Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production.
OBJECTIVE
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]-gamma) 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-gamma 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-gamma) 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.
Lafdil
Fouad
F
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
Wang
Hua
H
Park
Ogyi
O
Zhang
Weici
W
Moritoki
Yuki
Y
Yin
Shi
S
Fu
Xin Yuan
XY
Gershwin
M Eric
ME
Lian
Zhe-Xiong
ZX
Gao
Bin
B
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003208:Concanavalin A; D004195:Disease Models, Animal; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology*; D013997:Time Factors; D000097043:Interleukin-22
D003208:Concanavalin A; D007371:Interferon-gamma; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C098680:Il17a protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse
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