Studies on the COX inhibitor-induced PAF production and its pharmacological significance

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Stimulation of rat peritoneal macrophages by thapsigargin (46.1 nM) increased levels of tumor necrosis factor-a and prostaglandin E2 in the conditioned medium.Platelet-activating factor was not detected in the conditioned medium, but the level of cell-associated platelet-activating factor was increased transiently by thapsigargin.The receptor antagonists of platelet-activating factor such as E6123, L-652,731and CV-6209 inhibited thapsigargin-induced production of tumor necrosis factor-alpha. The cyclooxygenase inhibitor indomethacin inhibited prostaglandin E2production, and further enhanced thapsigargin-induced tumor necrosis factor-alphaproduction in parallel with further increase in cell-associated platelet-activating factor production.The enhancement of tumor necrosis factor-a production induced by thapsigarginplus indomethacin was also inhibited by E6123, L-652,731 and CV-6209.However, exogenously added platelet-activating factor up to 100 nM did not stimulate production of tumor necrosis factor-a.The level of tumor necrosis factor-alpha mRNA was increased by thapsigargin, but was lowered by the platelet-activating factor antagonist E6123, suggesting that the inhibition of tumor necrosis factor-a production by the platelet-activating factor antagonist is induced at the level of mRNA for tumor necrosis factor-a.These findings suggested that concurrently produced cell-associated platelet-activating factor up-regulates production of tumor necrosis factor-a by acting as an intracellular signaling molecule, and the antagonists of platelet-activating factor might penetrate into the cells and antagonize the action of intracellular platelet-activating factor.