OBJECTIVE: Tissue glucocorticoid levels are regulated by the glucocorticoid 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 implicated in inflammatory arthritis, osteoporosis, obesity and myopathy. Additionally, glucocorticoids act synergistically with pro-inflammatory cytokines to further increase enzyme expression. The mechanisms underlying this regulation are unknown. METHODS: 5' RACE, gene reporter analyses, chemical inhibitors and genetic disruption of intracellular signalling pathways in mouse embryonic fibroblasts (MEFs) were used to define the molecular mechanisms underlying the regulation of 11β-HSD1 expression. RESULTS: 5' RACE, gene reporter and chemical inhibitor studies demonstrated that the increase in 11β-HSD1 expression with TNFα/IL-1β?was via the proximal HSD11B1 gene promoter and depended on NF-κB signalling. These findings were confirmed using MEFs with targeted disruption of NF-κB signalling where RelA(p65) deletion prevented TNFα/IL-1β induction of 11β-HSD1? Glucocorticoids were unable to prevent TNFα-induced NF-κB nuclear translocation. The synergistic enhancement of TNFα-induced 11β-HSD1 expression with glucocorticoids was reproduced by specific inhibitors of p38MAPK. Inhibitor and gene deletion studies indicated that effects of glucocorticoids on p38MAPK activity were primarily through induction of dual specificity MAPK phosphatase-1 (DUSP1) expression. CONCLUSION: The mechanism by which stromal cell expression of 11β-HSD1 is regulated is novel and distinct from that in other tissues. These findings open up new opportunities to inhibit or stimulate local glucocorticoid levels in cells of mesenchymal stromal lineage during inflammation. © 2012 American College of Rheumatology.
Arthritis Research UK. Grant Numbers: 17730, 18081
Sir Jules Thorn Charitable Trust