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

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*One nanogram per milliliter*

THIS is why the presence of raw sewage in any appreciable quantity

makes any mold situation immeasurably more dangerous.

http://toxsci.oxfordjournals.org/cgi/content/abstract/92/2/445

# Toxicological Sciences

# Volume 92, Number 2

# Pp. 445-455

Toll-Like Receptor Priming Sensitizes Macrophages to Proinflammatory

Cytokine Gene Induction by Deoxynivalenol and Other Toxicants

Pestka*1 and Hui-Ren Zhou*,

* Department of Food Science and Human Nutrition, Department of

Microbiology and Molecular Genetics, and 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.