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Cutting Edge: A Key Pathogenic Role of IL-27 in T Cell- Mediated Hepatitis

Juergen Siebler^1,*, Stefan Wirtz^*, Christian Frenzel, Marcus Schuchmann^*, Ansgar W. Lohse, Peter R. Galle^* and Markus F. Neurath^*

^* First Department of Medicine, University of Mainz, Mainz, Germany; and First Department of Medicine, University of Hamburg, Hamburg, Germany

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Juergen Siebler, I. Department of Medicine, University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. E-mail: siebler{at}uni-mainz.de

² Abbreviations used in this paper: EBI3, EBV-induced gene 3; ALT, alanine aminotransferase; AST, aspartate aminotransferase; SEC, sinusoidal endothelial cell; sWSX, soluble WSX.

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