ToxSci Advance Access originally published online on July 3, 2008
Toxicological Sciences 2008 105(2):322-330; doi:10.1093/toxsci/kfn128
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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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* Department of Microbiology and Molecular Genetics
Center for Integrative Toxicology
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824-1224
Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, Peoples Republic of China
1 To whom correspondence should be addressed at 234 G.M. Trout Building, Michigan State University, East Lansing, MI 48824. Fax: (517) 353-8963. E-mail: pestka{at}msu.edu.
Received May 25, 2008; accepted June 23, 2008
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Abstract |
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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 making it uniquely positioned to sense 28S ribosomal RNA 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 interleukin (IL)-8 expression in monocytes by DON and two prototypical RIPs, ricin, and Shiga toxin 1 (Stx1). 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 with cells transfected with control plasmid (UK9C). Nuclear factor-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 with UK9C cells. As observed for DON, ricin-, and Stx1–induced IL-8 expression was suppressed by the PKR inhibitors C16 and 2-AP 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.
Key Words: kinase; immunotoxicity; ribotoxic stress chemokine.
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