The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme is a tissue specific regulator of glucocorticoid action that is linked to the development of osteoporosis, inflammatory arthritis and myopathy. Systemic inhibition of 11β-HSD1 enzyme activity has been proposed as a therapeutic option in these conditions. However, 11β-HSD1 activity has also been reported to be important in regulation of the immune response and the HPA axis. We have previously demonstrated that proinflammatory cytokines, glucocorticoids and their combination dramatically increase 11β-HSD1 expression and activity in osteoblasts, synovial fibroblasts and myoblasts. The mechanisms underlying this increase in activity are unknown.
We have now examined the mechanisms underlying the regulation of 11β-HSD1 activity in stromal cells. Regulation of activity was not due to any previously described mechanism. The increase in activity induced by TNFα/IL-1β was independent of new protein synthesis. 5′ RACE analysis and luciferase gene reporter studies demonstrated that this effect was mediated via the classical proximal HSD11B1 promoter. Chemical inhibitor studies demonstrated that this increase in activity, along with basal enzyme activity, was mediated via the NF-κB pathway. Unexpectedly, the induction of 11β-HSD1 by TNFα/IL-1β treatment (but not basal 11β-HSD1 activity) was increased in the presence of inhibitors of the p38MAPK pathway. This suggested that TNFα/IL-1β induced activation of the p38MAPK pathway resulted in an inhibition of 11β-HSD1 expression. Glucocorticoids had a minor inhibitory effect on NF-κB nuclear translocation and induction of 11β-HSD1 but appeared to have their stimulatory effect on 11β-HSD1 expression through inhibition of TNFα/IL-1β induced p38MAPK activity.
The mechanism by which expression of 11β-HSD1 is regulated in stromal cells appears distinct from that reported in non-stromal cells such as hepatocytes. The finding that stromal cell expression of 11β-HSD1 activity is regulated by NF-κB opens up new opportunities to inhibit 11β-HSD1 activity in a tissue restricted manner.