Local amplification of Glucocorticoids by 11 beta-hydroxysteroid dehydrogenase type 1 and its role in the inflammatory response

Glucocorticoids are widely used to treat chronic inflammatory conditions including rheumatoid arthritis. They promote mechanisms important for normal resolution of inflammation, notably macrophage phagocytosis of leukocytes undergoing apoptosis. Prereceptor metabolism of glucocorticoids by 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) amplifies intracellular levels of glucocorticoids by oxoreduction of intrinsically inert cortisone (in humans, 11-dehydrocorticosterone in mice) into active cortisol (corticosterone in mice) within cells expressing the enzyme. Recently, we have shown in a mouse model of acute inflammation, high expression of 11 beta-HSD oxoreductase but not dehydrogenase activity in cells elicited rapidly in the peritoneum by a single thioglycollate injection. 11 beta-HSD oxoreductase activity remained high in peritoneal cells until the inflammation resolved. In vitro, the 11 beta-HSD1 substrate, 11-dehydrocorticosterone, increased macrophage phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11 beta-HSD1: these cells solely expressed the type 1 11 beta-HSD isozyme (not 11 beta-HSD2), and carbenoxolone, an 11 beta-HSD inhibitor, prevented the increase in phagocytosis elicited by 11-dehydrocorticosterone. Macrophages from 11 beta-HSD1-deficient mice failed to respond to 11-dehydrocorticosterone. In vivo, 11 beta-HSD1-deficient mice showed a delay in acquisition of macrophage phagocytic competence and had an increased number of free apoptotic neutrophils during sterile peritonitis. Importantly, in preliminary experiments, 11 beta-HSD1-deficient mice exhibited delayed resolution of inflammation in experimental arthritis. These findings suggest 11 beta-HSD1 may be a component of mechanisms engaged early during the inflammatory response that promote its subsequent resolution.