Receptor-mediated effects of glucocorticoids on inflammation: enhancement of the inflammatory response with a glucocorticoid antagonist.
Glucocorticoids suppress the inflammatory response by altering leukocyte traffic and function, cytokine secretion and action, and phospholipid metabolism. We employed the glucocorticoid receptor antagonist RU 486, to examine whether glucocorticoids suppress the inflammatory response through a receptor-mediated mechanism and whether basal glucocorticoid secretion exerts antiinflammatory effects in the resting (non-stress) state. To test these hypotheses we evaluated the effects of increasing doses of dexamethasone, RU 486, or dexamethasone plus RU 486 on the exudate volume and concentrations of leukocytes, prostaglandin E2, (PGE2) and leukotriene B4 (LTB4) in intact rats that received subcutaneous carrageenin. Exudate volume, leukocyte concentration and LTB4 and PGE2 levels were all suppressed by dexamethasone in a dose-dependent fashion (P less than 0.005). RU 486 was able to antagonize fully the suppressive effects of dexamethasone on the inflammatory response (P less than 0.001) and to cause increases of exudate volume and leukocyte, PGE2 and LTB4 concentrations when given alone (P less than 0.05). These increases ranged between 30 and 100% above the basal inflammatory response. We conclude that glucocorticoids most likely suppress the inflammatory response by a glucocorticoid receptor-mediated mechanism and under basal conditions exert tonic antiinflammatory effects.
Laue
L
L
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892.
Kawai
S
S
Brandon
D D
DD
Brightwell
D
D
Barnes
K
K
Knazek
R A
RA
Loriaux
D L
DL
Chrousos
G P
GP
D000527:Alprostadil / Q000032:analysis; D000818:Animals; D002351:Carrageenan; D003907:Dexamethasone / Q000494:pharmacology*; D004963:Estrenes / Q000494:pharmacology*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000503:physiopathology* / Q000517:prevention & control; D007700:Kinetics; D007962:Leukocytes / Q000166:cytology; D007975:Leukotriene B4 / Q000032:analysis; D008297:Male; D015735:Mifepristone; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000502:physiology*
D004963:Estrenes; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D007975:Leukotriene B4; D015735:Mifepristone; D003907:Dexamethasone; D002351:Carrageenan; D000527:Alprostadil