ToxSci Advance Access published online on May 9, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl012
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1 Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan 48824; Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
* To whom correspondence should be addressed. 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 pre-exposure 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-1
Received February 23, 2006
Accepted May 4, 2006
Immunotoxiocology
Toll-Like Receptor Priming Sensitizes Macrophages to Proinflammatory Cytokine Gene Induction by Deoxynivalenol and Other Toxicants
James Pestka 1 *
and
Hui-Ren Zhou 2
2 Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824; Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
James Pestka, E-mail: Pestka{at}msu.edu
Abstract 
, IL-6 and TNF-
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-1 mRNA induction by DON in human whole blood cultures suggesting the relevance of the murine findings. As observed for LPS, pre-exposure to TLR agonists including zymosan (TLR2), poly [I:C] (TLR3), flagellin (TLR5), R848 (TLR 7/8) and ODN 1826 (TLR9) sensitized RAW 267.4 cells to DON-induced proinflammatory gene expression. Amplified proinflammatory mRNA expression was similarly demonstrated in LPS-sensitized RAW 267.4 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-tetrachloro-dibenzo-dioxin. 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.
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