Dexamethasone upregulates 11beta-hydroxysteroid dehydrogenase type 2 in BEAS-2B cells.
The actions of natural and synthetic glucocorticoids are in part determined by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). We examined whether carbenoxolone, a potent inhibitor of 11beta-HSD, would potentiate the inhibitory action of dexamethasone on interleukin-8 release from BEAS-2B cells, and whether prolonged treatment with dexamethasone at therapeutic doses would upregulate 11beta-HSD2 in the cells. We found that carbenoxolone increased the potency of dexamethasone almost 10-fold. Reverse transcription-polymerase chain reaction and Western blot revealed that BEAS-2B cells expressed 11beta-HSD2, but not 11beta-HSD1. An enzyme activity assay of the cell homogenate demonstrated only NAD+-dependent dehydrogenase activity. The Km value for cortisol in intact BEAS-2B cells was estimated to be 42 nM. When the cells were incubated with dexamethasone for up to 72 hours at increasing concentrations (10(-9) to 10(-5) M), there were considerable increases in mRNA and protein levels of 11beta-HSD2. Prolonged treatment with dexamethasone also increased the enzyme activity of 11beta-HSD in the cells in a dose- and time-dependent manner, with complete inhibition by RU38486. These results suggest that bronchial epithelial cells possess an autoregulatory system for glucocorticoids in the control of their own bioactive levels by inducing the expression of 11beta-HSD2, and that 11beta-HSD2 in the bronchial epithelium may play a role in the local regulation of inhaled glucocorticoid actions.
Suzuki
Satoshi
S
Department of Thoracic Surgery, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Japan 980-8575. satoshisuzuki@idac.tohoku.ac.jp
Koyama
Kaori
K
Darnel
Andrew
A
Ishibashi
Hironori
H
Kobayashi
Seiichi
S
Kubo
Hiroshi
H
Suzuki
Takashi
T
Sasano
Hironobu
H
Krozowski
Zygmund S
ZS
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D002229:Carbenoxolone / Q000494:pharmacology; D002460:Cell Line; D003907:Dexamethasone / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D007249:Inflammation; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects*
D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D002229:Carbenoxolone