Premium
Fas‐ and tumor necrosis factor receptor 1–dependent but not perforin‐dependent pathways cause injury in livers infected with an adenovirus construct in mice
Author(s) -
Liu ZhangXu,
Govindarajan Sugantha,
Okamoto Shigefumi,
Dennert Gunther
Publication year - 2000
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510310317
Subject(s) - fas ligand , perforin , tumor necrosis factor alpha , liver injury , biology , receptor , immunology , immune system , cancer research , apoptosis , cytokine , programmed cell death , cd8 , endocrinology , biochemistry
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 α (TNF‐α), 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‐α–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‐α–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‐α–mediated liver damage. The conclusion is drawn that although perforin mRNA is induced in the virus‐infected liver, Fas‐ and TNF‐α–mediated mechanisms constitute the principal pathways by which the cell‐mediated immune system causes acute liver injury.