Tumor necrosis factor α-mediated activation of c-Jun NH2-terminal kinase as a mechanism for fumonisin B1 induced apoptosis in murine primary hepatocytes

Authors

  • Neelesh Sharma,

    1. Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA
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  • Hirofumi Suzuki,

    1. Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA
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  • Quanren He,

    1. Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA
    Current affiliation:
    1. Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
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  • Raghubir P. Sharma

    Corresponding author
    1. Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA
    • Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA
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Abstract

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 indicated that fumonisin B1 caused localized activation of cytokines in liver produced by macrophages and other cell types that modulate fumonisin B1 induced hepatic apoptosis in mice. The role of tumor necrosis factor α (TNFα) in fumonisin B1 mediated hepatocyte apoptosis has been established; not much is known about the downstream events leading to apoptosis. In the current study, fumonisin B1 induced apoptosis in primary culture of liver cells. In consistence with previous reports, fumonisin B1 caused accumulation of sphingoid bases and led to increase in TNFα expression. Phosphorylated and total c-Jun NH2-terminal kinase (JNK) activities were increased after 24 h fumonisin B1 treatment. JNK inhibitor (SP600125) and anti-TNFα reduced the apoptosis induced by fumonisin B1. The role of JNK signaling in fumonisin B1 induced apoptosis is downstream of TNFα production, as fumonisin B1-mediated activation of JNK was reduced by the presence of anti-TNFα in the medium, whereas the presence of JNK inhibitor did not change the fumonisin B1 induced TNFα expression. Results of this study imply that generation of fumonisin B1 induced TNFα results in modulation of mitogen activated protein kinases, particularly of JNK, and provides a possible mechanism for apoptosis in murine hepatocytes. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:359-367, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20102

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