How does 11B-hydroxysteroid dehydrogenase type I limit inflammation?

Anti-inflammatory steroids (glucocorticoids) are among the most commonly prescribed drugs in the UK. Glucocorticoids are also produced naturally by the body, in both active (cortisol) and inactive (cortisone) forms, which help to control inflammation. The inactive cortisone is converted to active cortisol by an enzyme, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which thus acts to amplify active steroid levels in specific tissues. Levels of 11beta-HSD1 are rapidly increased in inflamed tissues, where it may promote the successful resolution of inflammation by increasing ?local? glucocorticoid action. This suggests that 11beta-HSD1 is anti-inflammatory. We have shown that mice lacking 11beta-HSD1 have an exaggerated (more severe and earlier onset) inflammatory response. We now aim to identify the cells responsible for the anti-inflammatory effects of 11beta-HSD1 and determine the mechanism by which it exerts these important effects. The results will be of potential therapeutic importance to target anti-inflammatory treatment.

Glucocorticoid (steroid) hormones circulate in the blood and have potent anti-inflammatory effects. However, intracellular glucocorticoid concentrations can differ greatly from blood levels due to metabolism by 11beta-hydroxysteroid dehydrogenase (11beta-HSD), an enzyme that interconverts active and inactive glucocorticoids. Two isozymes exist; 11beta-HSD1 predominantly reactivates glucocorticoids by converting inert 11-keto-glucocorticoids (cortisone in humans, 11-dehydrocorticosterone in rodents) into active forms (cortisol, 11-dehydrocorticosterone), thus amplifying glucocorticoid action in cells and tissues in which it is expressed. Levels of 11beta-HSD1 are rapidly increased in inflamed tissues and in macrophages, where it may promote the successful resolution of inflammation by increasing ?local? glucocorticoid action. Recently we have shown that mice lacking 11beta-HSD1 have an exaggerated (more severe and earlier onset) acute inflammatory response. These data allow the hypothesis that 11beta-HSD1 represents an endogenous anti-inflammatory mechanism engaged early during an inflammatory response that limits the onset and severity of inflammation and ?programmes? the trajectory of the subsequent resolution. We now aim to determine which cells and mechanisms are responsible for the acute anti-inflammatory effects of 11beta-HSD1, focussing on myeloid immune cells (mast cells, monocytes/macrophages) versus the host tissues (notably vasculature and fibroblasts).