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Inhibition of prostaglandin E 2 synthesis by SC‐560 is independent of cyclooxygenase 1 inhibition
Author(s) -
Brenneis Christian,
Maier Thorsten J.,
Schmidt Ronald,
Hofacker Annette,
Zulauf Lars,
Jakobsson Per-Johan,
Scholich Klaus,
Geisslinger Gerd
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-5346com
Subject(s) - cyclooxygenase , prostaglandin e2 , arachidonic acid , prostaglandin , chemistry , ic50 , tumor necrosis factor alpha , prostaglandin e , stimulation , pharmacology , medicine , endocrinology , biochemistry , in vitro , enzyme , biology
Prostaglandin E 2 (PGE 2 ) produced by cyclooxygenase‐2 (COX‐2) and microsomal prostaglandin E 2 synthase‐1 (mPGES‐1) plays an important role in the pathophysiology of inflammation, pain, and fever. We investigated the actions of TNFα toward stimulation of PGE 2 synthesis in primary spinal cord neurons. TNFα induced COX‐2 and mPGES‐1 expression in neurons, followed by formation of PGE 2 , which was blocked by a selective COX‐2 inhibitor. Surprisingly, the “selective COX‐1” inhibitor SC‐560 completely inhibited TNFα‐induced PGE 2 synthesis in neurons at nanomolar concentrations. Moreover, SC‐560 inhibited PGE 2 and thromboxane A 2 synthesis in human mono‐cytes and platelets with IC 50 of 1.8 nM and 2.5 nM, respectively. SC‐560 treatment neither altered TNFα‐induced COX‐2 or mPGES‐1 expression nor did the addition of the calcium ionophore A23187 or arachi‐donic acid reverse the inhibition by SC‐560. Moreover, no influence of SC‐560 on PGE 2 synthase activities or PGE 2 transport was seen. Most importantly, SC‐560 blocked TNFα‐induced PGE 2 synthesis in COX‐1‐defi‐cient spinal cord neurons, demonstrating a COX‐1‐independent inhibition of PGE 2 synthesis. Although SC‐560 inhibited LPS‐induced PGE 2 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 prostaglan‐din E 2 synthesis by SC‐560 is independent of cyclo‐oxygenase 1 inhibition. FASEB J. 20, 1352–1360 (2006)