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Title: INCREASED HEPATOTOXICITY OF FUMONISIN B1 IN TUMOR NECROSIS FACTOR A-KNOCKOUT MOUSE INVOLVES MODULATION OF FAS SIGNALING

Author
item SHARMA, R - VET MED/U GEORGIA,ATHENS
item HE, Q - VET MED/U GEORGIA,ATHENS
item JOHNSON, V - VET MED/U GEORGIA,ATHENS
item Voss, Kenneth

Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Abstract Only
Publication Acceptance Date: 2/15/2003
Publication Date: 4/1/2003
Citation: SHARMA, R.P., HE, Q., JOHNSON, V.J., VOSS, K.A. INCREASED HEPATOTOXICITY OF FUMONISIN B1 IN TUMOR NECROSIS FACTOR A-KNOCKOUT MOUSE INVOLVES MODULATION OF FAS SIGNALING [Abstract]. JOURNAL OF FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY. 17:A1040.

Interpretive Summary: ABstract only

Technical Abstract: Fumonisin B1 (FB1), a natural mycotoxin, is an inhibitor of ceramide synthase. It produces organ-, species, and even gender-specific toxic responses in animals, involving sphinganine accumulation and cytokine modulation. FB1-induced hepatotoxic responses were reduced in mice lacking tumor necrosis factor (TNF) ( receptor (TNFR)1, TNFR2, or interferon (. However, the hepatotoxicity was exxacerbated in mice lacking TNF(. We therefore compared the modulation of various apoptotic signaling factors in TNF(-knockout (TKO) mice compared to wild-type (WT) strain given repeated daily subcutaneous injections of 2.25 mg/kg FB1 for 5 days. Expression of CD95-lagand (FASL) more than doubled in TKO after FB1 whereas it was unaltered in WT. FB1 did not alter FAS expression in either strain; however, expressions of TRAIL, and down-stream signaling factors FADD, TRADD, and caspase 8 were higher in FB1-treated TKO than in corresponding WT. The TKO had a higher basal expression of several apoptotic factors except FASL. Expression of apoptotic molecules bcl-2, b-myc, c-myc, bax, max, mad and IL1( was induced by FB1 in TKO to a greater extent than in WT. Results indicated that FB1 can induce FAS modulated signaling when TNF( is absent. Elevated basal expression of apoptotic genes in TKO may be partially responsible for their increased sensitivity to FB1. These results are important in characterizing the modulating effect of TNF( on apoptotic signaling and in explaining the unexpected sensitivity of mice lacking this cytokine in response to hepatotoxic xenobiotics. (Supported in part by NIH ES09403)