Trimethyltin-activated cyclooxygenase stimulates tumor necrosis factor-α 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 tumor necrosis factor (TNF)-α. Prior treatment of glial cells with either the nonspecific inhibitor of cyclooxygenase and lypoxygenase eicosatetraynoic acid (ETYA) or the cyclooxygenase inhibitor indomethacin completely prevented TMT-induced PGE 2 production and TNF-α release, suggesting a role for cyclooxygenase metabolites in TMT-induced TNF-α release. Exposure of glial cells to increasing concentrations of PGE 2 or other prostanoids did not increase TNF-α synthesis, while the presence of exogenous PGE 2 during treatment of glial cells with TMT actually suppressed TNF-α release. The activation of arachidonic acid metabolism produces reactive oxygen species (ROS). Scavenging of ROS by means of the antioxidant trolox prevented the TMT-induced release of TNF-α from glial cells, while indomethacin was found to suppress ROS formation induced by 1 μM TMT in glial cells. These results suggest that activation of arachidonic acid metabolism causes TNF-α release through the production of ROS rather than PGE 2. Indeed, PGE 2 may exert negative feedback on the release of TNF-α