Inflammatory regulation of glucocorticoid metabolism in mesenchymal stromal cells

Objective Tissue glucocorticoid (GC) levels are regulated by the GC-activating enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1). This enzyme is expressed in cells and tissues arising from mesenchymal stromal cells. Proinflammatory cytokines dramatically increase expression of 11 beta-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 11 beta-HSD1 expression. Results Gene reporter, RACE, and chemical inhibitor studies demonstrated that the increase in 11 beta-HSD1 expression with tumor necrosis factor a (TNFa)/interleukin-1 beta (IL-1 beta) occurred via the proximal HSD11B1 gene promoter and depended on NF-?B signaling. These findings were confirmed using MEFs with targeted disruption of NF-?B signaling, in which RelA (p65) deletion prevented TNFa/IL-1 beta induction of 11 beta-HSD1. GC treatment did not prevent TNFa-induced NF-?B nuclear translocation. The synergistic enhancement of TNFa-induced 11 beta-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. Conclusion The mechanism by which stromal cell expression of 11 beta-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.