title: Intracrine modulation of gene expression by intracellular generation of active glucocorticoids.
abstract: Glucocorticoids (GC) by either up-regulating or down-regulating the expression of genes influence cellular processes in every tissue and organ of the body. The enzyme 11beta-hydroxysteroid dehydrogenase Type-1 (11beta-HSD-1) confers bioactivity upon the inactive GC cortisone (E) and prednisone (P) by converting them to cortisol (F) and prednisolone (L), respectively. We sought to investigate whether gene expression modulation by GC is under the regulation of an intracrine mechanism that determines the intracellular concentration of active GC. Human cell lines were transiently and stably co-transfected with an expression construct for 11beta-HSD-1 and a GC-responsive reporter gene and incubated with active and inactive GC. Whereas in cells that were not transfected with the expression construct for 11beta-HSD-1 inactive GC had no transcriptional activity, in both transiently and stably transfected cells E and P demonstrated a dose-dependent transcriptional activity. This transcriptional potency of both inactive GC was effectively abolished by carbenoxolone, an 11beta-HSD-1 inhibitor, and was directly related to the concentration of transfected 11beta-HSD-1. We conclude that gene expression modulation by GC is under a decisive influence of target cell 11beta-HSD-1 that modulates the intracellular concentration of active GC. The intracrine mechanism is an under-appreciated aspect of GC activity that could be a potential target for future therapies aimed at modulating GC effects at the cellular level.
authors.affiliation: Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. oren_md@inter.net.il
authors.forename: Oren
authors.initials: O
authors.lastname: Fruchter
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Zoumakis
authors.forename: Salvatore
authors.initials: S
authors.lastname: Alesci
authors.forename: Massimo
authors.initials: M
authors.lastname: De Martino
authors.forename: George
authors.initials: G
authors.lastname: Chrousos
authors.forename: Zeev
authors.initials: Z
authors.lastname: Hochberg
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism; D000897:Anti-Ulcer Agents / Q000378:metabolism; D002229:Carbenoxolone / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D000897:Anti-Ulcer Agents; D005938:Glucocorticoids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D002229:Carbenoxolone