title: Inflammatory regulation of glucocorticoid metabolism in mesenchymal stromal cells.
abstract: OBJECTIVE
  Tissue glucocorticoid (GC) levels are regulated by the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme is expressed in cells and tissues arising from mesenchymal stromal cells. Proinflammatory cytokines dramatically increase expression of 11β-HSD1 in stromal cells, an effect that has been implicated in inflammatory arthritis, osteoporosis, obesity, and myopathy. Additionally, GCs act synergistically with proinflammatory cytokines to further increase enzyme expression. The present study was undertaken to investigate the mechanisms underlying this regulation.
  
  
  METHODS
  Gene reporter analysis, rapid amplification of complementary DNA ends (RACE), chemical inhibition experiments, and genetic disruption of intracellular signaling pathways in mouse embryonic fibroblasts (MEFs) were used to define the molecular mechanisms underlying the regulation of 11β-HSD1 expression.
  
  
  RESULTS
  Gene reporter, RACE, and chemical inhibitor studies demonstrated that the increase in 11β-HSD1 expression with tumor necrosis factor α (TNFα)/interleukin-1β (IL-1β) occurred via the proximal HSD11B1 gene promoter and depended on NF-κB signaling. These findings were confirmed using MEFs with targeted disruption of NF-κB signaling, in which RelA (p65) deletion prevented TNFα/IL-1β induction of 11β-HSD1. GC treatment did not prevent TNFα-induced NF-κB nuclear translocation. The synergistic enhancement of TNFα-induced 11β-HSD1 expression with GCs was reproduced by specific inhibitors of p38 MAPK. Inhibitor and gene deletion studies indicated that the effects of GCs on p38 MAPK activity occurred primarily through induction of dual-specificity phosphatase 1 expression.
  
  
  CONCLUSIONS
  The mechanism by which stromal cell expression of 11β-HSD1 is regulated is novel and distinct from that in other tissues. These findings open new opportunities for development of therapeutic interventions aimed at inhibiting or stimulating local GC levels in cells of mesenchymal stromal lineage during inflammation.
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham and Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Ahasan
authors.forename: Rowan
authors.initials: R
authors.lastname: Hardy
authors.forename: Christopher
authors.initials: C
authors.lastname: Jones
authors.forename: Kirren
authors.initials: K
authors.lastname: Kaur
authors.forename: Dominika
authors.initials: D
authors.lastname: Nanus
authors.forename: Maria
authors.initials: M
authors.lastname: Juarez
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Morgan
authors.forename: Zaki
authors.initials: Z
authors.lastname: Hassan-Smith
authors.forename: Cécile
authors.initials: C
authors.lastname: Bénézech
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Caamaño
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
authors.forename: Gareth
authors.initials: G
authors.lastname: Lavery
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Rabbitt
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Clark
authors.forename: Andrew
authors.initials: A
authors.lastname: Filer
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.forename: Karim
authors.initials: K
authors.lastname: Raza
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cooper
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D053583:Interleukin-1beta; D016328:NF-kappa B; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1