Cutting edge: a key pathogenic role of IL-27 in T cell- mediated hepatitis.
The signals driving T cell activation in T cell-mediated fulminant hepatitis are not fully understood. In this study, we identify the cytokine IL-27p28/EBI3 as a major pathogenic factor in the ConA model of T cell-mediated hepatitis. We found an up-regulation of hepatic EBI3 and p28 expression and augmented levels of IL-27 in wild-type mice after ConA administration, suggesting a potential pathogenic role of this cytokine in ConA hepatitis. Consistently, IL-27 EBI3-deficient mice were almost completely protected from ConA-induced liver damage. Such protection was associated with reduced levels of IFN-gamma and its signaling proteins pSTAT-1 and T-bet. Finally, in vivo blockade of IL-27 function using a soluble IL-27 receptor fusion protein led to reduced pSTAT1 levels and suppression of liver injury. Taken together, these data demonstrate a key pathogenic role of IL-27 in T cell-mediated liver injury. Furthermore, in vivo blockade of IL-27 emerges as a novel potential therapy for T cell-mediated hepatitis.
Siebler
Juergen
J
First Department of Medicine, University of Mainz, Mainz, Germany. siebler@uni-mainz.de
Wirtz
Stefan
S
Frenzel
Christian
C
Schuchmann
Marcus
M
Lohse
Ansgar W
AW
Galle
Peter R
PR
Neurath
Markus F
MF
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000276:immunology*; D003208:Concanavalin A / Q000633:toxicity; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation
C499601:Ebi3 protein, mouse; D020381:Interleukin-17; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D003208:Concanavalin A; D007371:Interferon-gamma