Amelioration of fumonisin B1 hepatotoxicity in mice by depletion of T cells with anti-Thy-1.2.
Fumonisin B1 is a mycotoxin produced by Fusarium verticillioides, frequently associated with corn. It produces species-specific and organ-specific toxicity, including equine leukoencephalomalacia, porcine pulmonary edema, and hepatic or renal damage in most animal species. Fumonisin B1 perturbs sphingolipid metabolism by inhibiting ceramide synthase. Our previous studies in male mice indicated that fumonisin B1-induced hepatotoxicity is modulated by the localized activation of cytokines in liver macrophages and other cell types. In the current study, male athymic nude mice and their wild type counterparts (WT), the latter with or without depletion of T cells, were treated subcutaneously with fumonisin B1 at 2.25 mg/kg/day for 5 days and sampled 24 h after the last injection. Depletion of T cells in WT was achieved by a single intravenous injection of 50 microg monoclonal antibody against Thy-1.2 surface antigen of mature peripheral T lymphocytes 24 h before the first fumonisin B1 treatment. The depletion of T cells nearly abolished fumonisin B1-mediated liver toxicity as indicated by the near normal concentrations of circulating liver enzymes and by enumeration of apoptotic hepatocytes. There was no difference in the fumonisin B1-induced elevation in circulating liver enzymes between WT and nude mice. Fumonisin B1-induced mRNA expression of tumor necrosis factor alpha and interleukin-1alpha was observed in nude and WT mice but not in T cell-depleted mice. Hepatotoxic response to fumonisin B1 was unaltered in mice lacking natural killer cells. This study suggested that T cells and corresponding proinflammatory cytokines have a vital role in mediating fumonisin B1-induced hepatic toxicity.
Sharma
Neelesh
N
Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
He
Quanren
Q
Sharma
Raghubir P
RP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D016207:Cytokines / Q000276:immunology; D037341:Fumonisins / Q000633:toxicity*; D007518:Isoantibodies / Q000276:immunology / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D037341:Fumonisins; D007518:Isoantibodies; C035678:anti-Thy antibody; C056933:fumonisin B1