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Published ahead of print on February 5, 2003, doi:10.1164/rccm.200210-1139OC

Am. J. Respir. Crit. Care Med., Volume 167, Number 9, May 2003, 1244-1249

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Submitted on October 12, 2002
Accepted on February 2, 2003

Dexamethasone up-regulates 11{beta}-hydroxysteroid dehydrogenase type 2 in BEAS-2B cells

Satoshi Suzuki1*, Kaori Koyama2, Andrew Darnel3, Hironori Ishibashi3, Seiichi Kobayashi4, Hiroshi Kubo4, Takashi Suzuki3, Hironobu Sasano3, and Zygmund S Krozowski2

1 Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; Laboratory of Molecular Hypertension, Baker Medical Research Institute, Melbourne, Victoria, Australia, 2 Laboratory of Molecular Hypertension, Baker Medical Research Institute, Melbourne, Victoria, Australia, 3 Pathology, Tohoku University School of Medicine, Sendai, Japan, 4 Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai, Japan

* To whom correspondence should be addressed. E-mail: satoshisuzuki{at}idac.tohoku.ac.jp.

The actions of natural and synthetic glucocorticoids are in part determined by 11{beta}-hydroxysteroid dehydrogenase type 2 (11{beta}-HSD2). We examined whether carbenoxolone, a potent inhibitor of 11{beta}-HSD, would potentiate the inhibitory action of dexamethasone on interleukin (IL)-8 release from BEAS-2B cells, and whether prolonged treatment with dexamethasone at therapeutic doses would up-regulate 11{beta}-HSD2 in the cells. We found that carbenoxolone increased the potency of dexamethasone almost ten-fold. RT-PCR and Western blot revealed that BEAS-2B cells expressed 11{beta}-HSD2, but not 11{beta}-HSD1. Enzyme activity assay in 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 11{beta}-HSD2. Prolonged treatment with dexamethasone also increased enzyme activity of 11{beta}-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 auto-regulatory system for glucocorticoids in the control of their own bio-active levels by inducing the expression of 11{beta}-HSD2, and that 11{beta}-HSD2 in the bronchial epithelium may play a role in the local regulation of inhaled glucocorticoid actions.
Key words: 11beta-hydroxysteroid dehydrogenase type 2, bronchial epithelial cells, glucocorticoid, interleukin-8




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