GLUCOCORTICOIDS ENHANCE CORTICOTROPIN RECEPTOR MESSENGER-RNA LEVELS IN-OVINE ADRENOCORTICAL-CELLS

We have shown previously that chronic treatment with glucocorticoids e nhances both ACTH-induced cAMP production and ACTH- or 8Br-cAMP-induce d steroidogenesis of cultured ovine adrenocortical cells. This treatme nt has been shown to involve an increase in the number of ACTH recepto rs. The present study aimed to explore the mechanism of this effect of glucocorticoids on ACTH receptors. Ovine adrenocortical cells express ed one major ACTH receptor transcript of 3.6 kb and three minor ones o f 4.2, 1.8 and 1.3 kb. Dexamethasone treatment of cultured cells incre ased the levels of all these transcripts in a time- and dose-dependent manner, with an EC50 of (1.5 +/- 0.6) x 10(-8) M. The mean increase o ver control with 10(-6) M dexamethasone was 144 +/- 11% (n=14). This e nhancing effect was specific for glucocorticosteroids. The antiglucoco rticoid Ru38486 blocked the effect of dexamethasone. Testosterone did not modify, while high concentrations of 17 beta-estradiol decreased, ACTH receptor mRNA levels. Treatment of cells with aminoglutethimide ( an inhibitor of steroidogenesis) resulted in a dose-dependent decrease in ACTH receptor mRNA levels, which was prevented by concomitant trea tment with dexamethasone. Treatment with ACTH also increased ACTH rece ptor mRNA levels more than twofold. Addition of aminoglutethimide toge ther with ACTH resulted in a smaller increase than that achieved with ACTH alone. Neither dexamethasone nor ACTH modified ACTH receptor mRNA half-lives. However, these two hormones enhanced the levels of both n ewly synthesized and total ACTH receptor mRNAs. These results indicate that the positive trophic effect of glucocorticoids on ovine adrenoco rtical cells involves an enhancement of the transcription rate of the ACTH receptor gene. In addition, they suggest that part of the trophic action of ACTH on ACTH receptors may be mediated by ACTH-induced ster oidogenesis.