Deletion of IFN- γ Reduces Fumonisin-Induced Hepatotoxicity in Mice via Alterations in Inflammatory Cytokines and Apoptotic Factors

Abstract

Fumonisin B₁ (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-α (TNF-α) modify FB₁-induced hepatic apoptosis in male mice. FB₁ also caused induction of interferon-γ (IFN-γ) in mouse liver, and, therefore, it was worthwhile to determine the role IFN-γ plays in FB₁ toxicity. In the current study, male IFN-γ-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-α 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-γ in FB₁-induced hepatotoxicity, which can be explained by a lack of TNF-α 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-γ expression, decreased hepatotoxicity to FB₁ could result from alterations in sphingolipid metabolism in the GKO strain.