Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.3 (HSD)
3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) acts as a pre-receptor signaling mechanism for corticosteroids by regulating the access of active glucocorticoids to both glucocorticoid (GR) and mineralocorticoid receptors (MR). To examine the relationship between endogenous glucocorticoid metabolism and osteoblast function, we have characterized the expression of 11 beta-HSD isozymes in rat osteosarcoma cells. Analysis of mRNA from ROS 25/1, UMR 106 and ROS 17/2.8 cells revealed transcripts for both 11 beta-HSD type 1 (11 beta-HSD1) and type 2 (11 beta-HSD2) in all three cell lines. However, enzyme activity studies showed only high affinity dehydrogenase activity (inactivation of corticosterone (B) to 11-dehydrocorticosterone (A)), characteristic of 11 beta-HSD2; conversion of B to A was higher in ROS 25/1> UMR 106 cells>ROS 17/2.8. Although all three cell lines had similar numbers of GR (50,000/cell), glucocorticoid modulation of alkaline phosphatase activity and cell proliferation was only detectable in ROS 17/2.8 cells. Further studies showed that 11 beta-HSD2 activity in each of the cells was potently stimulated by both A and B, but not by synthetic dexamethasone. This effect was blocked by the 11 beta-HSD inhibitor, 18 beta-glycyrrhetinic acid (but not by GR or MR antagonists) suggesting direct, allosteric regulation of 11 beta-HSD2 activity. These data indicate that in osteosarcoma cells 11 beta-HSD2 plays a key role in controlling GR-mediated responses; cells with relatively high levels of 11 beta-HSD2 activity were insensitive to glucocorticoids, whilst cells with low levels showed functional responses to both dexamethasone and B. In addition to the established effects of 11 beta-HSD2 in protecting MR in the kidney and colon, our data suggest that 11 beta-HSD2 in bone represents an important pre-receptor mechanism in determining ligand availability to GR.
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PMID:Expression of 11 beta-hydroxysteroid dehydrogenase in rat osteoblastic cells: pre-receptor regulation of glucocorticoid responses in bone. 1125 28

Interconversion of active and inactive glucocorticoids, e.g. cortisol (F) and cortisone (E) is catalysed by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) which exists as two isoforms. We have used human placental bed biopsies and an in-vitro cytotrophoblast cell culture system to examine the expression and activity of the 11 beta-HSD isoforms along with that of the glucocorticoid and mineralocorticoid receptors (GR and MR). Immunohistochemistry localized 11 beta-HSD1 to decidualized stromal cells and 11 beta-HSD2 to villous cytotrophoblast, syncytiotrophoblasts and trophoblast cells invading the placental bed and maternal vasculature. In primary cultures of human cytotrophoblast, 11 beta-HSD2, GR and MR mRNA were expressed. Low levels of 11 beta-HSD1 mRNA were noted in these cultured cells, but could be explained on the basis of contaminating, vimentin-positive decidual stromal cells (< or =5%). Enzyme activity studies confirmed the presence of a high-affinity, NAD-dependent dehydrogenase activity (K(m) 137 nmol/l and V(max) 128 pmol E/h/mg protein), indicative of the 11 beta-HSD2 isoform. No reductase activity was observed. The presence of functional MR and GR was determined using Scatchard analyses of dexamethasone and aldosterone binding (MR K(d) 1.4 nmol/l B(max) 3.0; GR K(d) 6.6 nmol/l B(max) 16.2 fmol/ng protein). The expression of 11 beta-HSD1 in maternal decidua and 11 beta-HSD2 in adjacent trophoblast suggests an important role for glucocorticoids in determining trophoblast invasion. The presence of the MR within trophoblast indicates that some of the effects of cortisol could be MR- rather than GR-mediated.
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PMID:Expression of 11 beta-hydroxysteroid dehydrogenase isozymes and corticosteroid hormone receptors in primary cultures of human trophoblast and placental bed biopsies. 1127 98

The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes catalyze the interconversion of active glucocorticoids (GC) with their inert metabolites, thereby regulating the functional activity of GC. While 11beta-HSD type 1 (11beta-HSD1) activates GC from their 11-keto metabolites, 11beta-HSD type 2 (11beta-HSD2) inactivates GC. Here we report that both of these enzymes are expressed in human aortic smooth muscle cells (SMC), and that 11beta-HSD1 is more abundant and is differentially regulated relative to 11beta-HSD2. Stimulation of SMC with IL-1beta or TNFalpha led to a time- and dose-dependent increase of mRNA levels for 11beta-HSD1, while 11beta-HSD2 mRNA levels decreased. Parallel enzyme activity studies showed increased conversion of 3H-cortisone to 3H-cortisol but not 3H-cortisol to 3H-cortisone, demonstrating 11beta-HSD1 in SMC acts primarily as a reductase. A similar increase of 11beta-HSD1 mRNA expression was also found in human bronchial SMC upon stimulation, indicating the regulatory effect is not limited to vascular smooth muscle. Additional parallel studies revealed a similar pattern of induction for 11beta-HSD1 and monocyte chemoattractant protein-1, a well-defined proinflammatory molecule. These data suggest 11beta-HSD1 may play an important role in regulating inflammatory responses in the artery wall and lung.
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PMID:Induction of 11beta-hydroxysteroid dehydrogenase type 1 but not -2 in human aortic smooth muscle cells by inflammatory stimuli. 1137 76

Tissue damage by proinflammatory cytokines is attenuated at both systemic and cellular levels by counter anti-inflammatory factors such as corticosteroids. Target cell responses to corticosteroids are dependent on several factors including prereceptor regulation via local steroidogenic enzymes. In particular, two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD), by interconverting hormonally active cortisol (F) to inactive cortisone (E), regulate the peripheral action of corticosteroids 11beta-HSD1 by converting E to F and 11beta-HSD2 by inactivating F to E. In different in vitro and in vivo systems both 11beta-HSD isozymes have been shown to be expressed in osteoblasts (OBs). Using the MG-63 human osteosarcoma cell-line and primary cultures of human OBs, we have studied the regulation of osteoblastic 11beta-HSD isozyme expression and activity by cytokines and hormones with established roles in bone physiology. In MG-63 cells, interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) potently inhibited 11beta-HSD2 activity (cortisol-cortisone conversion) and messenger RNA (mRNA) levels in a dose-dependent manner while stimulating reciprocal expression of 11beta-HSD1 mRNA and activity (cortisone-cortisol conversion). A similar rise in 11beta-HSD1 reductase activity also was observed in primary cultures of OBs treated with 10 ng/ml TNF-alpha. Pretreatment of MG-63 cells with 0.1 ng/ml IL-1beta resulted in increased cellular sensitivity to physiological glucocorticoids as shown by induction of serum and glucocorticoid-inducible kinase (SGK; relative increase with 50 nM F but no IL-1beta pretreatment 1.12 +/- 0.34; with pretreatment 2.63 +/- 0.50; p < 0.01). These results highlight a novel mechanism within bone cells whereby inflammatory cytokines cause an autocrine switch in intracellular corticosteroid metabolism by disabling glucocorticoid inactivation (11beta-HSD2) while inducing glucocorticoid activation (11beta-HSD1). Therefore, it can be postulated that some of the effects of proinflammatory cytokines within bone (e.g., periarticular erosions in inflammatory arthritis) are mediated by this mechanism.
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PMID:Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation. 1139 80

One of the defining biochemical features of Cushing's disease is a relative insensitivity to glucocorticoid (GC) feedback, but an analysis of the GC receptor has failed to detect any major abnormalities. However, two isoenzymes of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD), either by converting cortisone (E) to cortisol (F) (type 1) or conversely by converting F to E (type 2), play an important prereceptor role in regulating corticosteroid hormone action at several sites. 11 beta HSD1 and -2 expression within the anterior pituitary gland itself may modulate GC feedback at an autocrine level, and we have speculated that this may be deranged in Cushing's disease. Detection of 11 beta HSD type 1 and 2 immunoreactive protein was performed using fluorescence immunohistochemistry. Double immunofluorescent studies were undertaken on normal pituitary to define the cellular localization of 11 beta HSD isoenzymes using antisera against GH, ACTH, LH, FSH, PRL, and S100, a nonhormonal marker of folliculo-stellate cells. In normal pituitary, positive staining for 11 beta HSD1-immunoreactive protein was observed in GH- and PRL-secreting cells and in folliculo-stellate cells; gonadotrophs, thyrotrophs, and ACTH-positive cells were negative. 11 beta HSD2 immunoreactivity was absent in all cell types. RT-PCR detected 11 beta HSD1 messenger ribonucleic acid (mRNA) expression in the normal pituitary; 11 beta HSD2 mRNA expression was also seen in most normal tissue. By contrast, in ACTH-secreting adenomas 11 beta HSD2 immunostaining was strongly positive in every case of corticotroph adenoma. 11 beta HSD1 immunoreactivity was also observed occasionally, but to a much lesser extent. In other pituitary tumors, both functional and nonfunctional, 11 beta HSD expression was variable in terms of isoenzyme mRNA and intensity of protein staining. The expression of 11 beta HSD1 (which generates F from E) in somatotrophs and lactotrophs suggests an autocrine role for this isoenzyme in the glucocorticoid regulation of pituitary GH and PRL secretion. 11 beta HSD2 expression is markedly induced in ACTH-secreting pituitary tumors and, by converting F to E, may explain the resetting of glucocorticoid feedback control in Cushing's disease.
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PMID:Expression of 11 beta-hydroxysteroid dehydrogenase isoenzymes in the human pituitary: induction of the type 2 enzyme in corticotropinomas and other pituitary tumors. 1139 78

11beta-hydroxysteroid dehydrogenases (11beta-HSD) perform prereceptor metabolism of glucocorticoids through interconversion of the active glucocorticoid, cortisol, with inactive cortisone. Although the immunosuppressive and anti-inflammatory activities of glucocorticoids are well documented, the expression of 11beta-HSD enzymes in immune cells is not well understood. Here we demonstrate that 11beta-HSD1, which converts cortisone to cortisol, is expressed only upon differentiation of human monocytes to macrophages. 11beta-HSD1 expression is concomitant with the emergence of peroxisome proliferator activating receptor gamma, which was used as a surrogate marker of monocyte differentiation. The type 2 enzyme, 11beta-HSD2, which converts cortisol to cortisone, was not detectable in either monocytes or cultured macrophages. Incubation of monocytes with IL-4 or IL-13 induced 11beta-HSD1 activity by up to 10-fold. IFN-gamma, a known functional antagonist of IL-4 and IL-13, suppressed the induction of 11beta-HSD1 by these cytokines. THP-1 cells, a human macrophage-like cell line, expressed 11beta-HSD1 and low levels of 11beta-HSD2. The expression of 11beta-HSD1 in these cells is up-regulated 4-fold by LPS. In summary, we have shown strong expression of 11beta-HSD1 in cultured human macrophages and THP-1 cells. The presence of the enzyme in these cells suggests that it may play a role in regulating the immune function of these cells.
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PMID:11 Beta-hydroxysteroid dehydrogenase type 1 is induced in human monocytes upon differentiation to macrophages. 1141 28

Two isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1 is believed to act in vivo predominantly as an oxo-reductase using NADP(H) as a cofactor to generate cortisol. In contrast, 11beta-HSD2 acts exclusively as an NAD-dependent dehydrogenase inactivating cortisol to cortisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol. In peripheral tissues, both enzymes serve to control the availability of cortisol to bind to the corticosteroid receptors. Defective expression of 11beta-HSD2 is implicated in patients with hypertension and intra-uterine growth retardation, while 11beta-HSD1 appears to be intricately involved in the conditions of apparent cortisone reductase deficiency, insulin resistance and visceral obesity. The ability of peripheral tissues to regulate corticosteroid concentrations through 11beta-HSD isozymes is established as an important mechanism in the pathogenesis of diverse human diseases. Modulation of enzyme activity may offer a novel therapeutic approach to treating human disease while circumventing the consequences of systemic glucocorticoid excess or deficiency.
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PMID:Cortisol metabolism and the role of 11beta-hydroxysteroid dehydrogenase. 1146 11

The 11beta-hydroxysteroid dehydrogenase types 1 and 2 enzymes (11beta-HSD1 and 11beta-HSD2), modulate glucocorticoid occupation of the mineralocorticoid and glucocorticoid receptors by interconverting corticosterone and cortisol to the inactive metabolites 11-dehydrocorticosterone and cortisone within the target cells. The NAD(+)-dependent 11-HSD 2 in the kidney inactivates corticosterone and cortisol, allowing aldosterone, which is not metabolized, access to the receptor. Studies of the kinetics of 11-HSD 2 activity in the rat kidney have produced inconsistent results. Western blots done in the absence of the reducing agent beta-mercaptoethanol showed two bands with approximate MW of 40 and 80 kDa. When beta-mercaptoethanol was used, only the 40 kDa was detected, indicating that under non-denaturing conditions a significant proportion of the 11beta-HSD 2 exists as a dimer. NAD(+)-dependent conversion of 3H-corticosterone by 20 microg of microsomal protein increased approximately 10 fold with the addition of 5 mM DTT concentration. NADP(+)-dependent activity with 20 microg of microsomal protein was very low and did not change significantly when using DTT. In the presence of DTT, the predominant 11-HSD activity in the rat kidney is NAD(+)-dependent with a K(m) of 15.1 nM, similar to that of the cloned and expressed enzyme. These data suggest that dimerization and subsequent enzyme inactivation occur when protocols promoting oxidation of this protein are used.
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PMID:The 11beta hydroxysteroid dehydrogenase 2 exists as an inactive dimer. 1157 24

An important determinant of the potency of steroid hormones is the presence of activating and inactivating enzymes in target cells. The 11 beta-hydroxysteroid dehydrogenase type 1 and type 2 enzymes (11 beta HSD1 and 11 beta HSD2) modulate glucocorticoid action and may be important in regulating cellular growth. In the present study we examined 11 beta-hydroxysteroid dehydrogenase in Ishikawa endometrial cancer cells to see if modulation of enzyme activity could potentiate the antiproliferative effects of glucocorticoids. Ishikawa cells contain an NAD dependent enzyme migrating at 41 kDa on Western blots, consistent with the presence of the glucocorticoid-inactivating enzyme 11 beta HSD2, while the NADP dependent 11 beta HSD1 is barely detectable. Given that glucocorticoids decrease cellular proliferation we asked whether inhibition of 11 beta HSD2 could further enhance this effect. Cultivation of cells in the presence of 1 microM cortisol resulted in an elevation of 11 beta HSD2 and this was associated with a decrease in cell number. Enzyme activity and cell proliferation showed a biphasic response to the synthetic anti-progestin and anti-glucocorticoid RU38486, with < or =10 nM exerting agonistic effects and > or =100 nM producing antagonist effects in the presence of 1 microM cortisol. Inhibition of 11 beta HSD2 activity by glycyrrhetinic acid did not enhance the anti-proliferative effects of 1 microM cortisol, but the inhibitor showed significant antiproliferative activity in the absence of added glucocorticoid, consistent with protection of the low levels of glucocorticoids present in culture medium. Interestingly, the commonly used 11 beta HSD inhibitor, Carbenoxolone, did not block 11 beta HSD2 activity in whole Ishikawa cells, and there was no effect on cell proliferation, however, complete inhibition of 11 beta HSD2 was achieved in cellular homogenates suggesting that a barrier exists to entry of the inhibitor into intact cells. This study suggests that inhibition of 11 beta HSD2 activity can enhance the antiproliferative effects of low, but not high concentrations of glucocorticoids, and that beneficial effects may be attained in vivo at the nadir of diurnal glucocorticoid levels.
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PMID:Modulation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in Ishikawa cells is associated with changes in cellular proliferation. 1160 36

In human pregnancy, cortisol and PGs are involved in the onset of labor and play an important role in the mechanisms leading to parturition. Recent studies have shown that at term, cortisol increases PG synthesis and decreases PG metabolism in chorion trophoblast (CT) cells. In CT, 11 beta-hydroxysteroid oxidase type 1 (11 beta-HSD1) converts biologically inactive cortisone to cortisol to regulate cortisol availability. In the present study, we have investigated whether 11 beta-HSD1 activity could be influenced by PGs. We have shown that in CT, PGF2alpha rapidly increased 11 beta-HSD1 reductase activity in a dose-dependent manner via the PGF2alpha receptor, localized in the fetal membranes. PGF2alpha stimulated 11 beta-HSD1 activity through increased intracellular calcium mobilization, activation of PKC, and the phosphorylation of the 11 beta-HSD enzyme. We propose that within CT there is a novel feed forward loop by which PGF2alpha acts to promote cortisol production from cortisone through increases in 11beta-HSD1, and this in turn leads to further net PG output for the onset of labor and birth.
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PMID:Prostaglandin F2alpha potentiates cortisol production by stimulating 11beta-hydroxysteroid dehydrogenase 1: a novel feedback loop that may contribute to human labor. 1170 39


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