Amelioration of fumonisin B 1 hepatotoxicity in mice by depletion of T cells with anti-Thy-1.2

Abstract

Fumonisin B 1 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 B 1 perturbs sphingolipid metabolism by inhibiting ceramide synthase. Our previous studies in male mice indicated that fumonisin B 1-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 B 1 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 μg monoclonal antibody against Thy-1.2 surface antigen of mature peripheral T lymphocytes 24 h before the first fumonisin B 1 treatment. The depletion of T cells nearly abolished fumonisin B 1-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 B 1-induced elevation in circulating liver enzymes between WT and nude mice. Fumonisin B 1-induced mRNA expression of tumor necrosis factor α and interleukin-1α was observed in nude and WT mice but not in T cell-depleted mice. Hepatotoxic response to fumonisin B 1 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 B 1-induced hepatic toxicity.