TY - JOUR T1 - Tumor Necrosis Factor-α as a Contributor in Fumonisin B<sub>1</sub> Toxicity JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 317 LP - 324 VL - 285 IS - 1 AU - Raviprakash R. Dugyala AU - Raghubir P. Sharma AU - Masashi Tsunoda AU - Ronald T. Riley Y1 - 1998/04/01 UR - http://jpet.aspetjournals.org/content/285/1/317.abstract N2 - Fumonisin B1 is a toxic product of Fusarium moniliforme, which inhibits ceramide synthase, leading to accumulation of free sphingoid bases. Despite its known biochemical action, the mechanism of toxicity is not fully understood. Male BALB/c mice were injected subcutaneously with 0 to 6.75 mg/kg/day of fumonisin B1 for 5 days. One day after the last treatment, spleens were collected, and peritoneal macrophages were obtained from separate groups after an intraperitoneal injection of thioglycolate broth. Peripheral leukocyte counts were increased and kidney weights were decreased by fumonisin B1 treatment. Presence of apoptotic cells in the liver and kidney of treated mice was confirmed by enzymatic immunoassay. Macrophages cultured with lipopolysaccharide indicated an increased secretion of tumor necrosis factor-α (TNF-α) but not of interleukin-1α. No effect was seen on interferon-γ production when splenocytes were incubated with concanavalin A. Elevation of leukocyte and reticulocyte counts was abrogated by pretreatment with anti-TNF-α antibody before a single dose of fumonisin B1 (25 mg/kg), supporting the hypothesis that the fumonisin B1 toxicity involves TNF-α. Cultures of J774A.1 cells, when treated with fumonisin B1, produced TNF-αin vitro. Results indicate that fumonisin B1toxicity may involve secretion of TNF-α by TNF-α-producing cells without altering interleukin-1α or interferon-γ. The influence on TNF-α-production may be a contributing factor to fumonisin B1-induced apoptosis and other observed toxic effects in animals. The American Society for Pharmacology and Experimental Therapeutics ER -