Regulation of the action of hydrocortisone in airway epithelial cells by 11β-hydroxysteroid dehydrogenase

Marc B. Feinstein, Robert P. Schleimer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

11β-hydroxysteroid dehydrogenase (11βHSD) reversibly converts hydrocortisone, the predominant active endogenous glucocorticoid in humans, to its inactive metabolite cortisone by oxidizing the 11-hydroxy group to an 11-keto group. Because this enzyme is highly expressed in human bronchial epithelial cells, we hypothesized that it regulates epithelial responses to glucocorticoids by reducing levels of hydrocortisone available to bind to the glucocorticoid receptor. Primary human bronchial epithelial cells (PBECs) were isolated from seven autopsy specimens and cultured in F12/Dulbecco's modified Eagle's medium with 5% fetal bovine serum until approximately 80% confluent. Cells were preincubated with 10 9 M to 10-5 M hydrocortisone for 24 h in the presence or absence of 10-6 M of the 11βHSD inhibitor glycyrrhetinic acid, after which the cells were stimulated with 5 ng/ml interleukin-1β for 24 h. Granulocyte macrophage colony-stimulating factor (GM-CSF) levels were quantitated in the resulting supernatants by enzyme-linked immunosorbent assay. Hydrocortisone inhibited GM-CSF release in stimulated PBEC with a concentration that produces 50% inhibition of maximum effect (IC1/2max) of 5.0 × 10 8 M. In the presence ot glycyrrhetinic acid, the potency of hydrocortisone was increased approximately 33-fold (IC1/2max with glycyrrhetinic acid, 1.5 × 10-9 M). Hydrocortisone activity was maximally enhanced at concentrations between 10-9 M and 10-8 M, levels that arc comparable to plasma levels of hydrocortisone not bound to plasma proteins. Glycyrrhetinic acid had no effect on the suppression of GM-CSF release by hydrocortisone in the transformed cell line BEAS-2B, which does not express the 11βHSD enzyme. Glycyrrhetinic acid also had no effect on the inhibition of GM-CSF release in PBECs by the synthetic glucocorticoids budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate, and triamcinolone acetonide, steroids not metabolized by 11βHSD. Together, these findings suggest that metabolism of hydrocortisone by 11βHSD may regulate glucocorticoid activity in human airway epithelial cells.

Original languageEnglish (US)
Pages (from-to)403-408
Number of pages6
JournalAmerican journal of respiratory cell and molecular biology
Volume21
Issue number3
DOIs
StatePublished - 1999

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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