The role and regulation of 11beta-hydroxysteroid dehydrogenase type 1 in the inflammatory response.

Cortisone, a glucocorticoid hormone, was first used to treat rheumatoid arthritis in humans in the late 1940s, for which Hench, Reichstein and Kendall were awarded a Nobel Prize in 1950 and which led to the discovery of the anti-inflammatory effects of glucocorticoids. To be effective, the intrinsically inert cortisone must be converted to the active glucocorticoid, cortisol, by the intracellular action of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Whilst orally administered cortisone is rapidly converted to the active hormone, cortisol, by first pass metabolism in the liver, recent work has highlighted an anti-inflammatory role for 11beta-HSD1 within specific tissues, including in leukocytes. Here, we review recent evidence pertaining to the anti-inflammatory role of 11beta-HSD1 and describe how inhibition of 11beta-HSD1, as widely proposed for treatment of metabolic disease, may impact upon inflammation. Finally, the mechanisms that regulate 11beta-HSD1 transcription will be discussed.

11Beta-hydroxysteroid dehydrogenase type 1--a role in inflammation?

Glucocorticoids are widely used for their potent anti-inflammatory effects. Endogenous glucocorticoids are immunomodulatory and shape both adaptive and innate immune responses. Over the past decade, it has become apparent that an important level of control over endogenous glucocorticoid action is exerted by the 11beta-hydroxysteroid dehydrogenase enzymes. The type 1 enzyme, 11beta-HSD1, reduces inert glucocorticoids into active forms, thereby increasing intracellular ligand availability to receptors. Although 11beta-HSD1 activity has been shown to play an important role in the metabolic actions of glucocorticoids, its role in the immune response has, until recently, remained unclear. Here we review recent evidence pertaining to the role of 11beta-HSD1 in the inflammatory response.

Local amplification of glucocorticoids by 11beta-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 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.

11ß-Hydroxysteroid Dehydrogenase Type 1 Is Expressed in Neutrophils and Restrains an Inflammatory Response in Male Mice.

Endogenous glucocorticoid action within cells is enhanced by prereceptor metabolism by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which converts intrinsically inert cortisone and 11-dehydrocorticosterone into active cortisol and corticosterone, respectively. 11ß-HSD1 is highly expressed in immune cells elicited to the mouse peritoneum during thioglycollate-induced peritonitis and is down-regulated as the inflammation resolves. During inflammation, 11ß-HSD1-deficient mice show enhanced recruitment of inflammatory cells and delayed acquisition of macrophage phagocytic capacity. However, the key cells in which 11ß-HSD1 exerts these effects remain unknown. Here we have identified neutrophils (CD11b(+),Ly6G(+),7/4(+) cells) as the thioglycollate-recruited cells that most highly express 11ß-HSD1 and show dynamic regulation of 11ß-HSD1 in these cells during an inflammatory response. Flow cytometry showed high expression of 11ß-HSD1 in peritoneal neutrophils early during inflammation, declining at later states. In contrast, expression in blood neutrophils continued to increase during inflammation. Ablation of monocytes/macrophages by treatment of CD11b-diphtheria-toxin receptor transgenic mice with diphtheria toxin prior to thioglycollate injection had no significant effect on 11ß-HSD1 activity in peritoneal cells, consistent with neutrophils being the predominant 11ß-HSD1 expressing cell type at this time. Similar to genetic deficiency in 11ß-HSD1, acute inhibition of 11ß-HSD1 activity during thioglycollate-induced peritonitis augmented inflammatory cell recruitment to the peritoneum. These data suggest that neutrophil 11ß-HSD1 increases during inflammation to contribute to the restraining effect of glucocorticoids upon neutrophil-mediated inflammation. In human neutrophils, lipopolysaccharide activation increased 11ß-HSD1 expression, suggesting the antiinflammatory effects of 11ß-HSD1 in neutrophils may be conserved in humans.

11ß-Hydroxysteroid dehydrogenase type 1, but not type 2, deficiency worsens acute inflammation and experimental arthritis in mice.

Glucocorticoids profoundly influence immune responses, and synthetic glucocorticoids are widely used clinically for their potent antiinflammatory effects. Endogenous glucocorticoid action is modulated by the two isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD). In vivo, 11ß-HSD1 catalyzes the reduction of inactive cortisone or 11-dehydrocorticosterone into active cortisol or corticosterone, respectively, thereby increasing intracellular glucocorticoid levels. 11ß-HSD2 catalyzes the reverse reaction, inactivating intracellular glucocorticoids. Both enzymes have been postulated to modulate inflammatory responses. In the K/BxN serum transfer model of arthritis, 11ß-HSD1-deficient mice showed earlier onset and slower resolution of inflammation than wild-type controls, with greater exostoses in periarticular bone and, uniquely, ganglion cysts, consistent with greater inflammation. In contrast, K/BxN serum arthritis was unaffected by 11ß-HSD2 deficiency. In a distinct model of inflammation, thioglycollate-induced sterile peritonitis, 11ß-HSD1-deficient mice had more inflammatory cells in the peritoneum, but again 11ß-HSD2-deficient mice did not differ from controls. Additionally, compared with control mice, 11ß-HSD1-deficient mice showed greater numbers of inflammatory cells in pleural lavages in carrageenan-induced pleurisy with lung pathology consistent with slower resolution. These data suggest that 11ß-HSD1 limits acute inflammation. In contrast, 11ß-HSD2 plays no role in acute inflammatory responses in mice. Regulation of local 11ß-HSD1 expression and/or delivery of substrate may afford a novel approach for antiinflammatory therapy.

Local amplification of glucocorticoids by 11 beta-hydroxysteroid dehydrogenase type 1 promotes macrophage phagocytosis of apoptotic leukocytes.

Glucocorticoids promote macrophage phagocytosis of leukocytes undergoing apoptosis. Prereceptor metabolism of glucocorticoids by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) modulates cellular steroid action. 11beta-HSD type 1 amplifies intracellular levels of active glucocorticoids in mice by reactivating corticosterone from inert 11-dehydrocorticosterone in cells expressing the enzyme. In this study we describe the rapid (within 3 h) induction of 11beta-HSD activity in cells elicited in the peritoneum by a single thioglycolate injection in mice. Levels remained high in peritoneal cells until resolution. In vitro experiments on mouse macrophages demonstrated that treatment with inert 11-dehydrocorticosterone for 24 h increased phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11beta-HSD1, as 11beta-HSD1 mRNA, but not 11beta-HSD2 mRNA, was expressed in these cells; 11-dehydrocorticosterone was ineffective in promoting phagocytosis by Hsd11b1(-/-) macrophages, and carbenoxolone, an 11beta-HSD inhibitor, prevented the increase in phagocytosis elicited in wild-type macrophages by 11-dehydrocorticosterone. Importantly, as experimental peritonitis progressed, clearance of apoptotic neutrophils was delayed in Hsd11b1(-/-) mice. These data point to an early role for 11beta-HSD1 in promoting the rapid clearance of apoptotic cells during the resolution of inflammation and indicate a novel target for therapy.