title: Stimulation of 11β-HSD1 expression by IL-1β via a C/EBP binding site in human fetal lung fibroblasts.
abstract: Proinflammatory cytokines, just like glucocorticoids (GCs), have been reported to upregulate 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression in many cell types. This concerted regulation of 11β-HSD1 by interleukin-1β (IL-1β) and GCs is in marked contrast to their antagonistic effects on inflammation. Further, the molecular mechanisms underlying the induction of 11β-HSD1 by IL-1β are not very well understood. In this study, we demonstrated that IL-1β dramatically stimulated 11β-HSD1 expression and enzyme activity as well as promoter activity including the -64 bp fragment upstream to the transcription start site in human fetal lung fibroblasts (HFL-1). Nucleotide mutations of the proximal CCAAT box within this region abolished the induction of 11β-HSD1 promoter activity by IL-1β. Western blotting analysis demonstrated that IL-1β induced the expression of C/EBPβ dramatically while C/EBPα was barely detectable in HFL-1 cells. Global inhibition of CCAAT/enhancer-binding proteins (C/EBPs) with transfection of C/EBP-specific dominant-negative expression plasmid (CMV500-A-C/EBP) significantly attenuated the induction of 11β-HSD1 by IL-1β, whereas over-expression of C/EBPβ enhanced the expression of 11β-HSD1. Chromatin immunoprecipitation assay revealed the recruitment of C/EBPβ to the promoter region containing the C/EBP binding site. In conclusion, IL-1β induces the expression of 11β-HSD1 mRNA in the fetal lung tissue through mechanisms that involve C/EBPβ binding to the promoter. This impact of IL-1β on the expression of 11β-HSD1 in human fetal lung cells may explain the alternate mechanism for the lung maturation that appears to occur when there is a risk of premature delivery of the fetus due to the presence of infection.
authors.affiliation: School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.forename: Xiaoou
authors.initials: X
authors.lastname: Zhu
authors.forename: Chunming
authors.initials: C
authors.lastname: Guo
authors.forename: Kang
authors.initials: K
authors.lastname: Sun
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics*; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D053583:Interleukin-1beta / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000196:embryology / Q000201:enzymology / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding / Q000187:drug effects; D020218:Response Elements / Q000187:drug effects
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D053583:Interleukin-1beta; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1