title: Inhibition of tumor necrosis factor alpha signaling by anti-tumor necrosis factor alpha antibodies and pentoxifylline is unable to prevent fumonisin hepatotoxicity in mice.
abstract: 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) alpha. Current study investigated the effect of interrupting TNFalpha signaling, known to be involved in FB1 hepatotoxicity. Male C57BL/6N mice were injected intravenously once with anti-TNFalpha antibodies or treated with pentoxifylline at 150 mg/kg intraperitoneally twice a day for 5 days to inhibit TNFalpha production before and during subcutaneous injection of 2.25mg FB1/kg daily for 5 days; mice were sampled one day after the last treatment. Results showed that both anti-TNFalpha 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-TNFalpha antibodies did not alter FB1-induced accumulation of free sphingoid bases or expression of TNFalpha in liver following the FB1 treatment. Pentoxifylline significantly reduced accumulation of free sphinganine and expression of TNFalpha. Neither anti-TNFalpha antibodies nor pentoxifylline altered FB1-induced expression of interleukin-12, interferongamma, lymphotoxinbeta, and c-myc. Expression of c-myc, an inducer of cell death, increased after interference with TNFalpha signaling. These findings suggest a dual role of TNFalpha signaling activation in FB1 hepatotoxicity.
authors.affiliation: Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
authors.forename: Quanren
authors.initials: Q
authors.lastname: He
authors.forename: Raghubir P
authors.initials: RP
authors.lastname: Sharma
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000517:prevention & control*; D017931:DNA Primers; D037341:Fumonisins / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009183:Mycotoxins / Q000633:toxicity*; D010431:Pentoxifylline / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000906:Antibodies; D017931:DNA Primers; D037341:Fumonisins; D009183:Mycotoxins; D014409:Tumor Necrosis Factor-alpha; C056933:fumonisin B1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D013110:Sphingosine; C005682:safingol; D010431:Pentoxifylline