Deletion of IFN-γ reduces fumonisin-induced hepatotoxicity in mice via alterations in inflammatory cytokines and apoptotic factors

Fumonisin B-1 (FB1) produces species-specific and organ-specific toxicity, including equine leukoencephalomalacia, porcine pulmonary edema, and hepatic or renal damage in other animals. FB1 causes inhibition of ceramide synthase, leading to accumulation of free sphingoid bases. We previously reported that such cytokines as tumor necrosis factor-alpha (TNF-alpha) modify FB1-induced hepatic apoptosis in male mice. FB1 also caused induction of interferon-gamma (IFN-gamma) in mouse liver, and, therefore, it was worthwhile to determine the role IFN-gamma plays in FB1 toxicity. In the current study, male IFN-gamma-knockout (GKO) mice and their wild-type (WT) counterparts, C57BL/6J, were treated subcutaneously (s.c.) with 2.25 mg/kg/day of FB1 for 5 days and sampled 1 day after the last injection. The levels of circulating liver enzymes were increased in WT animals but considerably less in GKO mice. Reduced hepatotoxicity in GKO mice was evident by histologic evaluation and enumeration of apoptotic cells. The induction of TNF-alpha and interleukin-12 (IL-12) p40 by FB1 in liver was less in GKO mice compared with WT animals. The GKO mice also had a reduced accumulation of liver sphinganine than did WT mice after FB1 treatment. Results suggested the implication of IFN-gamma in FB1-induced hepatotoxicity, which can be explained by a lack of TNF-alpha and IL-12 amplification in the liver of the GKO mice. In addition, the GKO mice had altered expression of various apoptotic and antiapoptotic factors in liver. These changes were accompanied by a greater number of proliferating cells in the liver of GKO mice after FB1 treatment, which may also contribute to the reduced hepatotoxicity of FB1 in GKO mice. Whereas the GKO mice show reduced sensitivity to FB1 and FB1 treatment elevates IFN-gamma expression, decreased hepatotoxicity to FB1 could result from alterations in sphingolipid metabolism in the GKO strain.