Phospholipase A 2 Is Involved in the Mechanism of Activation of Neutrophils by Polychlorinated Biphenyls

Abstract

Aroclor 1242, a mixture of polychlorinated biphenyls (PCBs), activates neutrophils to produce superoxide anion (O2-) by a mechanism that involves phospholipase C-dependent hydrolysis of membrane phosphoinositides; however, subsequent signal transduction mechanisms are unknown. We undertook this study to determine whether phospholipase A2-dependent release of arachidonic acid is involved in PCB-induced O2- production. We measured O2- production in vitro in glycogen-elicited, rat neutrophils in the presence and absence of the inhibitors of phospholipase A2: quinacrine, 4-bromophenacyl bromide (BPB), and manoalide. All three agents significantly decreased the amount of O2- detected during stimulation of neutrophils with Aroclor 1242. Similar inhibition occurred when neutrophils were activated with the classical stimuli, formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol myristate acetate. The effects of BPB and manoalide were not a result of cytotoxicity or other nonspecific effects, although data suggest that quinacrine is an O2- scavenger. Significant release of 3H-arachidonic acid preceded O2- production in neutrophils stimulated with Aroclor 1242 or fMLP. Manoalide, at a concentration that abolished O2- production, also inhibited the release of 3H-arachidonate. Aspirin, zileuton, or WEB 2086 did not affect Aroclor 1242-induced O2- production, suggesting that eicosanoids and platelet-activating factor are not needed for neutrophil activation by PCBs. Activation of phospholipase A2 and O2- production do not appear to involve the Ah receptor because a congener with low affinity, but not one with high affinity for this receptor, stimulated the release of arachidonic acid and O2-. These data suggest that Aroclor 1242 stimulates neutrophils to produce O2- by a mechanism that involves phospholipase A2-dependent release of arachidonic acid.

Effects of the Solvent 1,2,4‐Trimethylcyclohexane on Respiratory Burst in Human Neutrophil Granulocytes: A Chemiluminescence and Electron Paramagnetic Resonance Spectrometry Study

“…7 PLA 2 are shown to be involved in the mechanism of activation of neutrophils by polychlorinated biphenyls. 8 In conclusion, our results indicate that Ca 2+ activation of PLA 2 is involved in the TMCH-induced activation of respiratory burst. The consequence is a rapid activation of the general immune system and unessecary production of free radicals that can be harmful to the tissue.…”

High-throughput evaluation of aryl hydrocarbon receptor-binding sites selected via chromatin immunoprecipitation-based screening in Hepa-1c1c7 cells stimulated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

“…This gene encodes cytosolic phospholipase A 2 -α (cPLA 2 -α) playing a central role in the release of arachidonic acid (AA) from sn2 position of membrane phospholipids, and AA metabolism is involved in a number of biological events such as inflammatory and carcinogenic processes. Previous studies revealed that TCDD promoted the release of AA from membranes as a result of its ability to stimulate membrane lipid oxidation and phospholipase A 2 (PLA 2 ) activity (al-Bayati and Stohs, 1991;Forsell et al, 2005;Tithof et al, 1996Tithof et al, , 2002. Therefore, our finding might fill-in the missing link between TCDD stimulation and phospholipase A 2 induction.…”

Polychlorinated biphenyls induce arachidonic acid release in human platelets in a tamoxifen sensitive manner via activation of group IVA cytosolic phospholipase A2-α

“…PCB exposure is also associated with a modest decrease in maternal and umbilical cord serum arachidonic acid concentrations [37]. Several reports describe cellular activation by PCBs as well as induction of arachidonic acid release from different mammalian cells including rat neutrophils, myometrial cells and neuronal cells [38][39][40][41][42][43][44]. In neuronal cell culture model, PCBs induce arachidonic acid release and perturbed intracellular signaling [43,45], suggesting a possible link between arachidonic acid metabolism and neurotoxicity.…”