Fas- and tumor necrosis factor receptor 1-dependent but not perforin-dependent pathways cause injury in livers infected with an adenovirus construct in mice.

Intravenous injection of type 5 adenovirus, deleted in the E1 and E3 regions, is shown to result in expression of viral antigens in the liver, initiating lymphocyte infiltration and liver injury. Following this infection, induction of Fas ligand (FasL), tumor necrosis factor alpha (TNF-alpha), and perforin mRNA are all demonstrable in the liver, pointing to a role of respective pathways in liver injury. Making use of mice in which the genes coding for Fas, FasL, TNF receptors (TNFRs), and perforin are inactivated, as well as recombinant proteins that inhibit Fas- and TNF-alpha-mediated apoptosis, it is shown that a functional perforin-mediated mechanism is not obligatory for cellular infiltration and progression of liver injury. In contrast functional Fas- and TNF-alpha-mediated mechanisms were found to be essential for liver injury to occur. Results are presented demonstrating that signaling through TNFR1, but not TNFR2, is involved in TNF-alpha-mediated liver damage. The conclusion is drawn that although perforin mRNA is induced in the virus-infected liver, Fas- and TNF-alpha-mediated mechanisms constitute the principal pathways by which the cell-mediated immune system causes acute liver injury.