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ToxSci Advance Access originally published online on July 16, 2007
Toxicological Sciences 2007 99(2):502-511; doi:10.1093/toxsci/kfm182
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Transcriptional Regulation of Deoxynivalenol-Induced IL-8 Expression in Human Monocytes

Jennifer S. Gray*,{dagger} and James J. Pestka*,{dagger},{ddagger},1

* Department of Microbiology and Molecular Genetics {dagger} Center for Integrative Toxicology {ddagger} Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824-1224

1 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; accepted July 3, 2007


  Abstract

The trichothecene mycotoxin deoxynivalenol (DON), commonly present in contaminated grains worldwide, induces expression of the chemokine interleukin (IL)-8 in human monocytes. The purpose of this study was to test the hypothesis that DON modulates transcriptional and posttranscriptional 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, lipopolysaccharide (LPS) (1 µg/ml), there was a significant increase in luciferase expression. Mutation of the nuclear factor-{kappa}B (NF-{kappa}B) binding site significantly impaired both DON- and LPS-induced luciferase expression. In contrast, mutating the activator protein-1 binding site resulted in significantly increased DON- and LPS-induced luciferase expression. CCAAT/enhancer-binding protein ß, octamer-1, or NF-{kappa}B repressing factor binding site mutations did not affect DON-induced luciferase activity. Consistent with reporter studies, the NF-{kappa}B inhibitor caffeic acid phenethyl ester completely ablated both DON-induced IL-8 mRNA and protein expression. When NF-{kappa}B subunit binding to a specific IL-8 promoter probe was evaluated by enzyme-linked immunosorbent assay (ELISA), DON 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-{kappa}B, specifically p65, but does not appear to involve mRNA stabilization.

Key Words: mycotoxin; trichothecene; chemokine; transcription; immunotoxicity.


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J. S. Gray, H. K. Bae, J. C. B. Li, A. S. Lau, and J. J. Pestka
Double-Stranded RNA-Activated Protein Kinase Mediates Induction of Interleukin-8 Expression by Deoxynivalenol, Shiga Toxin 1, and Ricin in Monocytes
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[Abstract] [Full Text] [PDF]


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