Inhibition of tumor necrosis factor α signaling by anti-tumor necrosis factor α antibodies and pentoxifylline is unable to prevent fumonisin hepatotoxicity in mice

Fumonisin B1 (FB1), a mycotoxin from Fusarium verticillioides, disrupts sphingolipid metabolism by inhibiting ceramide synthase leading to modulation of cytokines including tumor necrosis factor (TNF) α. Current study investigated the effect of interrupting TNFα signaling, known to be involved in FB1 hepatotoxicity. Male C57BL/6N mice were injected intravenously once with anti-TNFα antibodies or treated with pentoxifylline at 150 mg/kg intraperitoneally twice a day for 5 days to inhibit TNFα production before and during subcutaneous injection of 2.25 mg FB1/kg daily for 5 days; mice were sampled one day after the last treatment. Results showed that both anti-TNFα antibodies and pentoxifylline did not prevent FB1 hepatotoxicity; the latter was somewhat augmented, indicated by increases in circulating alanine aminotransferase and aspartate aminotransferase, and incidence of apoptotic hepatocytes. Anti-TNFα antibodies did not alter FB1-induced accumulation of free sphingoid bases or expression of TNFα in liver following the FB1 treatment. Pentoxifylline significantly reduced accumulation of free sphinganine and expression of TNFα. Neither anti-TNFα antibodies nor pentoxifylline altered FB1-induced expression of interleukin-12, interferonγ, lymphotoxinβ, and c-myc. Expression of c-myc, an inducer of cell death, increased after interference with TNFα signaling. These findings suggest a dual role of TNFα signaling activation in FB1 hepatotoxicity.