Regulation of 11 beta-hydroxysteroid dehydrogenase activity in human skin fibroblasts: enzymatic modulation of glucocorticoid action.
The regulation of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) was studied in cultured human skin fibroblasts. 11-Oxo-reductase activity was 5- to 10-fold higher than 11 beta-dehydrogenase activity. Cells treated with 100 nM dexamethasone (Dex) showed a 3-fold increase in the maximum velocity of both activities without a change in the Km values. Dex induction of 11 beta HSD was half-maximal at 48 h and was blocked by glucocorticoid receptor antagonists. Nonglucocorticoid steroids were ineffective. Removal of serum from the culture medium increased maximum velocity values up to 6-fold. Treatment of cells grown in the absence of serum with 8-bromo-cAMP, phorbol esters, or insulin decreased both 11 beta HSD activities. The effects of Dex treatment and serum removal were additive and were blocked by cycloheximide and actinomycin-D. In all experiments both 11 beta HSD activities were modulated in parallel. Both cortisone (200 nM) and cortisol increased the aromatase activity of fibroblasts in the presence of serum. Prior induction of 11 beta HSD by serum removal increased the potency of cortisone from 10-15% to 50% that of cortisol. We conclude that 1) in human fibroblasts 11 beta HSD appears to be a single protein that is under multifactorial regulation; 2) 11 beta HSD may increase or decrease cortisol availability to glucocorticoid receptors; and 3) plasma cortisone levels may be important in assessing glucocorticoid status.
Hammami
M M
MM
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco 94143.
Siiteri
P K
PK
D042842:11-beta-Hydroxysteroid Dehydrogenases; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D001141:Aromatase / Q000096:biosynthesis; D002478:Cells, Cultured; D003348:Cortisone / Q000494:pharmacology*; D003470:Culture Media; D003907:Dexamethasone / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004790:Enzyme Induction; D004958:Estradiol / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D006913:Hydroxysteroid Dehydrogenases / Q000096:biosynthesis / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D011374:Progesterone / Q000494:pharmacology; D012867:Skin / Q000201:enzymology*; D013997:Time Factors; D014284:Triiodothyronine / Q000494:pharmacology
D003470:Culture Media; D007328:Insulin; D014284:Triiodothyronine; D013196:Dihydrotestosterone; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011374:Progesterone; D004958:Estradiol; D003907:Dexamethasone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D001141:Aromatase; D003348:Cortisone; D006854:Hydrocortisone