Gastroenterology

Gastroenterology

Volume 137, Issue 6, December 2009, Pages 2125-2135.e2
Gastroenterology

Basic—Liver, Pancreas, and Biliary Tract
Myeloid STAT3 Inhibits T Cell-Mediated Hepatitis by Regulating T Helper 1 Cytokine and Interleukin-17 Production

https://doi.org/10.1053/j.gastro.2009.08.004Get rights and content

Background & Aims

T cell-mediated hepatitis is a leading cause of acute liver failure; there is no effective treatment, and the mechanisms underlying its pathogenesis are obscure. The aim of this study was to investigate the immune cell-signaling pathways involved—specifically the role of signal transducer and activator of transcription 3 (STAT3)—in T cell-mediated hepatitis in mice.

Methods

T cell-mediated hepatitis was induced in mice by injection of concanavalin A (Con A). Mice with myeloid cell-specific and T-cell-specific deletion of STAT3 were generated.

Results

STAT3 was activated in myeloid and T cells following Con A injection. Deletion of STAT3 specifically from myeloid cells exacerbated T-cell hepatitis and induced STAT1-dependent production of a T helper cell (Th)1 cytokine (interferon [IFN]-γ) and to a lesser extent of Th17 cytokines (interleukin [IL]-17 and IL-22) in a STAT1-independent manner. In contrast, deletion of STAT3 in T cells reduced T cell-mediated hepatitis and IL-17 production. Furthermore, deletion of IFN-γ completely abolished Con A-induced T-cell hepatitis, whereas deletion of IL-17 slightly but significantly reduced such injury. In vitro experiments indicated that IL-17 promoted liver inflammation but inhibited hepatocyte apoptosis.

Conclusions

Myeloid STAT3 activation inhibits T cell-mediated hepatitis via suppression of a Th1 cytokine (IFN-γ) in a STAT1-dependent manner, whereas STAT3 activation in T cells promotes T-cell hepatitis to a lesser extent, via induction of IL-17. Therefore, activation of STAT3 in myeloid cells could be a novel therapeutic strategy for patients with T-cell hepatitis.

Section snippets

Animals

Eight- to 10-week-old male mice were used in all studies performed. T cell-specific STAT3 knockout (STAT3T-cell−/−), myeloid-specific STAT3 knockout (STAT3Mye−/−), STAT3Mye−/−STAT1−/−, and STAT3Mye−/−IL-17−/− mice are described in the Supplementary Materials and Methods. For each group, respective littermates were used as wild-type mice. IL-17A−/− mice on a C57BL/6 background were provided generously by Dr. Iwakura of the University of Tokyo. IL-6−/−, IL-10−/−, and IFN-γ−/− mice on a C57BL/6

Activation of STAT3 in Myeloid Cells and T Cells During Con A-Induced Hepatitis

Our previous studies showed that STAT3 and STAT1 were activated in the liver during Con A-induced hepatitis.15 Here, we showed by immunostaining that STAT3 activation occurs not only in hepatocytes but also in virtually all other nonparenchymal cells including inflammatory cells (Figure 1A). Next, we found that STAT3 and STAT1 were also activated in the spleen after Con A injection (Figure 1B). Flow cytometry analyses further revealed that STAT3 and STAT1 phosphorylation occurred in CD3+ T

Discussion

T-cell activation in antigen dependent- (eg, hepatitis C virus [HCV] and hepatitis B virus [HBV]) as well as in antigen-independent- (eg drug intoxication, alcoholic liver diseases) mediated hepatitis has been shown to play a critical role in the pathogenesis of liver diseases.1, 2, 3, 4, 5, 6, 7 For example, in chronic HCV infection, whereas the virus itself has a noncytolytic function, activation of CD8+ T cells kills viral infected hepatocytes via releasing perforin and granzyme, while

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the intramural program of NIAAA, NIH.

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