulin (16 and 32 μmol/L) dose-dependently suppressed the proliferation of Con A-stimulated mouse splenocytes in vitro. In Con A-challenged mice, preinjection with betulin (20 mg· kg -1 ·d -1 ) significantly decreased the levels of proinflammatory cytokines IFN-γ, TNF-α and IL-6, and ameliorated liver injury. Furthermore, pretreatment with betulin (20 mg· kg -1 ·d -1 ) significantly inhibited the Con A-induced activation of NKT and conventional T cells, and decreased production of proinflammatory cytokines IFN-γ, TNF-α and IL-6 in these two cell populations. Betulin has immunomodulatory effect on overly activated conventional T and NKT cells and exerts hepatoprotective action in mouse autoimmune hepatitis. The findings provide evidence for the use of H hedyotidea and its constituent betulin in the treatment of autoimmune diseases.

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Myeloid STAT3 Inhibits T Cell-Mediated Hepatitis by Regulating T Helper 1 Cytokine and Interleukin-17 Production

Cited by 106 publications

References 50 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

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

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