Organophosphorus Pesticides Induce Cytokine Release from Differentiated Human THP1 Cells.
- Author(s): Proskocil, Becky J
- Grodzki, Ana Cristina G
- Jacoby, David B
- Lein, Pamela J
- Fryer, Allison D
- et al.
Published Web Locationhttps://doi.org/10.1165/rcmb.2018-0257oc
Epidemiologic studies link organophosphorus pesticides (OPs) to increased incidence of asthma. In guinea pigs, OP-induced airway hyperreactivity requires macrophages and TNFα. Here, we determine whether OPs interact directly with macrophages to alter cytokine expression or release. Human THP1 cells differentiated into macrophages were exposed to parathion, chlorpyrifos, diazinon, or their oxon, phosphate or phosphorothioate metabolites for 24 h, in the absence or presence of reagents that block cholinergic receptors. TNFα, IL-1β, PDGF and TGFβ mRNA and protein were quantified by qPCR and ELISA, respectively. OP effects on NF-κB, acetylcholinesterase, and intracellular calcium were also measured. Parent OPs and their oxon metabolites upregulated cytokine mRNA and stimulated cytokine release. TNFα release, which was the most robust response, was triggered by parent but not oxon compounds. Cytokine expression was also increased by diethyl dithiophosphate, but not diethyl thiophosphate or diethyl phosphate metabolites. Parent OPs, but not oxon metabolites, activated NF-κB. Parent and oxon metabolites decreased acetylcholinesterase activity, but comparable acetylcholinesterase inhibition by eserine did not mimic OP effects on cytokines. Consistent with non-cholinergic mechanisms of OP effects on macrophages, pharmacologic antagonism of muscarinic or nicotinic receptors did not prevent OP-induced cytokine expression or release. These data indicate that phosphorothioate OP compounds directly stimulate macrophages to release TNFα, potentially via activation of NF-κB, and suggest that therapies that target NF-κB may prevent OP-induced airway hyperreactivity.
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