Organophosphorus pesticides induce cytokine release from differentiated human THP1 cells

Becky J. Proskocil, Ana Cristina G. Grodzki, David B. Jacoby, Pamela J. Lein, Allison D. Fryer

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Epidemiologic studies link organophosphorus pesticides (OPs) to increased incidence of asthma. In Guinea pigs, OP-induced airway hyperreactivity requires macrophages and TNF-α. Here, we determined whether OPs interact directly with macrophages to alter cytokine expression or release. Human THP1 cells were differentiated into macrophages and then exposed to parathion, chlorpyrifos, or diazinon, or their oxon, phosphate, or phosphorothioate metabolites for 24 hours in the absence or presence of reagents that block cholinergic receptors. TNF-α, IL-1β, plateletderived growth factor, and transforming growth factor-bmRNAand protein were quantified by qPCR and ELISA, respectively. The effects of OPs on NF-κB, acetylcholinesterase, and intracellular calcium were also measured. Parent OPs and their oxon metabolites upregulated cytokinemRNAand stimulated cytokine release. TNF-α 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 the noncholinergic 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 releaseTNF-α, potentially via activation ofNF-κB, and suggest that therapies that target NF-κB may prevent OP-induced airway hyperreactivity.

Original languageEnglish (US)
Pages (from-to)620-630
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Volume61
Issue number5
DOIs
StatePublished - 2019

Keywords

  • Chlorpyrifos
  • Diazinon
  • Macrophages
  • NF-κB
  • Parathion

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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