Mechanism of steroid action in inflammation: inhibition of prostaglandin synthesis and release.
Acute arthritis was induced by injection of cell-free extract of group A Streptococci into the knee joints of mature male rats. Slices of control and inflamed synovia were incubated for 30 to 240 minutes and the rate of prostaglandin E (PGE) released into the medium was measured by radioimmunoassay. PGE release from inflamed synovia was 5-8 fold higher than that in normal tissue. Incubation of inflamed synovia with corticosterone acetate, dexamethasone or prednisone (100 mug/ml) for one or four hours reduced PGE release by 33% and 55% respectively. Lower concentrations of corticosterone (10 - 30 mug/ml) were ineffective. Aldosterone and progesterone (100 mug/ml) had no effect on PGE release throughout the incubation period. Chloroquine (10 mug/ml) inhibited PGE release from inflamed synovia by 50%. Indomethacin (1 mug/ml) abolished PGE release by 90%. Corticosterone, dexamethasone and prednisone reduced PGE content of inflamed synovia by approximately 45% during a 4-h incubation period. Aldosterone and progesterone were ineffective, while indomethacin reduced PGE content by 70%. The suppressive action of corticosterone on PGE release was prevented by addition to the medium of arachidonic acid (2 mug/ml). By contrast, the inhibitory action of indomethacin was not affected by provision of exogenous substrate. We suggest that glucocorticosteroids reduce PGE release by limiting the availability of the substrate for prostaglandin biosynthesis, and this may well explain some of their anti-inflammatory properties.
D000208:Acute Disease; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001168:Arthritis / Q000378:metabolism*; D002738:Chloroquine / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007596:Joints / Q000378:metabolism; D008297:Male; D011241:Prednisone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D011458:Prostaglandins E / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D012636:Secretory Rate / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D011458:Prostaglandins E; D000450:Aldosterone; D011374:Progesterone; D003907:Dexamethasone; D002738:Chloroquine; D011241:Prednisone; D003345:Corticosterone; D007213:Indomethacin