Local Amplification of Glucocorticoids by 11β‐Hydroxysteroid Dehydrogenase Type 1 and Its Role in the Inflammatory Response

Abstract

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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 11beta-HSD oxoreductase but not dehydrogenase activity in cells elicited rapidly in the peritoneum by a single thioglycollate injection. 11beta-HSD oxoreductase activity remained high in peritoneal cells until the inflammation resolved. In vitro, the 11beta-HSD1 substrate, 11-dehydrocorticosterone, increased macrophage phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11beta-HSD1: these cells solely expressed the type 1 11beta-HSD isozyme (not 11beta-HSD2), and carbenoxolone, an 11beta-HSD inhibitor, prevented the increase in phagocytosis elicited by 11-dehydrocorticosterone. Macrophages from 11beta-HSD1-deficient mice failed to respond to 11-dehydrocorticosterone. In vivo, 11beta-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, 11beta-HSD1-deficient mice exhibited delayed resolution of inflammation in experimental arthritis. These findings suggest 11beta-HSD1 may be a component of mechanisms engaged early during the inflammatory response that promote its subsequent resolution.

Pharmacological significance of triazole scaffold

“…Glucocorticoid excess as epitomised by Cushing′s syndrome can lead to insulin resistance/type 2 diabetes, dyslipidaemia and a redistribution of fat to visceral areas associated with increased cardiovascular risks [66,67]. Therefore, selective inhibition of 11β-HSDI enzyme by triazole derivatives may lead to an effective treatment for metabolic syndrome.…”

Acute alcohol intake impairs lung inflammation by changing pro- and anti-inflammatory mediator balance

“…While the recruited PMNs aid the resident alveolar macrophages (AMs) in responding efficiently to the immune challenge (Cox et al, 1995;Ishii et al, 1998), the local endogenous anti-inflammatory mediators (e.g. IL-10, IL-13, lipoxins and glucocorticoids) help in containing and resolving the inflammation (Chapman et al, 2006;Fan et al, 2001;Serhan, 2004;Scannell and Maderna, 2006).…”

Regulation of 11<i>β</i>-Hydroxysteroid Dehydrogenase Type 1 and 2 in Rheumatoid Arthritis

“…The balance between serum cortisol and cortisone is altered during the acute phase response in inflammatory disease, with a shift towards active cortisol [1]. Thus there is evidence that 11β-HSD enzymes play an important role in the modulation of systemic availability of cortisol during acute illness [2,3].…”