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ToxSci Advance Access originally published online on May 9, 2006
Toxicological Sciences 2006 92(2):445-455; doi:10.1093/toxsci/kfl012
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Toll-Like Receptor Priming Sensitizes Macrophages to Proinflammatory Cytokine Gene Induction by Deoxynivalenol and Other Toxicants

James Pestka*,{dagger},{ddagger},1 and Hui-Ren Zhou*,{ddagger}

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

Received February 23, 2006; accepted May 4, 2006

Activation of the innate immune system might predispose a host to toxicant-induced inflammation. In vitro macrophage models were employed to investigate the effects of preexposure to Toll-like receptor (TLR) agonists on induction of proinflammatory cytokine gene expression by the trichothecene mycotoxin deoxynivalenol (DON) and other toxicants. Priming of the murine RAW 264.7 macrophage line or peritoneal murine macrophages with the TLR4 agonist lipopolysaccharide (LPS) at 100 ng/ml for 4, 8, and 16 h significantly increased DON-induced IL-1ß, IL-6, and TNF-{alpha} mRNA expression as compared to LPS or DON alone. The minimum LPS concentration for sensitization of both cell types was 1 ng/ml. LPS priming also potentiated IL-1ß mRNA induction by DON in human whole-blood cultures, suggesting the relevance of the murine findings. As observed for LPS, preexposure to TLR agonists including zymosan (TLR2), poly (I:C) (TLR3), flagellin (TLR5), R848 (TLR7/8), and ODN1826 (TLR9) sensitized RAW 267.4 cells to DON-induced proinflammatory gene expression. Amplified proinflammatory mRNA expression was similarly demonstrated in LPS-sensitized RAW 264.7 cells exposed to the microbial toxins satratoxin G, Shiga toxin, and zearalenone as well as the anthropogenic toxicants nickel chloride, triphenyltin, 2,4-dinitrochlorobenzene, and 2,3,7,8-tetrachlorodibenzodioxin. The results suggest that prior TLR activation might render macrophages highly sensitive to subsequent induction of proinflammatory gene expression by xenobiotics with diverse mechanisms of action.

Key Words: TLR; deoxynivalenol; LPS; macrophages; xenobiotics.


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