Effects of chrisotherapeutic gold compounds on prostaglandin E2 production.
The mechanism of action of anti-rheumatic gold compounds on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced prostaglandin E(2) (PGE(2)) production in rat peritoneal macrophages were examined. Auranofin (AF) at 3-10 muM inhibited TPA-induced PGE(2) production in a concentration-dependent manner. In the pharmacological experiments, prostaglandin G/H synthase (PGHS)-2-dependent PGE(2) production was inhibited by 10 muM of AF. The enzyme activities of both PGHS-1 and PGHS-2 were not affected by the 10 muM AF. Other gold compounds, aurothioglucose (ATG) and aurothiomalate (ATM) did not inhibit PGE2 production at 10 muM. AF decreased the PGHS-2 protein content, but had no effect on the PGHS-1 protein content. AF at 3-10 muM decreased the PGHS-2 messenger RNA (mRNA) level by RT-PCR determination. Then, the effect of AF on nuclear factor kappa B (NF-kappaB), one of the transcription factors known to regulate transcription of a group of proinflammatory proteins, was determined. AF at 1-10 muM inhibited nuclear translocation of NF-kappaB in a concentration-dependent manner. ATG and ATM at 10 muM did not inhibit NF-kappaB nuclear translocation, but with 20 h preincubation, ATG and ATM inhibited PGE(2) production and NF-kappaB nuclear translocation. AF, ATG, and ATM did not affect the binding of NF-kappaB to its specific DNA. These observations may suggest that the effects of gold compounds on the inhibition of NF-kappaB nuclear translocation plays one of the major role in its anti-inflammatory effects in rat peritoneal macrophages.
Yamashita
Masamichi
M
Department of Pathophysiological Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558 Japan. may@tohoku-pharm.ac.jp
Ohuchi
Kazuo
K
Takayanagi
Motoaki
M
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D050607:Organogold Compounds; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology
D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D050607:Organogold Compounds; D011448:Prostaglandin Antagonists; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone