Glucocorticoids were traditionally thought to exert their effects through direct actions of adrenally synthesised steroids on target tissues. However, it is now clear that a proportion of glucocorticoid action at a tissue level is through local reactivation of inactive precursors via the 11b-hydroxysteroid dehydrogenase type 1 enzyme (11b-HSD1). 11b-HSD1 converts inactive glucocorticoids such as cortisone (human) and dehydrocorticosterone (DHC) to their active counterparts cortisol and corticosterone. The enzyme is also essential for the conversion of prednisone (inactive) to prednisolone (active). In both normal physiology and in states of glucocorticoid excess the relative contributions of circulating active and locally reactivated glucocorticoids to (patho)physiology is unclear but there is increasing data to suggest that local reactivation is of critical importance in various situations.
In an early human clinical study the effects of prednisolone on bone were predicted by an individuals 11b-HSD1 activity rather than the level of active drug in the circulation. Additionally, 11b-HSD1 knockout mice appear strongly protected against the effect of glucocorticoid excess on metabolic parameters again indicating an important role for indirect reactivation of glucocorticoids.
We have further examined this issue in relation to inflammation in knockout models of murine joint and muscle inflammation with and without treatment with therapeutic glucocorticoids. In these models the immunosuppressive effects of glucocorticoids appear to be mediated primarily via 11b-HSD1 activity and the consequent regeneration of inactive to active glucocorticoids. Our current studies examining healing after burn injury demonstrate that application of active and inactive glucocorticoids influences the healing process but that inactive glucocorticoids have a greater ability to optimise wound outcomes that active glucocorticoids.
The realisation that glucocorticoids can exert their actions through direct and indirect routes creates opportunities to separate out these functions and enables novel therapeutic strategies to be employed.