Mechanisms of anti-inflammatory action of dexamethasone: blockade by hydrocortisone mesylate and actinomycin D of the inhibitory effect of dexamethasone on leukocyte infiltration in inflammatory sites.
The present study was designed to clarify molecular mechanisms underlying inhibitory effect of dexamethasone on leukocyte infiltration in the inflammatory site. For the assay of leukocyte infiltration, two or four blebs were made s.c. on the back of rats by injecting with 2% carboxymethyl cellulose solution containing a chemoattractant, casein. Leukocyte accumulation in the bleb was inhibited considerably by local application of dexamethasone at a concentration of 0.6 X 10(-6) M. Hydrocortisone mesylate, which was reported in the study with hepatoma tissue culture cells to be a long-acting antagonist against glucocorticoid in binding to the corticoid receptor, blocked the above leukocyte inhibitory effect of dexamethasone when applied simultaneously with dexamethasone. The leukocyte infiltration was unaffected by the application of hydrocortisone mesylate alone. Treatment with androstenedione, which was reported to be inactive in the hepatoma tissue culture cells, did not interfere with the inhibitory effect of dexamethasone at all. Actinomycin D, when applied simultaneously with dexamethasone, significantly suppressed the leukocyte-inhibitory effect of dexamethasone. In contrast with those observations, the inhibitory effect of dexamethasone was not affected at all in cases that actinomycin D and hydrocortisone mesylate, respectively, were applied after the administration of dexamethasone. These results indicate essential roles of glucocorticoid receptor and gene expression for the manifestation of the inhibitory effect of dexamethasone on leukocyte infiltration in the inflammatory site.
D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D003609:Dactinomycin / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006854:Hydrocortisone / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology*; D007962:Leukocytes / Q000187:drug effects*; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D003609:Dactinomycin; D000735:Androstenedione; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003907:Dexamethasone; D006854:Hydrocortisone; D007213:Indomethacin