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Dual effects of auranofin on prostaglandin E2 production by rat peritoneal macrophages
M Yamashita1, H Niki, M Yamada
1Department of Pathophysiological Biochemistry, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
Abstract:
Incubation of rat peritoneal macrophages in medium containing various concentrations of auranofin (1, 3 and 10 microM) increased prostaglandin E2 production at 4 h in a concentration-dependent manner, in accordance with the increase in the release of [3H]arachidonic acid from membrane phospholipids. However, at 20 h, no stimulation of prostaglandin E2 production by auranofin was observed. When the peritoneal macrophages were incubated in the presence of 12-O-tetradecanoylphorbol 13-acetate (TPA), thapsigargin or A23187, prostaglandin E2 production at 4 and 20 h was enhanced. The stimulator-induced prostaglandin E2 production at 20 h was suppressed by 10 microM of auranofin. Western blot analysis demonstrated that auranofin inhibited the induction of cyclooxygenase 2 by TPA, thapsigargin or A23187 at 4 and 20 h. The level of cyclooxygenase 1 did not change by treatment with these stimulators in the presence or absence of auranofin. These findings suggest that auranofin has dual effects on prostaglandin E2 production: without stimulation, auranofin increases prostaglandin E2 production at 4 h due to the increased release of arachidonic acid which is converted to prostaglandin E2 mainly by cyclooxygenase 1, but inhibits the stimulator-induced late-phase prostaglandin E2 production by inhibiting the induction of cyclooxygenase 2.
Insights
Auranofin initially boosts prostaglandin E2 (PGE2) via arachidonic acid release in macrophages. However, it later inhibits PGE2 production by blocking cyclooxygenase-2 induction, revealing dual effects on inflammation.
Area of Science:
- Immunology
- Pharmacology
- Biochemistry
Background:
- Prostaglandin E2 (PGE2) is a key inflammatory mediator.
- Auranofin is a gold-based drug with anti-inflammatory properties.
- Understanding auranofin's precise molecular targets is crucial for its therapeutic application.
Purpose of the Study:
- To investigate the effects of auranofin on prostaglandin E2 (PGE2) production in rat peritoneal macrophages.
- To elucidate the mechanisms underlying auranofin's influence on PGE2 synthesis, particularly concerning cyclooxygenase (COX) enzymes.
Main Methods:
- Rat peritoneal macrophages were incubated with varying concentrations of auranofin.
- Prostaglandin E2 production and [3H]arachidonic acid release were measured.
- Western blot analysis was used to assess cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) expression.
Main Results:
- Auranofin increased PGE2 production and arachidonic acid release at 4 hours in a concentration-dependent manner.
- Auranofin suppressed stimulator-induced (TPA, thapsigargin, A23187) late-phase (20 h) PGE2 production.
- Auranofin inhibited the induction of COX-2 by stimulators, while COX-1 levels remained unchanged.
Conclusions:
- Auranofin exhibits dual effects on macrophage PGE2 production.
- Early-phase PGE2 increase is linked to COX-1 and arachidonic acid release.
- Late-phase, stimulator-induced PGE2 production is inhibited by auranofin through COX-2 induction blockade.