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

Abstract

Fumonisin B(1) (FB(1)) produces species-specific and organ-specific toxicity, including equine leukoencephalomalacia, porcine pulmonary edema, and hepatic or renal damage in other animals. FB(1) 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 FB(1)-induced hepatic apoptosis in male mice. FB(1) also caused induction of interferon-gamma (IFN-gamma) in mouse liver, and, therefore, it was worthwhile to determine the role IFN-gamma plays in FB(1) 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 FB(1) 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 FB(1) 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 FB(1) treatment. Results suggested the implication of IFN-gamma in FB(1)-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 FB(1) treatment, which may also contribute to the reduced hepatotoxicity of FB(1) in GKO mice. Whereas the GKO mice show reduced sensitivity to FB(1) and FB(1) treatment elevates IFN-gamma expression, decreased hepatotoxicity to FB(1) could result from alterations in sphingolipid metabolism in the GKO strain.