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.

Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis.

Apoptosis is essential for clearance of potentially injurious inflammatory cells and subsequent efficient resolution of inflammation. Here we report that human neutrophils contain functionally active cyclin-dependent kinases (CDKs), and that structurally diverse CDK inhibitors induce caspase-dependent apoptosis and override powerful anti-apoptosis signals from survival factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We show that the CDK inhibitor R-roscovitine (Seliciclib or CYC202) markedly enhances resolution of established neutrophil-dependent inflammation in carrageenan-elicited acute pleurisy, bleomycin-induced lung injury, and passively induced arthritis in mice. In the pleurisy model, the caspase inhibitor zVAD-fmk prevents R-roscovitine-enhanced resolution of inflammation, indicating that this CDK inhibitor augments inflammatory cell apoptosis. We also provide evidence that R-roscovitine promotes apoptosis by reducing concentrations of the anti-apoptotic protein Mcl-1. Thus, CDK inhibitors enhance the resolution of established inflammation by promoting apoptosis of inflammatory cells, thereby demonstrating a hitherto unrecognized potential for the treatment of inflammatory disorders.

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.

Apoptosis in glomerulonephritis.

Apoptosis is of fundamental importance and plays a key role in determining the outcome of glomerulonephritis. Under ideal circumstances,apoptosis deletes infiltrating leukocytes and excess numbers of resident cells that are surplus to requirements, thereby facilitating tissue remodeling and the restoration of normal tissue architecture. Apoptosis also has a darker side, however, and may be responsible for the deletion of critically important resident glomerular cells, resulting in hypocellular scarring and loss of renal function. Recent data indicate that glomerular cell apoptosis may be manipulated to improve outcome in experimental models of renal inflammation. It is hoped that further research will provide novel therapeutic strategies for patients with inflammatory glomerulonephritis.

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, 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.