Expression of 11beta-hydroxysteroid dehydrogenase type 1 in human fetal lung and regulation of its expression by interleukin-1beta and cortisol.

Abstract

Glucocorticoids are crucial in fetal lung function. The amount of cortisol available to its receptors is increased by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Glucocorticoids and IL-1beta are known to induce 11beta-HSD1 expression in a number of tissues, but controversial results were obtained with regard to 11beta-HSD1 expression in human fetal lung. We examined the expression of 11beta-HSD1 and its regulation by cortisol and IL-1beta in human fetal lung. Immunohistochemistry revealed 11beta-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 11beta-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-1beta (0.1 to 10 ng/ml) induced 11beta-HSD1 mRNA expression in a concentration-dependent manner. The induction of 11beta-HSD1 by IL-1beta was further increased by cortisol, whereas the induction of cyclooxygenase 2 by IL-1beta was inhibited by cortisol. Nuclear factor kappaB activation inhibitor could only block the induction of cyclooxygenase 2 but not 11beta-HSD1 by IL-1beta, suggesting that different mechanisms were utilized by IL-1beta in the regulation of 11beta-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 11beta-HSD1 by IL-1beta, suggesting that C/EBPs may mediate the induction of 11beta-HSD1 by IL-1beta. 11beta-HSD1 is expressed in human fetal lung; cortisol and IL-1beta could synergistically induce its expression.