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Pestka J, Zhou HR.
Toll-Like Receptor Priming Sensitizes Macrophages to
Proinflammatory Cytokine Gene Induction by Vomitoxin
(deoxynivalenol) and Other Toxicants.
Toxicol Sci. 2006 May 9
Department of Food Science and Human Nutrition, and Center
for Integrative Toxicology, Michigan State University, East
Lansing, 48824, USA. pestka@msu.edu
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 (Vomitoxin (deoxynivalenol) ) 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 Vomitoxin (deoxynivalenol) -induced
IL-1beta, IL-6, and TNF-alpha mRNA expression as compared to LPS
or Vomitoxin (deoxynivalenol) alone. The minimum LPS
concentration for sensitization of both cell types was 1 ng/ml.
LPS priming also potentiated IL-1beta mRNA induction by
Vomitoxin (deoxynivalenol) 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 Vomitoxin (deoxynivalenol)
-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.
PMID: 16687389
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