title: Fas ligand is responsible for CXCR3 chemokine induction in CD4+ T cell-dependent liver damage.
abstract: Immune-mediated hepatic damage has been demonstrated in the pathogenesis of hepatitis C virus (HCV) and other hepatotrophic infections. Fas/Fas ligand (FasL) interaction plays a critical role in immune-mediated hepatic damage. To understand the molecular mechanism(s) of FasL-mediated liver inflammation, we examined the effect of CD4(+) T cells expressing high levels of FasL on the initiation of hepatic damage through analysis of chemokine and chemokine receptor expression in HCV core x TCR (DO11.10) double-transgenic mice. In vivo antigenic stimulation triggers a marked influx of core-expressing Ag-specific CD4(+) T cells into the liver of the immunized core(+) TCR mice but not their core(-) TCR littermates. Strikingly, the inflammatory process in the liver of core(+) TCR mice was accompanied by a dramatic increase in IFN-inducible protein 10 and monokine induced by IFN-gamma production. The intrahepatic lymphocytes were primarily CXCR3-positive and anti-CXCR3 Ab treatment abrogates migration of CXCR3(+) lymphocytes into the liver and hepatic damage. Importantly, the blockade of Fas/FasL interaction reduces the expression of IFN-inducible protein 10 and monokine induced by IFN-gamma and cellular infiltration into the liver. These findings suggest that activated CD4(+) T cells with elevated FasL expression are involved in promoting liver inflammation and hepatic damage through the induction of chemokines.
authors: Beirne Carter Center for Immunology Research, and Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.
authors: Michael W
authors: MW
authors: Cruise
authors: John R
authors: JR
authors: Lukens
authors: Aileen P
authors: AP
authors: Nguyen
authors: Matthew G
authors: MG
authors: Lassen
authors: Stephen N
authors: SN
authors: Waggoner
authors: Young S
authors: YS
authors: Hahn