A Key Pathogenic Role for the Stat1/T–Bet Signaling Pathway in T–Cell-Mediated Liver Inflammation

Publisher Website
Google Scholar
Abstract
TH1 cytokines have been suggested to contribute to the pathogenesis of T–cell–mediated liver injury and inflammation. However, the molecular signaling pathways involved in such injury are still poorly understood. In the present study, we investigated the role of the STAT1/T–bet signaling pathway in a murine model of T–cell–mediated liver inflammation induced by the application of concanavalin A (Con A) using newly created STAT1 transgenic mice as well as STAT1– and T–bet–deficient mice. Liver injury induced by Con A was associated with an increase of both pSTAT1 and T–bet levels in the liver. Furthermore, functional studies suggested a pathogenic role for STAT1 in Con A–induced liver injury, because transgenic mice overexpressing STAT1 under the control of the CD2 promoter/enhancer construct showed elevated interferon gamma (IFN–γ) and IRF–1 levels as well as significantly augmented liver injury following administration of Con A. Consistently, we observed that both STAT1–deficient and T–bet–deficient mice were protected from such T–cell–dependent liver injury. In conclusion, these findings suggest a key pathogenic role for the STAT1/T–bet signaling pathway for T–cell activation in the Con A model of T–cell–mediated liver pathology.