Organophosphorus Pesticides Induce Cytokine Release from Differentiated Human THP1 Cells

Am J Respir Cell Mol Biol. 2019 Nov;61(5):620-630. doi: 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 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, platelet-derived growth factor, and transforming growth factor-β mRNA and 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 cytokine mRNA and 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 release TNF-α, potentially via activation of NF-κB, and suggest that therapies that target NF-κB may prevent OP-induced airway hyperreactivity.

Keywords: NF-κB; chlorpyrifos; diazinon; macrophages; parathion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asthma / chemically induced
  • Asthma / drug therapy
  • Bronchial Hyperreactivity / chemically induced
  • Bronchial Hyperreactivity / drug therapy*
  • Bronchoconstriction / drug effects*
  • Cell Differentiation / drug effects
  • Chlorpyrifos / pharmacology*
  • Cytokines / pharmacology
  • Diazinon / pharmacology
  • Humans
  • Insecticides / pharmacology*
  • Organophosphorus Compounds / pharmacology
  • Parathion


  • Cytokines
  • Insecticides
  • Organophosphorus Compounds
  • Parathion
  • Chlorpyrifos
  • Diazinon