Macrophage 11ß-HSD-1 deficiency promotes inflammatory angiogenesis.

11ß-Hydroxysteroid dehydrogenase-1 (11ß-HSD1) predominantly converts inert glucocorticoids into active forms, thereby contributing to intracellular glucocorticoid levels. 11ß-HSD1 is dynamically regulated during inflammation, including in macrophages where it regulates phagocytic capacity. The resolution of inflammation in some disease models including inflammatory arthritis is impaired by 11ß-HSD1 deficiency or inhibition. However, 11ß-HSD1 deficiency/inhibition also promotes angiogenesis, which is beneficial in mouse models of surgical wound healing, myocardial infarction or obesity. The cell types responsible for the anti-inflammatory and anti-angiogenic roles of 11ß-HSD1 have not been characterised. Here, we generated Hsd11b1MKO mice with LysM-Cre mediated deletion of Hsd11b1 to investigate whether 11ß-HSD1 deficiency in myeloid phagocytes is pro-angiogenic and/or affects the resolution of inflammation. Resolution of inflammatory K/BxN-induced arthritis was impaired in Hsd11b1MKO mice to a similar extent as in mice globally deficient in 11ß-HSD1. This was associated with >2-fold elevation in levels of the endothelial marker Cdh5 mRNA, suggesting increased angiogenesis in joints of Hsd11b1MKO mice following arthritis. A pro-angiogenic phenotype was confirmed by measuring angiogenesis in subcutaneously implanted polyurethane sponges, in which Hsd11b1MKO mice showed 20% greater vessel density than their littermate controls, associated with higher expression of Cdh5 Thus, 11ß-HSD1 deficiency in myeloid phagocytes promotes angiogenesis. Targeting 11ß-HSD1 in macrophages may be beneficial in tissue repair.

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.

Changing glucocorticoid action: 11ß-hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation.

Since the discovery of cortisone in the 1940s and its early success in treatment of rheumatoid arthritis, glucocorticoids have remained the mainstay of anti-inflammatory therapies. However, cortisone itself is intrinsically inert. To be effective, it requires conversion to cortisol, the active glucocorticoid, by the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). Despite the identification of 11ß-HSD in liver in 1953 (which we now know to be 11ß-HSD1), its physiological role has been little explored until recently. Over the past decade, however, it has become apparent that 11ß-HSD1 plays an important role in shaping endogenous glucocorticoid action. Acute inflammation is more severe with 11ß-HSD1-deficiency or inhibition, yet in some inflammatory settings such as obesity or diabetes, 11ß-HSD1-deficiency/inhibition is beneficial, reducing inflammation. Current evidence suggests both beneficial and detrimental effects may result from 11ß-HSD1 inhibition in chronic inflammatory disease. Here we review recent evidence pertaining to the role of 11ß-HSD1 in inflammation. This article is part of a Special Issue entitled 'CSR 2013'.

Mast cells express 11ß-hydroxysteroid dehydrogenase type 1: a role in restraining mast cell degranulation.

Mast cells are key initiators of allergic, anaphylactic and inflammatory reactions, producing mediators that affect vascular permeability, angiogenesis and fibrosis. Glucocorticoid pharmacotherapy reduces mast cell number, maturation and activation but effects at physiological levels are unknown. Within cells, glucocorticoid concentration is modulated by the 11ß-hydroxysteroid dehydrogenases (11ß-HSDs). Here we show expression and activity of 11ß-HSD1, but not 11ß-HSD2, in mouse mast cells with 11ß-HSD activity only in the keto-reductase direction, regenerating active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone). Mast cells from 11ß-HSD1-deficient mice show ultrastructural evidence of increased activation, including piecemeal degranulation and have a reduced threshold for IgG immune complex-induced mast cell degranulation. Consistent with reduced intracellular glucocorticoid action in mast cells, levels of carboxypeptidase A3 mRNA, a glucocorticoid-inducible mast cell-specific transcript, are lower in peritoneal cells from 11ß-HSD1-deficient than control mice. These findings suggest that 11ß-HSD1-generated glucocorticoids may tonically restrain mast cell degranulation, potentially influencing allergic, anaphylactic and inflammatory responses.

11ß-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis.

11ß-Hydroxysteroid dehydrogenase type-1 (11ß-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11ß-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11ß-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11ß-HSD1 inhibitor or crossed with 11ß-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11ß-HSD1 inhibition or deficiency attenuated atherosclerosis (74-76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM-1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11ß-HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11ß-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11ß-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages.

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.

The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights.

Since the discovery of glucocorticoids in the 1940s and the recognition of their anti-inflammatory effects, they have been amongst the most widely used and effective treatments to control inflammatory and autoimmune diseases. However, their clinical efficacy is compromised by the metabolic effects of long-term treatment, which include osteoporosis, hypertension, dyslipidaemia and insulin resistance/type 2 diabetes mellitus. In recent years, a great deal of effort has been invested in identifying compounds that separate the beneficial anti-inflammatory effects from the adverse metabolic effects of glucocorticoids, with limited effect. It is clear that for these efforts to be effective, a greater understanding is required of the mechanisms by which glucocorticoids exert their anti-inflammatory and immunosuppressive actions. Recent research is shedding new light on some of these mechanisms and has produced some surprising new findings. Some of these recent developments are reviewed here.

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.

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.

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.

Metabolic effects of voluntary wheel running in young and old Syrian golden hamsters.

To explore the metabolic effects of high volume wheel running in the Syrian golden hamster, 6-week old (YOUNG) and 6-month old (OLD) male animals were randomly divided into sedentary (i.e., YOUNG-S or OLD-S) or running wheel (i.e., YOUNG-RW or OLD-RW) groups (n = 8/group). RW groups had 24-h access to activity wheels while S were housed in standard rodent cages. At the start of wheel exposure, the number of revolutions were similar in both groups, but by day 15 were nearly two-fold higher in the YOUNG vs. OLD. OLD ate more than YOUNG and wheel running increased food intake by approximately 50%. YOUNG-RW maintained the same total body mass as YOUNG-S, while OLD-RW had a transient weight loss of approximately 10 g. Perirenal fat mass was smaller in YOUNG- and OLD-RW groups compared with S groups (45% and 66%, respectively. Plantaris muscle cytochrome c oxidase activity was also approximately 2-fold higher in YOUNG-RW than in YOUNG-S hamsters but was similar between OLD-RW and OLD-S groups. Plasma leptin levels were approximately 60% lower in YOUNG-RW compared with YOUNG-S and correlated significantly with visceral fat pad mass (r2 = 0.58, p = 0.001). Corticosterone levels were lower in YOUNG-RW (13.0 +/- 0.36 ng/ml) than in YOUNG-S (16.4 +/- 0.83 ng/ml) hamsters and higher in OLD-RW (22.62 +/- 0.47 ng/ml) than in OLD-S (15.54 +/- 0.13 ng/ml) hamsters. These observations reveal that the hamster is a suitable model for accelerating the effects of exercise on body composition and metabolic alterations associated with training and that the training adaptations are more pronounced in younger compared with older hamsters, possibly as a result of the higher voluntary wheel activity in the former group.

Effect of voluntary exercise on peripheral tissue glucocorticoid receptor content and the expression and activity of 11beta-HSD1 in the Syrian hamster.

Recent findings indicate that elevated levels of glucocorticoids (GC), governed by the expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and GC receptors (GR), in visceral adipose tissue and skeletal muscle lead to increased insulin resistance and the metabolic syndrome. Paradoxically, evidence indicates that aerobic exercise attenuates the development of the metabolic syndrome even though it stimulates acute increases in circulating GC levels. To investigate the hypothesis that training alters peripheral GC action to maintain insulin sensitivity, young male hamsters were randomly divided into sedentary (S) and trained (T) groups (n = 8 in each). The T group had 24-h access to running wheels over 4 wk of study. In muscle, T hamsters had lower 11beta-HSD1 protein expression (19.2 +/- 1.40 vs. 22.2 +/- 0.96 optical density, P < 0.05), similar 11beta-HSD1 enzyme activity (0.9 +/- 0.27% vs. 1.1 +/- 0.26), and lower GR protein expression (9.7 +/- 1.86 vs. 15.1 +/- 1.78 optical density, P < 0.01) than S hamsters. In liver, 11beta-HSD1 protein expression tended to be lower in T compared with S (19.2 +/- 0.56 vs. 21.4 +/- 1.05, P = 0.07), whereas both enzyme activity and GR protein expression were similar. In contrast, visceral adipose tissue contained approximately 2.7-fold higher 11beta-HSD1 enzyme activity in T compared with S (12.9 +/- 3.3 vs. 4.8 +/- 1.5% conversion, P < 0.05) but was considerably smaller in mass (0.24 +/- 0.02 vs. 0.71 +/- 0.06 g). Thus the intracellular adaptation of GC regulators to exercise is tissue specific, resulting in decreases in GC action in skeletal muscle and increases in GC action in visceral fat. These adaptations may have important implications in explaining the protective effects of aerobic exercise on insulin resistance and other symptoms of the metabolic syndrome.