Mice lacking both TNFα receptors show increased constitutive expression of IFNγ: A possible reason for lack of protection from fumonisin B1 hepatotoxicity

Fumonisin B1 is a mycotoxin prevalent in corn that produces species-, gender-, and organ-specific diseases. Mice lacking TNFα receptor (TNFR) 1 or 2 exhibited a diminished hepatotoxic response to fumonisin B1; however, the protection was lost when both TNFRs were deleted. We therefore investigated the constitutive expression of selected apoptotic factors and their response to fumonisin B1 in the liver from mice lacking both TNFRs (DRKO). Compared to their wild-type (WT) counterparts the DRKO strain had a higher constitutive mRNA expression of interferon (IFN)γ, Fas, and interleukin (IL)-18. The mRNA expression of Bcl-2 was also higher in DRKO than in WT mice. The mRNA expression of IL-1 receptor antagonist (IL-1Ra) was decreased; that of TNF-related apoptosis-inducing ligand (TRAIL) was dramatically reduced. Induction of most apoptotic genes in response to fumonisin B1 was similar in both WT and DRKO strains; except in DRKO mice it was greater for Max and lesser for IL-1Ra than that in WT strain. Fumonisin B1 hepatotoxicity in DRKO mice was reduced by pretreatment with anti-IFNγ antibody. It appears that in the absence of TNFα signaling other apoptotic pathways become operative; particularly the increase of IFNγ, Fas and IL-18 may compensate for the loss of TNFα effects. Fumonisin B1 toxicity therefore appears to be a complex phenomenon that may utilize more than one cytotoxic pathway consequent to sphingoid deregulation; a higher expression of IFNγ and other apoptotic factors in DRKO may be responsible for the observed fumonisin hepatotoxicity.