Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production

F Lafdil, H Wang, O Park, W Zhang, Y Moritoki, S Yin… - Gastroenterology, 2009 - Elsevier
F Lafdil, H Wang, O Park, W Zhang, Y Moritoki, S Yin, XY Fu, ME Gershwin, ZX Lian, B Gao
Gastroenterology, 2009Elsevier
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 …
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.
Elsevier