title: Lupus-prone NZBWF1/J mice, defective in cytokine signaling, are resistant to fumonisin hepatotoxicity despite accumulation of liver sphinganine.
abstract: Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides, commonly present in corn and other cereals. Exposure to FB1 causes organ-specific diseases in various species, e.g., equine leukoencephalomalacia and porcine pulmonary edema; in mice the response is hepatotoxicity. We earlier reported that ceramide synthase inhibition by FB1, the initial biochemical effect of this mycotoxin, results in modulation of cytokine network in response to accumulated free sphingoid bases. In the current study we used NZB/NZW-F1 (NZBW) mice that have modified cytokine expression and develop lupus beginning at 5 months of age. The NZBW and C57BL/6J (CBL) mice (appropriate control) were given five daily subcutaneous injections of either saline or 2.25 mg FB1/kg/day and euthanized 24 h after the last treatment. Peripheral leukocyte counts were higher after exposure to FB1 in CBL but not in NZBW. FB1 treatment caused increases of plasma alanine aminotransferase and aspartate aminotransferase activity in CBL mice indicating hepatotoxicity; no elevation of circulating liver enzymes was recorded in NZBW mice. Hepatotoxic responses were confirmed by microscopic evaluation of apoptotic cells. The FB1-induced proliferation of cells observed in CBL strain was abolished in NZBW animals. The sphinganine accumulation in liver after FB1 was equal in both strains of mice. The NZBW strain lacked the FB1-induced increases in the expression of liver tumor necrosis factor alpha, interferon gamma, receptor interacting protein (RIP), and tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL), observed in CBL. Results confirmed our hypothesis that initial altered sphingolipid metabolism caused by FB1 leads to perturbation of liver cytokine network and ultimate cellular injury; the mice deficient in cytokine signaling are refractory to FB1 hepatotoxicity.
authors.affiliation: Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA. rpsharma@vet.uga.edu
authors.forename: Raghubir P
authors.initials: RP
authors.lastname: Sharma
authors.forename: Quanren
authors.initials: Q
authors.lastname: He
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Riley
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D037341:Fumonisins / Q000633:toxicity*; D006505:Hepatitis / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D006520:Hepatitis, Animal / Q000150:complications / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008177:Lupus Vulgaris / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D016207:Cytokines; D037341:Fumonisins; C056933:fumonisin B1; D013110:Sphingosine; C005682:safingol