Addressing the role of 11ß-hydroxysteroid dehydrogenase type 1 in the development of polycystic ovary syndrome and the putative therapeutic effects of its selective inhibition in a preclinical model.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common metabolic and endocrine disorder among reproductive-age women, and the leading cause of anovulatory infertility. 11ß-hydroxysteroid dehydrogenases-1 (11ß-HSD1) catalysing the conversion of inactive cortisone to active cortisol plays a crucial role in various metabolic diseases. However, whether 11ß-HSD1 is associated with the pathogenesis of PCOS and whether 11ß-HSD1 can be a treating target of PCOS remain unknown. METHODS: This study was first designed to explore the role of 11ß-HSD1 in PCOS development and the effect of selective 11ß-HSD1 inhibitor administration on PCOS treatment. Follicular fluid and granulosa cells (GCs) were collected from 32 non-PCOS patients and 37 patients with PCOS to measure cortisol and 11ß-HSDs levels. Female Sprague-Dawley rats (3-week-old) were injected with dehydroepiandrosterone (DHEA) to induce PCOS and their ovaries were collected to measure the abundance of corticosterone (CORT) and 11ß-HSDs. To determine the role of 11ß-HSD1 in PCOS development, we overexpressed 11ß-HSD1 in the ovaries of female rats (5-week-old) or knocked down the expression of 11ß-HSD1 in the ovaries from PCOS rats via lentivirus injection. After lentivirus infection, the body weights, ovarian weights, estrous cycles, reproductive hormones and morphology of the ovary were analysed in rats from different experimental groups. Then to figure out the translational potential of the selective 11ß-HSD1 inhibitor in treating PCOS, PCOS rats were treated with BVT.2733, a selective 11ß-HSD1 inhibitor and a cluster of PCOS-like traits were analysed, including insulin sensitivity, ovulatory function and fertility of rats from the Control, PCOS and PCOS+BVT groups. Rat ovarian explants and human GCs were used to explore the effect of CORT or cortisol on ovarian extracellular matrix remodelling. RESULTS: The elevated expression of 11ß-HSD1 contributed to the increased cortisol and corticosterone (CORT) concentrations observed in the ovaries of PCOS patients and PCOS rats respectively. Our results showed that ovarian overexpression of 11ß-HSD1 induced a cluster of PCOS phenotypes in rats including irregular estrous cycles, reproductive hormone dysfunction and polycystic ovaries. While knockdown of ovarian 11ß-HSD1 of PCOS rats reversed these PCOS-like changes. Additionally, the selective 11ß-HSD1 inhibitor BVT.2733 alleviated PCOS symptoms such as insulin resistance (IR), irregular estrous cycles, reproductive hormone dysfunction, polycystic ovaries, ovulatory dysfunction and subfertility. Moreover, we showed that cortisol target ovarian insulin signalling pathway and ovarian extracellular matrix (ECM) remodelling in vivo, in ovarian explants and in GCs. CONCLUSION: Elevated 11ß-HSD1 abundance in ovarian is involved in the pathogenesis of PCOS by impairing insulin signalling pathway and ECM remodelling. Selective inhibition of 11ß-HSD1 ameliorates a cluster of PCOS phenotypes. Our study demonstrates the selective 11ß-HSD1 inhibitor as a novel and promising strategy for the treatment of PCOS.

Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats.

OBJECTIVE: Obesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing's Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoid levels have been implicated in the development of the metabolic phenotype of obesity. Tissue glucocorticoid levels are regulated by 11ß-hydroxysteroid dehydrogenase type1 (11ßHSD1), which increases the local concentration of active glucocorticoids by the production of corticosterone from 11-dehydrocorticosterone. 11ßHSD1 is expressed in the hypothalamic arcuate nucleus (ARC), a major weight and appetite-regulating centre, and therefore represents a target for novel anti-obesity therapeutic agents. Thus, we sought to investigate the effect of chronic alterations of ARC corticosterone levels (mediated by 11ßHSD1) on food intake and body weight in adult male rats. METHODS: Recombinant adeno-associated virus particles bearing sense 11ßHSD1 (rAAV-S11ßHSD1) and small interfering 11ßHSD1 (rAAV-si11ßHSD1), respectively, were stereotactically injected into the ARC (bilaterally) of adult male Wistar rats. rAAV-GFP was injected into control groups of male Wistar rats. Food intake and body weight were measured three times a week for 70 days. Terminal brain, plasma and intrascapular brown adipose tissue (iBAT) samples were taken for measurement of mRNA expression and hormone levels. RESULTS: Compared to controls, rAAV-S11ßHSD1 injection resulted in higher ARC corticosterone levels, hyperphagia and increased weight gain. Conversely, rAAV-si11ßHSD1 injection (compared to controls) resulted in lower ARC corticosterone levels, higher iBAT uncoupling protein-1 mRNA expression and less weight gain despite similar food intake. CONCLUSIONS: Therefore ARC corticosterone, regulated by 11ßHSD1, may play a role in food intake and body weight regulation. These data have important implications for the development of centrally-acting 11ßHSD1 inhibitors, which are currently being developed for the treatment of obesity, metabolic disorders, and other conditions.

Epidermal Mineralocorticoid Receptor Inactivation Affects the Homeostasis of All Skin Layers in Chronologically Aged Mice.

The increased production of endogenous glucocorticoids (GCs) in the skin of the elderly population contributes to age-related defects strikingly similar to those occurring after pharmacologic treatments with GCs. GCs act through the ligand-dependent transcription factors GC receptor (GR) and mineralocorticoid receptor (MR). We reported that epidermal MR plays nonredundant roles relative to GR in adult mouse skin homeostasis; however, its relative contribution to natural skin aging has not been previously investigated. A 13-month-old MR epidermal knockout (MREKO) mice showed differential features of aging relative to controls (CO) in all skin compartments. MREKO mice were resistant to age-induced epidermal atrophy but showed reduced dermal thickness, with decreased collagen deposition and decreased SMAD2 and 3 activity. Importantly, the dermal white adipose tissue (dWAT) was 2.5-fold enlarged in 13-month MREKO versus CO, featuring adipocyte hyperplasia and hypertrophy at least in part through early increases in Pparg. These changes correlated with compartment-specific alterations in GC signaling. In addition, conditioned medium from MREKO keratinocytes increased adipocyte differentiation, indicating paracrine regulation of adipogenesis through mechanisms that include activation of ß-catenin signaling. These findings highlight the importance of epidermal MR in regulating cross-talk among skin compartments in naturally aged skin through GC and ß-catenin signaling pathways.

Reciprocal Regulation of HSD11B1 and HSD11B2 Predicts Glucocorticoid Sensitivity in Childhood Acute Lymphoblastic Leukemia.

There are few biomarkers to predict efficacy of glucocorticoid treatment in childhood acute lymphoblastic leukemia (ALL) at diagnosis. Here, we demonstrate reciprocal regulation of 11beta-hydroxysteroid dehydrogenase (11ß-HSD), may predict the apoptotic response of ALL to glucocorticoid treatment. Our data may be useful to refine glucocorticoid treatment, to retain benefit while minimizing side effects.

11ß-HSD1 Modulates the Set Point of Brown Adipose Tissue Response to Glucocorticoids in Male Mice.

Glucocorticoids (GCs) are potent regulators of energy metabolism. Chronic GC exposure suppresses brown adipose tissue (BAT) thermogenic capacity in mice, with evidence for a similar effect in humans. Intracellular GC levels are regulated by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity, which can amplify circulating GC concentrations. Therefore, 11ß-HSD1 could modulate the impact of GCs on BAT function. This study investigated how 11ß-HSD1 regulates the molecular architecture of BAT in the context of GC excess and aging. Circulating GC excess was induced in 11ß-HSD1 knockout (KO) and wild-type mice by supplementing drinking water with 100 µg/mL corticosterone, and the effects on molecular markers of BAT function and mitochondrial activity were assessed. Brown adipocyte primary cultures were used to examine cell autonomous consequences of 11ß-HSD1 deficiency. Molecular markers of BAT function were also examined in aged 11ß-HSD1 KO mice to model lifetime GC exposure. BAT 11ß-HSD1 expression and activity were elevated in response to GC excess and with aging. 11ß-HSD1 KO BAT resisted the suppression of uncoupling protein 1 (UCP1) and mitochondrial respiratory chain subunit proteins normally imposed by GC excess. Furthermore, brown adipocytes from 11ß-HSD1 KO mice had elevated basal mitochondrial function and were able to resist GC-mediated repression of activity. BAT from aged 11ß-HSD1 KO mice showed elevated UCP1 protein and mitochondrial content, and a favorable profile of BAT function. These data reveal a novel mechanism in which increased 11ß-HSD1 expression, in the context of GC excess and aging, impairs the molecular and metabolic function of BAT.

Forebrain-Specific Transgene Rescue of 11ß-HSD1 Associates with Impaired Spatial Memory and Reduced Hippocampal Brain-Derived Neurotrophic Factor mRNA Levels in Aged 11ß-HSD1 Deficient Mice.

Mice lacking the intracellular glucocorticoid-regenerating enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) are protected from age-related spatial memory deficits. 11ß-HSD1 is expressed predominantly in the brain, liver and adipose tissue. Reduced glucocorticoid levels in the brain in the absence of 11ß-HSD1 may underlie the improved memory in aged 11ß-HSD1 deficient mice. However, the improved glucose tolerance, insulin sensitisation and cardioprotective lipid profile associated with reduced peripheral glucocorticoid regeneration may potentially contribute to the cognitive phenotype of aged 11ß-HSD1 deficient mice. In the present study, transgenic mice with forebrain-specific overexpression of 11ß-HSD1 (Tg) were intercrossed with global 11ß-HSD1 knockout mice (HSD1KO) to examine the influence of forebrain and peripheral 11ß-HSD1 activity on spatial memory in aged mice. Transgene-mediated delivery of 11ß-HSD1 to the hippocampus and cortex of aged HSD1KO mice reversed the improved spatial memory retention in the Y-maze but not spatial learning in the watermaze. Brain-derived neurotrophic factor (BDNF) mRNA levels in the hippocampus of aged HSD1KO mice were increased compared to aged wild-type mice. Rescue of forebrain 11ß-HSD1 reduced BDNF mRNA in aged HSD1KO mice to levels comparable to aged wild-type mice. These findings indicate that 11ß-HSD1 regenerated glucocorticoids in the forebrain and decreased levels of BDNF mRNA in the hippocampus play a role in spatial memory deficits in aged wild-type mice, although 11ß-HSD1 activity in peripheral tissues may also contribute to spatial learning impairments in aged mice.

11ß-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.

Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), although effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a bidirectional GC-activating enzyme that is potently upregulated by inflammation within mesenchymal-derived tissues. We assessed the regulation of this enzyme with inflammation in muscle, and examined its functional impact on muscle. The expression of 11ß-HSD1 in response to proinflammatory stimuli was determined in a transgenic murine model of chronic inflammation (TNF-Tg) driven by overexpression of tumour necrosis factor (TNF)-α within tissues, including muscle. The inflammatory regulation and functional consequences of 11ß-HSD1 expression were examined in primary cultures of human and murine myotubes and human and murine muscle biopsies ex vivo. The contributions of 11ß-HSD1 to muscle inflammation and wasting were assessed in vivo with the TNF-Tg mouse on an 11ß-HSD1 null background. 11ß-HSD1 was significantly upregulated within the tibialis anterior and quadriceps muscles from TNF-Tg mice. In human and murine primary myotubes, 11ß-HSD1 expression and activity were significantly increased in response to the proinflammatory cytokine TNF-α (mRNA, 7.6-fold, p < 0.005; activity, 4.1-fold, p < 0.005). Physiologically relevant levels of endogenous GCs activated by 11ß-HSD1 suppressed proinflammatory cytokine output (interkeukin-6, TNF-α, and interferon-γ), but had little impact on markers of muscle wasting in human myotube cultures. TNF-Tg mice on an 11ß-11ß-HSD1 knockout background developed greater muscle wasting than their TNF-Tg counterparts (27.4% less; p < 0.005), with smaller compacted muscle fibres and increased proinflammatory gene expression relative to TNF-Tg mice with normal 11ß-HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11ß-HSD1 expression and GC activation within muscle. Although concerns have been raised that excess levels of GCs may be detrimental to muscle, in this inflammatory TNF-α-driven model, local endogenous GC activation appears to be an important anti-inflammatory response that protects against inflammatory muscle wasting in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Biological Roles of Hydroxysteroid (11-Beta) Dehydrogenase 1 (HSD11B1), HSD11B2, and Glucocorticoid Receptor (NR3C1) in Sheep Conceptus Elongation.

In sheep, the elongating conceptus synthesizes and secretes interferon tau (IFNT) as well as prostaglandins (PGs) and cortisol. The enzymes, hydroxysteroid (11-beta) dehydrogenase 1 (HSD11B1) and HSD11B2 interconvert cortisone and cortisol. In sheep, HSD11B1 is expressed and active in the conceptus trophectoderm as well as in the endometrial luminal epithelia; in contrast, HSD11B2 expression is most abundant in conceptus trophectoderm. Cortisol is a biologically active glucocorticoid and ligand for the glucocorticoid receptor (NR3C1 or GR) and mineralocorticoid receptor (NR3C2 or MR). Expression of MR is not detectable in either the ovine endometrium or conceptus during early pregnancy. In tissues that do not express MR, HSD11B2 protects cells from the growth-inhibiting and/or proapoptotic effects of cortisol, particularly during embryonic development. In study one, an in utero loss-of-function analysis of HSD11B1 and HSD11B2 was conducted in the conceptus trophectoderm using morpholino antisense oligonucleotides (MAOs) that inhibit mRNA translation. Elongating, filamentous conceptuses were recovered on Day 14 from ewes infused with control morpholino or HSD11B2 MAO. In contrast, HSD11B1 MAO resulted in severely growth-retarded conceptuses or conceptus fragments with apoptotic trophectoderm. In study two, clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing was used to determine the role of GR in conceptus elongation and development. Elongating, filamentous-type conceptuses (12-14 cm in length) were recovered from ewes gestating control embryos (n = 7/7) and gestating GR-edited embryos (n = 6/7). These results support the idea that the effects of HSD11B1-derived cortisol on conceptus elongation are indirectly mediated by the endometrium and are not directly mediated through GR in the trophectoderm.

Greater glucocorticoid receptor activation in hippocampus of aged rats sensitizes microglia.

Healthy aging individuals are more likely to suffer profound memory impairments following an immune challenge than are younger adults. These challenges produce a brain inflammatory response that is exaggerated with age. Sensitized microglia found in the normal aging brain are responsible for this amplified response, which in turn interferes with processes involved in memory formation. Here, we examine factors that may lead aging to sensitize microglia. Aged rats exhibited higher corticosterone levels in the hippocampus, but not in plasma, throughout the daytime (diurnal inactive phase). These elevated hippocampal corticosterone levels were associated with increased hippocampal 11ß-hydroxysteroid dehydrogenase type 1 protein expression, the enzyme that catalyzes glucocorticoid formation and greater hippocampal glucocorticoid receptor (GR) activation. Intracisternal administration of mifepristone, a GR antagonist, effectively reduced immune-activated proinflammatory responses, specifically from hippocampal microglia and prevented Escherichia coli-induced memory impairments in aged rats. Voluntary exercise as a therapeutic intervention significantly reduced total hippocampal GR expression. These data strongly suggest that increased GR activation in the aged hippocampus plays a critical role in sensitizing microglia.

Diurnal and stress-induced intra-hippocampal corticosterone rise attenuated in 11ß-HSD1-deficient mice: a microdialysis study in young and aged mice.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) locally regenerates active glucocorticoids from their inert forms thereby amplifying intracellular levels within target tissues including the brain. We previously showed greater increases in intra-hippocampal corticosterone (CORT) levels upon Y-maze testing in aged wild-type than in 11ß-HSD1(-/-) mice coinciding with impaired and intact spatial memory, respectively. Here we examined whether ageing influences 11ß-HSD1 regulation of CORT in the dorsal hippocampus under basal conditions during the diurnal cycle and following stress. Intra-hippocampal CORT levels measured by in vivo microdialysis in freely behaving wild-type mice displayed a diurnal variation with peak levels in the evening that were significantly elevated with ageing. In contrast, the diurnal rise in intra-hippocampal CORT levels was greatly diminished in 11ß-HSD1(-/-) mice and there was no rise with ageing; basal intra-hippocampal CORT levels were similar to wild-type controls. Furthermore, a short (3 min) swim stress induced a longer lasting increase in intra-hippocampal CORT levels in wild-type mice than in 11ß-HSD1(-/-) mice despite no genotypic differences in elevation of plasma CORT. These data indicate that 11ß-HSD1 activity contributes substantially to diurnal and stress-induced increases in hippocampal CORT levels. This contribution is even greater with ageing. Thus, 11ß-HSD1 inhibition may be an attractive target for treating cognitive impairments associated with stress or ageing.

Short-term inhibition of 11ß-hydroxysteroid dehydrogenase type 1 reversibly improves spatial memory but persistently impairs contextual fear memory in aged mice.

High glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11ß-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11ß-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design. Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle-treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11ß-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals.

Intrahippocampal glucocorticoids generated by 11ß-HSD1 affect memory in aged mice.

11Beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) locally amplifies active glucocorticoids within specific tissues including in brain. In the hippocampus, 11ß-HSD1 messenger RNA increases with aging. Here, we report significantly greater increases in intrahippocampal corticosterone (CORT) levels in aged wild-type (WT) mice during the acquisition and retrieval trials in a Y-maze than age-matched 11ß-HSD1(-/-) mice, corresponding to impaired and intact spatial memory, respectively. Acute stress applied to young WT mice led to increases in intrahippocampal CORT levels similar to the effects of aging and impaired retrieval of spatial memory. 11ß-HSD1(-/-) mice resisted the stress-induced memory impairment. Pharmacologic inhibition of 11ß-HSD1 abolished increases in intrahippocampal CORT levels during the Y-maze trials and prevented spatial memory impairments in aged WT mice. These data provide the first in vivo evidence that dynamic increases in hippocampal 11ß-HSD1 regenerated CORT levels during learning and retrieval play a key role in age- and stress-associated impairments of spatial memory.

Circadian rhythms in rheumatology--a glucocorticoid perspective.

The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in regulating and controlling immune responses. Dysfunction of the HPA axis has been implicated in the pathogenesis of rheumatoid arthritis (RA) and other rheumatic diseases. The impact of glucocorticoid (GC) therapy on HPA axis function also remains a matter of concern, particularly for longer treatment duration. Knowledge of circadian rhythms and the influence of GC in rheumatology is important: on the one hand we aim for optimal treatment of the daily undulating inflammatory symptoms, for example morning stiffness and swelling; on the other, we wish to disturb the HPA axis as little as possible. This review describes circadian rhythms in RA and other chronic inflammatory diseases, dysfunction of the HPA axis in RA and other rheumatic diseases and the recent concept of the hepato-hypothalamic-pituitary-adrenal-renal axis, the problem of adrenal suppression by GC therapy and how it can be avoided, and evidence that chronotherapy with modified release prednisone effective at 02:00 a.m. can inhibit proinflammatory sequelae of nocturnal inflammation better compared with GC administration in the morning but does not increase the risk of HPA axis insufficiency in RA.

11ß-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes.

The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1). We recently reported that 11ß-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11ß-HSD1 in skin inflammation. Expression of 11ß-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1ß and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11ß-HSD1 in response to pro-inflammatory cytokines, we knocked down 11ß-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1ß or TNFα stimulation was attenuated in NHEKs transfected with si11ß-HSD1 compared with control cells. In addition, IL-1ß-induced IL-6 production was enhanced in cultures containing 1 × 10(-13) M cortisol, whereas 1 × 10(-5) M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11ß-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol concentrations by 11ß-HSD1 appears to modulate expression of inflammatory cytokines in NHEKs.

Human but not mouse adipogenesis is critically dependent on LMO3.

Increased visceral fat is associated with a high risk of diabetes and metabolic syndrome and is in part caused by excessive glucocorticoids (GCs). However, the molecular mechanisms remain undefined. We now identify the GC-dependent gene LIM domain only 3 (LMO3) as being selectively upregulated in a depot-specific manner in human obese visceral adipose tissue, localizing primarily in the adipocyte fraction. Visceral LMO3 levels were tightly correlated with expression of 11ß-hydroxysteroid dehydrogenase type-1 (HSD11B1), the enzyme responsible for local activation of GCs. In early human adipose stromal cell differentiation, GCs induced LMO3 via the GC receptor and a positive feedback mechanism involving 11ßHSD1. No such induction was observed in murine adipogenesis. LMO3 overexpression promoted, while silencing of LMO3 suppressed, adipogenesis via regulation of the proadipogenic PPARγ axis. These results establish LMO3 as a regulator of human adipogenesis and could contribute a mechanism resulting in visceral-fat accumulation in obesity due to excess glucocorticoids.

Modulation of 11ß-hydroxysteroid dehydrogenase as a strategy to reduce vascular inflammation.

Atherosclerosis is a chronic inflammatory disease in which initial vascular damage leads to extensive macrophage and lymphocyte infiltration. Although acutely glucocorticoids suppress inflammation, chronic glucocorticoid excess worsens atherosclerosis, possibly by exacerbating systemic cardiovascular risk factors. However, glucocorticoid action within the lesion may reduce neointimal proliferation and inflammation. Glucocorticoid levels within cells do not necessarily reflect circulating levels due to pre-receptor metabolism by 11ß-hydroxysteroid dehydrogenases (11ß-HSDs). 11ß-HSD2 converts active glucocorticoids into inert 11-keto forms. 11ß-HSD1 catalyses the reverse reaction, regenerating active glucocorticoids. 11ß-HSD2-deficiency/inhibition causes hypertension, whereas deficiency/inhibition of 11ß-HSD1 generates a cardioprotective lipid profile and improves glycemic control. Importantly, 11ß-HSD1-deficiency/inhibition is atheroprotective, whereas 11ß-HSD2-deficiency accelerates atherosclerosis. These effects are largely independent of systemic risk factors, reflecting modulation of glucocorticoid action and inflammation within the vasculature. Here, we consider whether evidence linking the 11ß-HSDs to vascular inflammation suggests these isozymes are potential therapeutic targets in vascular injury and atherosclerosis.

11ß-hydroxysteroid dehydrogenase type 1 is expressed in human sebaceous glands and regulates glucocorticoid-induced lipid synthesis and toll-like receptor 2 expression in SZ95 sebocytes.

BACKGROUND: Glucocorticoids (GCs) affect the pathophysiology of sebaceous glands, causing development or exacerbation of acne. The availability of GCs is regulated by isoenzymes of 11ß-hydroxysteroid dehydrogenase (11ßHSD) at tissue-specific levels. 11ßHSD type 1 (HSD11ß1) is a reductase, catalysing the conversion of cortisone to active cortisol, and is highly expressed in liver and adipose tissue. Recently, HSD11ß1 was observed in human skin in keratinocytes and fibroblasts. OBJECTIVES: To investigate the expression of HSD11ß1 in sebaceous glands of normal and acne-involved skin, and to examine the role of HSD11ß1 in GC-induced lipid synthesis and toll-like receptor 2 (TLR2) expression in sebocytes. METHODS: Expression of HSD11ß1 was examined by immunohistochemistry in acne lesional skin and normal skin of healthy volunteers. The cultured SZ95 sebocytes were treated with dexamethasone, and the lipid synthesis and mRNA levels of sterol regulatory element binding protein 1 (SREBP-1) and TLR2 were determined. Use of an HSD11ß1 inhibitor and the small interference RNA (siRNA) approach were used to investigate the role of HSD11ß1 on the GC regulation of sebocyte functions. RESULTS: HSD11ß1 was expressed in human sebaceous glands and upregulated in acne lesional skin. HSD11ß1 mRNA was enhanced by dexamethasone and cytokines in SZ95 sebocytes. Dexamethasone enhanced lipid synthesis, partially through the transcriptional induction of SREBP-1, and also by increasing TLR2 mRNA levels. Inhibition of HSD11ß1 by PF-915275 or siRNA significantly inhibited the GC-induced lipid synthesis and the mRNA expression of SREBP-1 and TLR2. CONCLUSIONS: Our results indicate that HSD11ß1 plays a key role in the modulation of GC action on sebocytes, including sebum production and TLR2-mediated inflammation, thereby influencing the pathogenesis of acne.

11ß-Hydroxysteroid dehydrogenase type 1: potential therapeutic target for metabolic syndrome.

Obesity and associated metabolic syndrome is one of the greatest health threat to the modern society. Cortisol excess and the glucocorticoid receptor signaling pathway in the metabolically active tissues have been implicated in the development of diabetes and obesity. The key enzyme in the regeneration of intracellular cortisol is 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). 11ß-HSD1 increases local cortisol production in metabolically active tissue types such as adipose and liver. Recent studies have shown that mice deficient in this enzyme are resistant to diet induced obesity and have increased insulin and leptin sensitivity. Clinical and preclinical studies indicate that 11ß-HSD1 inhibitors are likely to exert major pharmacological actions in metabolically active tissues. These effects suggest that inhibition of 11ß-HSD1 in vivo may be a novel therapeutic target for obesity, diabetes, and metabolic syndrome. The advancement of numerous structural classes of selective 11ß-HSD1 inhibitors further indicates that more refined design and screening for isoform and tissue selectivity would yield potential therapeutics in this area.