VESNARINONE INHIBITS IMMUNE-MEDIATED BUT NOT FAS (CD95) AGONIST-MEDIATED HEPATIC-INJURY

Previous studies have shown that the administration of concanavalin A (ConA) into mice induces immune-mediated liver injury, which can be la rgely abrogated by neutralizing tumor necrosis factor(TNF)alpha. Vesna rinone is an experimental drug which is known to inhibit TNF alpha rel ease. Here we demonstrate that vesnarinone inhibits ConA-induced hepat ic injury. In a dose-dependent manner, vesnarinone inhibits in several mouse strains the increase of serum aminotransferase concentrations. Additional experiments show that vesnarinone inhibits ConA-mediated ac cumulation of DNA fragmentation in the liver. Furthermore, the drug si gnificantly reduces the levels of circulating TNF alpha and interleuki n-6 (IL-6). Vesnarinone does not modulate TNF alpha and IL-6 action on hepatic cells, as shown by its failure to reduce the cytokine specifi c-stimulation of acute phase plasma proteins in the rat hepatoma H-35 cell line. Neither vesnarinone nor anti-TNF alpha protect against dire ct liver injury induced by a sublethal dose of agonist anti-Fas (CD95) antibody. Taken together, these results suggest that vesnarinone bloc ks hepatic injury, in part by inhibiting the release of TNF alpha in v ivo. (C) 1997 International Society for Immunopharmacology.