A76 Ann Rheum Dis 2013;72(Suppl 1):A1-A88 EWRR abstracts macrophages: blood and macrophages were induced with LPS and incubated with compound III for 24 h. Air pouch model: the inflammatory reaction was triggered by a carrageenan injection intrapouch. Inhibitors were injected i.p. and exudates were collected after 6 h. Prostanoid analysis: Prostanoids were measured by mass spectrometry or enzyme immunoassay. Results Compound III has an IC 50 of 0.4 µM and 1 µM in human and murine mPGES-1

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... ively. It has no activity on other enzymes of the prostanoid pathway and did not inhibit thromboxane release from human platelets. In cellular assays, it reduced PGE 2 production in A549 cells, mouse peritoneal macrophages and LPSstimulated whole blood. In mouse peritoneal macrophages, compound III caused a shunt to the prostacyclin pathway. Lastly, we assayed compound III in the air pouch model to verify its impact on the prostanoid profile and compare it to the profile obtained in mPGES-1 k.o. mice. As opposed to mPGES-1 genetic deletion, which attenuated PGE 2 induction and caused a shunt to the thromboxane pathway, mPGES-1 inhibition with compound III reduced PGE 2 production and tended to decrease the levels of other prostanoids. Conclusions Compound III is an active and selective inhibitor of mPGES-1. Its impact on the prostanoid profile was assay dependent. However, in the air pouch, contrary to mPGES-1 gene deletion, compound III did not trigger shunting, a scenario more likely to represent the outcome of mPGES-1 inhibition at the inflammatory site.