Abstract
A single s.c. injection of the organophosphorus pesticides (OPs) parathion, chlorpyrifos, or diazinon causes airway hyperreactivity and neuronal M2 muscarinic receptor dysfunction in guinea pigs 24 hr later. OP-induced airway hyperreactivity is dependent on tumor necrosis factor α (TNFα) but independent of interleukin-1β (IL-1β) or inhibition of acetylcholinesterase (AChE) (Proskocil BJ et al., Am J Physiol Lung Cell Mol Physiol. 2013; 304:L519-29). We tested whether OPs and their oxon metabolites directly stimulate human macrophages to increase expression of factors that modulate neuronal M2 receptors. THP1 cells, a human monocyte cell line differentiated into macrophage-like cells, were treated with 1-100 μM parathion, chlorpyrifos, or diazinon or 1-100 nM paraoxon, chlorpyrifos oxon, or diazoxon for 24 hr. mRNA was measured by real-time PCR and released proteins were analyzed by ELISA. None of the OPs or oxons affected cell viability. Parathion, chlorpyrifos, and diazinon increased mRNA expression of TNFα, IL-1β, platelet derived growth factor (PDGF), and transforming growth factor β (TGFβ) in a concentration-dependent manner. TNFα protein was significantly increased at 100 μM, however IL-1β and PDGF proteins were not increased and fibroblast growth factor (FGF) and TGFβ proteins were undetectable. No oxon metabolite increased mRNA or protein levels of these factors. Thus, the parent compounds, but not the oxon metabolites, directly stimulate THP-1 TNFα protein and RNA expression of factors known to modulate M2 muscarinic receptors. These data correlate with our in vivo data demonstrating that OP-induced airway hyperreactivity occurs independent of AChE inhibition.
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