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dc.contributor.authorSharma, Neelesh
dc.description.abstractFumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides present on corn worldwide. Fumonisin B1 inhibits ceramide synthase and induces expression of cytokines in liver. Fumonisin B1 induces apoptosis in some cells whereas other cells are resistant to its apoptotic effects. We hypothesized that sphingolipid metabolism and interaction of different cytokines may be important in rendering some cells resistant to fumonisin B1 induced apoptosis. We found that despite the accumulation of sphinganine, human embryonic kidney (HEK-293) cells are resistant to fumonisin B1 toxicity and DL-threo-dihydrosphingosine, the sphingosine kinase inhibitor (SKI), considerably increased the sensitivity of HEK-293 cells to fumonisin B1. Results indicated that HEK-293 cells are resistant to fumonisin B1 due to rapid conversion of sphingosine to sphingosine-1-phosphate, which imparts survival properties. Cellular interactions in fumonisin B1 induced toxicity were investigated using co-cultures of murine macrophages (J774A.1) and nonparenchymatous liver epithelial cells (NMuLi). Treatment of the co-cultures with fumonisin B1 produced cytotoxicity whereas either J774A.1 or NMuLi cultures alone showed no response to the mycotoxin. Expression of cytokines was increased in co-cultures but not in individual cultures. Results indicated that macrophages and liver epithelial cells interact in response to fumonisin B1 and potentiate the cytokines expression, which may have implications in making hepatocytes responsive to cytotoxicity of fumonisin B1. Fumonisin B1 induced apoptosis and activated c-Jun NH2-terminal kinase (JNK) in primary culture of liver cells. JNK inhibitor (SP600125) and anti-TNFa reduced the apoptosis induced by fumonisin B1. The role of JNK signaling in fumonisin B1 induced apoptosis is downstream of TNFa production, as fumonisin B1 mediated activation of JNK was reduced by the presence of anti TNFa in the medium, whereas presence of JNK inhibitor did not change the fumonisin B1 induced TNFa expression. To determine the role of T cells in fumonisin B1-induced apoptosis in mice liver, we depleted T cells in wild-type mice by injecting monoclonal antibodies directed against Thy-1.2 surface antigens of mature T cells. Results obtained in this study indicated that T cell activation followed by production of proinflammatory cytokines is an important mechanism for fumonisin B1-induced hepatotoxicity in mice.
dc.subjectFumonisin B1
dc.subjectTumor necrosis factor ‡, Sphingosine kinase
dc.subjectc-Jun NH2-terminal kinase
dc.subjectT cell depletion,
dc.titleMechanism of resistance to fumonisin B1-induced cytotoxicity
dc.description.advisorRaghubir P. Sharma
dc.description.committeeRaghubir P. Sharma
dc.description.committeeRonald T. Riley
dc.description.committeeCham E. Dallas

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