Trimethyltin-activated cyclooxygenase stimulates tumor necrosis factor-alpha release from glial cells through reactive oxygen species

Exposure of a primary culture of glial cells to the classical neurotoxicant trimethyltin (TMT) results in the release of prostaglandin (PG)E-2 and tum or necrosis factor (TNF)-alpha, Prior treatment of glial cells with either the nonspecific inhibitor of cyclooxygenase and lypoxygenase eicosatetrayno ic acid (ETYA) or the cyclooxygenase inhibitor indomethacin completely prev ented TMT-induced PGE(2) production and TNF-alpha release, suggesting a rol e for cyclooxygenase metabolites in TMT-induced TNF-alpha release. Exposure of glial cells to increasing concentrations of PGE(2) or other prostanoids did not increase TNF-alpha synthesis, while the presence of exogenous PGE( 2) during treatment of glial cells with TMT actually suppressed TNF-alpha r elease. The activation of arachidonic acid metabolism produces reactive oxy gen species (ROS), Scavenging of ROS by means of the antioxidant trolox pre vented the TMT-induced release of TNF-alpha from glial cells, while indomet hacin was found to suppress ROS formation induced by 1 muM TMT in glial cel ls, These results suggest that activation of arachidonic acid metabolism ca uses TNF-alpha release through the production of ROS rather than PGE(2). In deed, PGE, may exert negative feedback on the release of TNF-alpha. (C) 200 1 Academic Press.