title: Inhibition of prostaglandin E2 synthesis by SC-560 is independent of cyclooxygenase 1 inhibition.
abstract: 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 TNFalpha toward stimulation of PGE2 synthesis in primary spinal cord neurons. TNFalpha 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 TNFalpha-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 TNFalpha-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 TNFalpha-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.
authors.affiliation: Pharmazentrum Frankfurt, ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Brenneis
authors.forename: Thorsten J
authors.initials: TJ
authors.lastname: Maier
authors.forename: Ronald
authors.initials: R
authors.lastname: Schmidt
authors.forename: Annette
authors.initials: A
authors.lastname: Hofacker
authors.forename: Lars
authors.initials: L
authors.lastname: Zulauf
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D015777:Eicosanoids / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000196:embryology / Q000502:physiology; D013929:Thromboxane B2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D008070:Lipopolysaccharides; D011720:Pyrazoles; C115461:SC 560; D014409:Tumor Necrosis Factor-alpha; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D015232:Dinoprostone