Organophosphorus Pesticides Promote Cytokine Production in Human Macrophages

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Macrophages are sentinel immune cells that reside in most if not all tissues and play a critical role in innate immunity. We previously established that exposure to organophosphorus pesticides (OPs) increases airway hyperreactivity in animal models. OPs are neurotoxicants that cause acute cholinergic toxicity via inhibition of the enzyme acetylcholinesterase (AChE); however, our studies demonstrated that the OP parathion causes airway hyperreactivity independent of inhibition of AChE activity. Rather, parathion‐induced airway hyperreactivity is mediated by dysfunction of autoinhibitory muscarinic M2 receptors expressed on the parasympathetic nerves that innervate airway smooth muscle. Recently, we reported that the airway hyperreactivity triggered by parathion requires macrophages and immune cytokines. Here, we test the hypothesis that OPs interact directly with macrophages to stimulate them to express cytokines that modulate neuronal M2 receptors. Using the human THP‐1 monocyte line, we evaluated cytokine expression, NFkB activation through a secreted embryonic alkaline phosphatase (SEAP) reporter expression and nuclear localization of the NFkB p65 subunit and intracellular calcium mobilization in PMA‐differentiated THP‐1 cells exposed to different OPs and their metabolites. Preliminary experiments indicate that in differentiated THP‐1 macrophages, OPs significantly increase the mRNA expression of the pro‐inflammatory cytokines TNFα and IL‐1β. OPs also significantly increased NFkB activation but did not increase intracellular calcium levels. Therefore, our in vitro data strongly indicate that OPs interact directly with macrophages to provoke release of pro‐inflammatory mediators via activation of the NFkB signaling pathway. Ongoing studies are exploring the action of carbamates and pyrethrins on macrophages and further evaluating the mechanism by which these pesticides stimulate macrophages.Support or Funding InformationThis work was supported by funding from the National Institutes of Health grant R01 ES017592.