Expression of 11β-Hydroxysteroid Dehydrogenase Type 1 in Human Fetal Lung and Regulation of Its Expression by Interleukin-1β and Cortisol

Abstract

AbstractContext: Glucocorticoids are crucial in fetal lung function. The amount of cortisol available to its receptors is increased by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Glucocorticoids and IL-1β are known to induce 11β-HSD1 expression in a number of tissues, but controversial results were obtained with regard to 11β-HSD1 expression in human fetal lung.Objective: We examined the expression of 11β-HSD1 and its regulation by cortisol and IL-1β in human fetal lung.Results: Immunohistochemistry revealed 11β-HSD1 expression in the epithelium and mesenchymal layer of the small bronchus and bronchiole of human fetal lung at 8 months but not at 4 months gestation, which was confirmed by PCR revealing 11β-HSD1 mRNA expression in the fetal lung tissue. By using a cell line derived from human fetal lung fibroblasts, we demonstrated that cortisol (10−5 to 10−3 mmol/liter) or IL-1β (0.1 to 10 ng/ml) induced 11β-HSD1 mRNA expression in a concentration-dependent manner. The induction of 11β-HSD1 by IL-1β was further increased by cortisol, whereas the induction of cyclooxygenase 2 by IL-1β was inhibited by cortisol. Nuclear factor κB activation inhibitor could only block the induction of cyclooxygenase 2 but not 11β-HSD1 by IL-1β, suggesting that different mechanisms were utilized by IL-1β in the regulation of 11β-HSD1 versus proinflammatory mediators. Global inhibition of CCAAT-enhancer-binding proteins (C/EBPs) with transfection of C/EBP-specific dominant-negative expression plasmid could attenuate the induction of 11β-HSD1 by IL-1β, suggesting that C/EBPs may mediate the induction of 11β-HSD1 by IL-1β.Conclusions: 11β-HSD1 is expressed in human fetal lung; cortisol and IL-1β could synergistically induce its expression.