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ToxSci Advance Access published online on July 3, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn128
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Double-Stranded RNA-Activated Protein Kinase (PKR) Mediates Induction of IL-8 Expression by Deoxynivalenol, Shiga Toxin 1 and Ricin in Monocytes

Jennifer S. Gray*,{dagger}, Hee Kyong Bae{dagger},{ddagger}, C. B. Li James#, Alan S. Lau# and James J. Pestka*,{dagger},{ddagger},1

* Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824-1224, USA {dagger} Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1224, USA {ddagger} Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824-1224, USA # Department of Pediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, PRC

1 To whom correspondence should be addressed at 234 G.M. Trout Building, Michigan State University, East Lansing, MI 48824, Fax: 517-353-8963. Email: pestka{at}msu.edu.

Received May 25, 2008; revision received June 21, 2008; accepted June 23, 2008


  Abstract

Translational inhibitors such as the trichothecene mycotoxin deoxynivalenol (DON) and ribosomal inhibitory proteins (RIPs) induce mitogen-activated protein kinase (MAPK)-driven chemokine and cytokine production by a mechanism known as the ribotoxic stress response (RSR). Double-stranded RNA-activated protein kinase (PKR) associates with the ribosome in close proximity to the peptidyl transferase center making it uniquely positioned to sense 28S rRNA damage and initiate the RSR. We have previously shown that PKR mediates DON-induced MAPK phosphorylation in macrophages and monocytes. The purpose of this study was to test the hypothesis that PKR is essential for induction of IL-8 expression in monocytes by DON and two prototypical RIPs, ricin and Shiga toxin 1 (Stx-1). Preincubation of human monocytic U937 cells with the PKR inhibitors C16 and 2-aminopurine (2-AP) blocked DON-induced expression of IL-8 protein and mRNA. Induction of IL-8 expression was similarly impaired in U937 cells stably transfected with a dominant negative PKR plasmid (UK9M) as compared to cells transfected with control plasmid (UK9C). NF-{kappa}B binding, which has been previously shown to be a requisite for DON-induced IL-8 transcription, was markedly reduced in UK9M cells as compared to UK9C cells. As observed for DON, ricin- and Stx-1-induced IL-8 expression was suppressed by the PKR inhibitors C16 and 2-aminopurine as well as impaired in UK9M cells. Taken together, these data indicate that PKR plays a common role in IL-8 induction by DON and the two RIPs, suggesting that this kinase might be a critical factor in RSR.


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