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Inhibition of prostaglandin E₂ synthesis by SC-560 is independent of cyclooxygenase 1 inhibition

Christian Brenneis^*, Thorsten J. Maier^*, Ronald Schmidt^*, Annette Hofacker^*, Lars Zulauf^*, Per-Johan Jakobsson, Klaus Scholich^* and Gerd Geisslinger^*,1

^* Pharmazentrum Frankfurt, ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Frankfurt, Germany; and

Karolinska Hospital, Stockholm, Sweden

¹ Correspondence: Pharmazentrum Frankfurt, ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany. E-mail: geisslinger{at}em.uni-frankfurt.de

Prostaglandin E₂ (PGE₂) produced by cyclooxygenase-2 (COX-2) and microsomal prostaglandin E₂ synthase-1 (mPGES-1) plays an important role in the pathophysiology of inflammation, pain, and fever. We investigated the actions of TNF toward stimulation of PGE₂ synthesis in primary spinal cord neurons. TNF induced COX-2 and mPGES-1 expression in neurons, followed by formation of PGE₂, which was blocked by a selective COX-2 inhibitor. Surprisingly, the "selective COX-1" inhibitor SC-560 completely inhibited TNF-induced PGE₂ synthesis in neurons at nanomolar concentrations. Moreover, SC-560 inhibited PGE₂ and thromboxane A₂ synthesis in human monocytes and platelets with IC₅₀ of 1.8 nM and 2.5 nM, respectively. SC-560 treatment neither altered TNF-induced COX-2 or mPGES-1 expression nor did the addition of the calcium ionophore A23187 or arachidonic acid reverse the inhibition by SC-560. Moreover, no influence of SC-560 on PGE₂ synthase activities or PGE₂ transport was seen. Most importantly, SC-560 blocked TNF-induced PGE₂ synthesis in COX-1-deficient spinal cord neurons, demonstrating a COX-1-independent inhibition of PGE₂ synthesis. Although SC-560 inhibited LPS-induced PGE₂ synthesis in neurons and RAW264.7 macrophages in whole cell assays, no inhibition was observed in lysates of the same cells. Taken together our data demonstrate that SC-560 acts at least in some cell types as an unselective COX inhibitor despite its selectivity toward COX-1 under cell-free conditions.—Brenneis, C., Maier, T. J., Schmidt, R., Hofacker, A., Zulauf, L., Jakobsson, P-J., Scholich, K., Geisslinger, G. Inhibition of prostaglandin E₂ synthesis by SC-560 is independent of cyclo-oxygenase 1 inhibition.

Key Words: PGE2 • cyclooxygenase • TNF

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