title: Influence of organophosphate poisoning on human dendritic cells.
abstract: Organophosphourus compounds (OPC, including nerve agents and pesticides) exhibit acute toxicity by inhibition of acetylcholinesterase. Lung affections are frequent complications and a risk factor for death. In addition, epidemiological studies reported immunological alterations after OPC exposure. In our experiments we investigated the effects of organophosphourus pesticides dimethoate and chlorpyrifos on dendritic cells (DC) that are essential for the initial immune response, especially in the pulmonary system. DC, differentiated from the monocyte cell line THP-1 by using various cytokines (IL-4, GM-CSF, TNF-α, Ionomycin), were exposed to organophosphourus compounds at different concentrations for a 24h time period. DC were characterized by flow cytometry and immunofluorescence using typical dendritic cell markers (e.g., CD11c, CD209 and CD83). After OPC exposure we investigated cell death, the secretion profile of inflammatory mediators, changes of DC morphology, and the effect on protein kinase signalling pathways. Our results revealed a successful differentiation of THP-1 into DC. OPC exposure caused a significant concentration-dependent influence on DC: Dendrites of the DC were shortened and damaged, DC-specific cell surface markers (i.e., CD83and CD209) decreased dramatically after chlorpyrifos exposure. Interestingly, the effects caused by dimethoate were in general less pronounced. The organophosphourus compounds affected the release of inflammatory cytokines, such as IL-1ß and IL-8. The anti-inflammatory cytokine IL-10 was significantly down regulated. Protein kinases like the Akt family or ERK, which are essential for cell survival and proliferation, were inhibited by both OPC. These findings indicate that the tested organophosphourus compounds induced significant changes in cell morphology, inhibited anti-inflammatory cytokines and influenced important protein signalling pathways which are involved in regulation of apoptosis. Thus our results highlight novel aspects -apparently independent of AChE inhibition- of OPC poisoning with regard to lung toxicity. Our findings contribute to the basic understanding of pulmonary complications caused by OPC poisoning.
authors.affiliation: Institute of Pathology, Repair-Lab, Johannes Gutenberg University Mainz, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Schäfer
authors.forename: Franziska
authors.initials: F
authors.lastname: Koppe
authors.forename: Bernhard
authors.initials: B
authors.lastname: Stenger
authors.forename: Christoph
authors.initials: C
authors.lastname: Brochhausen
authors.forename: Annette
authors.initials: A
authors.lastname: Schmidt
authors.forename: Dirk
authors.initials: D
authors.lastname: Steinritz
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.forename: Charles James
authors.initials: CJ
authors.lastname: Kirkpatrick
authors.forename: Christine
authors.initials: C
authors.lastname: Pohl
mesh_terms: D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004390:Chlorpyrifos / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D004117:Dimethoate / Q000633:toxicity; D006801:Humans; D007306:Insecticides / Q000506:poisoning; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D062025:Organophosphate Poisoning / Q000276:immunology* / Q000473:pathology; D010575:Pesticides / Q000633:toxicity
chemical_list: D016207:Cytokines; D007306:Insecticides; D010575:Pesticides; D004390:Chlorpyrifos; D004117:Dimethoate
keywords: Chlorpyrifos; Dendritic cells; Dimethoate; Inflammatory cytokines; Organophosphourus compounds; Protein kinases