ToxSci Advance Access published online on July 16, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm182
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Transcriptional Regulation of Deoxynivalenol-Induced IL-8 Expression In Human Monocytes
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* Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, 48824-1224
Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan, 48824-1224
Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan, 48824-1224
* To whom correspondence should be addressed at 234 G.M. Trout Building, Michigan State University, East Lansing, MI 48824-1224. Fax: 517-353-8963. E-mail: pestka{at}msu.edu.
Received June 5, 2007; revision received June 29, 2007; accepted July 3, 2007
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Abstract |
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The trichothecene mycotoxin deoxynivalenol (DON), commonly present in contaminated grains worldwide, induces expression of the chemokine IL-8 in human monocytes. The purpose of this study was to test the hypothesis that DON modulates transcriptional and post-transcriptional regulation of IL-8 expression in the U937 human monocyte model. When U937 cells were transfected with a wild-type IL-8 promoter luciferase construct (–162/+44 IL-8 LUC) and incubated with DON (1 µg/ml) or the positive control, LPS (1 µg/ml), there was a significant increase in luciferase expression. Mutation of the nuclear factor-
B (NF-B) binding site significantly impaired both DON- and LPS-induced luciferase expression. In contrast, mutating the activator protein-1 (AP-1) binding site resulted in significantly increased DON- and LPS-induced luciferase expression. CCAAT/enhancer binding protein ß (C/EBPß), octamer-1 (Oct-1) or NF-B repressing factor (NRF) binding site mutations did not affect DON-induced luciferase activity. Consistent with reporter studies, the NF-B inhibitor caffeic acid phenethyl ester (CAPE) completely ablated both DON-induced IL-8 mRNA and protein expression. When NF-B subunit binding to a specific IL-8 promoter probe was evaluated by ELISA, DON and was observed to increase p65 binding by 21-fold, have no effect on p50 binding and decrease p52 binding. DON was not found to stabilize IL-8 mRNA in U937 cells. Taken together, these data suggest that DON-induced IL-8 expression is likely to be mediated at the transcriptional level by NF-B, specifically p65, but does not appear to involve mRNA stabilization.
Key Words: mycotoxin; trichothecene; chemokine; transcription; immunotoxicity.
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