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)

We have examined the effects of IL-6 and bFGF on growth and reductive 17 beta-hydroxysteroid dehydrogenase (17-HSD) activity in a human ovarian cell line A2780 under defined culture conditions (standard RPMI (GM+PHR), phenol red-free RPMI (GM-PHR), or GM-PHR supplemented with 17 beta-estradiol). In media GM+PHR, neither factor influenced terminal cell density. However there was a 2-fold stimulation in 17-HSD activity (E1- > E2) in the presence of IL-6 and a 3-fold increase in the presence of bFGF. Cells cultured GM-PHR showed a 25-30% reduction in terminal cell density compared with cells cultured GM+PHR, and addition of factors resulted in a modest reduction (10-15%) in cell growth, with no detectable changes in 17-HSD. Addition of 17 beta-estradiol to GM-PHR cultures increased terminal cell density by up to 3-fold, with no effect on 17-HSD, and when combined with IL-6 or bFGF, a synergistic effect on growth was observed, but 17-HSD levels were unchanged. Our results suggest that cultured ovarian tumour cells respond to paracrine factors likely to be present in the ovary in vitro, and there is a possible interactive effect of estromedins with these factors.
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PMID:Growth factor regulation of 17 beta-hydroxysteroid dehydrogenase activity in a human ovarian cell line: modulation by 17 beta-estradiol. 823 11

It is well established that there are interactions between the immune and reproductive systems. The ovary contains indigenous macrophages, as well as other classes of leukocytes in smaller numbers. Cytokines secreted by these cells have been shown to have the ability to regulate ovarian steroidogenesis. In the present study, the effect of leukocytes on 11beta-hydroxysteroid dehydrogenase (11beta-HSD) in human granulosa-lutein cells was examined. In addition, individual cytokines were also tested for their ability to regulate this enzyme. The follicular aspirates of patients undergoing IVF treatment were used as a source of granulosa cells. Cells isolated from these aspirates were found to contain between 15 and 60% leukocytes as assessed by flow cytometry (FACS). Leukocytes were removed from the sample preparations by the use of immunomagnetic beads coated with CD45 antibody, which recognises a surface antigen on all classes of leukocyte. Removal of leukocytes significantly decreased the 11beta-HSD activity in the granulosa cells, assayed after 3 days of culture, from 7.3 (2-20) to 3.5 (1-10) pmol cortisone formed/50000 cells/4 h (medians and ranges, n = 15). Addition of IL-5 and IL-6 significantly increased the 11beta-HSD activity in granulosa cell cultures both in the presence and absence of leukocytes. Addition of IL-4 and IFN-gamma increased 11beta-HSD activity only in the leukocyte-depleted granulosa cell cultures, whereas IL-2 had no effect on either of the cultures. The data suggests that leukocytes interact with the ovarian cells through cytokine secretion and/or cell-cell contact to increase the 11beta-HSD activity in human granulosa cells.
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PMID:Leukocytes modulate 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity in human granulosa-lutein cell cultures. 940 53

Sex steroids play a predominant role in the development and differentiation of normal mammary gland as well as in the regulation of hormone-sensitive breast cancer growth. There is evidence suggesting that local intracrine formation of sex steroids from inactive precursors secreted by the adrenals namely, dehydroepiandrosterone (DHEA) and 4-androstenedione (4-dione) play an important role in the regulation of growth and function of peripheral target tissues, including the breast. Moreover, human breast carcinomas are often infiltrated by stromal/immune cells secreting a wide spectra of cytokines. These might in turn regulate the activity of both immune and neoplastic cells. The present study was designed to examine the action of cytokines on 17beta-hydroxysteroid dehydrogenase (17beta-HSD) and 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) activities in human breast cancer cells. The various types of human 17beta-HSD (five types) and 3beta-HSD (two types), because of their tissue- and cell-specific expression and substrate specificity, provide each cell with necessary mechanisms to control the level of intracellular active androgens and estrogens. We first investigated the effect of exposure to IL-4 and IL-6 on reductive and oxidative 17beta-HSD activities in both intact ZR-75-1 and T-47D human breast cancer cells. In ZR-75-1 cells, a 6 d exposure to IL-4 and IL-6 decreased E2-induced cell proliferation, the half maximal inhibitory effect being exerted at 88 and 26 pM, respectively. In parallel, incubation with IL-4 and IL-6 increased oxidative 17beta-HSD activity by 4.4- and 1.9-fold, respectively, this potent activity being observed at EC50 values of 22.8 and 11.3 pM, respectively. Simultaneously, reductive 17beta-HSD activity leading to E2 formation was decreased by 70 and 40% by IL-4 and IL-6, respectively. Moreover, IL-4 and IL-6 exerted the same regulatory effects on 17beta-HSD activities when testosterone and 4-dione were used as substrates, thus strongly suggesting the expression of the type 2 17beta-HSD ZR-75-1 cells. In contrast, in T-47D cells, IL-4 increased the formation of E2, whereas IL-6 exerts no effect on this parameter. However, we found that T-47D cells failed to convert testosterone efficiently into 4-DIONE, thus suggesting that there is little or no expression of type 2 17beta-HSD in this cell line. The present findings demonstrate that the potent regulatory effects of IL-4 and IL-6 on 17beta-HSD activities depend on the cell-specific gene expression of various types of 17beta-HSD enzymes. We have also studied the effect of cytokines on the regulation of the 3beta-HSD expression in both ZR-75-1 and T-47D human breast cancer cells. Under basal culture conditions, there is no 3beta-HSD activity detectable in these cells. However, exposure to IL-4 caused a rapid and potent induction of 3beta-HSD activity, whereas IL-6 failed to induce 3beta-HSD expression. Our data thus demonstrate that cytokines may play a crucial role in sex steroid biosynthesis from inactive adrenal precursors in human breast cancer cells.
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PMID:Regulation of sex steroid formation by interleukin-4 and interleukin-6 in breast cancer cells. 969 68

Enzymes modulating local steroid availability play an important role in the progression of human breast cancer. These include isoforms of 17beta-hydroxysteroid dehydrogenase (17-HSD), aromatase and steroid sulphatase (STS). The aim of this study was to investigate the expression, by reverse transcription polymerase chain reaction, of 17-HSD types I-IV, aromatase and steroid STS in a series of 51 human breast tumour biopsies and 22 primary cultures of epithelial and stromal cells derived from these tumours, giving a profile of the steroid-regulating network for individual tumours. Correlations between enzyme expression profiles and expression of the interleukin (IL)-6 gene were also sought. All except one tumour expressed at least one isoform of 17-HSD, either alone or in combination with aromatase and STS. Expression of 17-HSD isoforms I-IV were observed in nine tumours. Of the 15 tumours which expressed three isoforms, a combination of 17-HSD II, III and IV was most common (6/15 samples). The majority of tumours (n = 17) expressed two isoforms of 17-HSD with combinations of 17-HSD II and IV predominant (7/17 samples). Eight tumours expressed a single isoform and of these, 17-HSD I was in the majority (5/8 samples). In primary epithelial cultures, enzyme expression was ranked: HSD I (86%) > STS (77%) > HSD II (59%) > HSD IV (50%) = aromatase (50%) > HSD III (32%). Incidence of enzyme expression was generally reduced in stromal cultures which were ranked: HSD I (68%) > STS (67%) > aromatase (48%) > HSD II (43%) > HSD IV (28%) > HSD III (19%). Expression of IL-6 was associated with tumours that expressed > or = 3 steroid-converting enzymes. These tumours were of higher grade and tended to come from patients with family history of breast cancer. In conclusion, we propose that these enzymes work in tandem with cytokines thereby providing sufficient quantities of bioactive oestrogen from less active precursors which stimulates tumour growth.
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PMID:In vivo and in vitro expression of steroid-converting enzymes in human breast tumours: associations with interleukin-6. 1057 57

There is evidence suggesting that local intracrine formation of sex steroids from inactive precursors, dehydroepiandrosterone (DHEA), its sulfate (DHEA-S) and 4-androstenedione (4-DIONE) plays an important role in the regulation of growth and function of peripheral target tissues. Moreover, human solid tumors are often infiltrated by stromal/immune cells secreting a wide spectra of cytokines. These cytokines might in turn regulate the activity of both immune and neoplastic cells. Our data demonstrate that the potent regulatory effects of interleukin-4 (IL-4) and IL-6 on both estrogenic and androgenic 17beta-HSD/KSR activities in breast cancer cells depend on the cell-specific gene expression of various types of 17beta-HSD/KSR enzymes. However, in both estrogen-receptor (ER)-positive (ZR-75-1, T-47D) and ER-negative (MDA-MB-231, BT-20) human breast cancer cells, exposure to IL-4 and IL-13 caused a rapid and potent induction of 3beta-HSD type 1 gene expression. Such an induction was also observed in normal human mammary and prostate epithelial cells in primary culture as well as in human HaCaT immortalized keratinocytes, ME-180 cervix cancer cells, and HT-29 colon cancer cells. The DNA-binding activity of Stat6, a member of the Signal Transducers and Activators of Transcription gene family, was activated after a 30 min exposure to IL-4 in all the cell types where IL-4 induced 3beta-HSD expression, but not in those that failed to respond to IL-4. Our data therefore suggest that IL-4 and IL-13 may play a role in the biosynthesis of active sex steroids from the inactive adrenal steroid DHEA, not only in breast cells but also in various cell types derived from peripheral target tissues.
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PMID:Crucial role of cytokines in sex steroid formation in normal and tumoral tissues. 1116 8

Excessive fetal exposure to glucocorticoids has been implicated in the etiology of adult metabolic and cardiovascular disease. Placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) may protect the fetus from excessive glucocorticoid exposure. Maternal stress may be accompanied by elevated levels of cortisol and increased proinflammatory cytokines [interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha)]. We hypothesize that proinflammatory cytokines inhibit human placental 11beta-HSD activity. We incubated explant cultures of term human placental villi in the presence or absence of 10 ng/ml IL-1beta, IL-6, or TNF-alpha, with or without agonists or antagonists of intracellular Ca2+ and adenylyl cyclase. Activity for 11beta-HSD2 was estimated using a radioisotope assay, and mRNA was measured using quantitative RT-PCR. All cytokines significantly (P < or = 0.05) reduced 11beta-HSD2 activity (>75% suppression); maximal inhibition occurred within 2 h and was maintained for at least 24 h. The IL-1beta-induced inhibitory activity was attenuated using a Ca2+ channel blocker (nifedipine), an intracellular Ca2+ antagonist [8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate], or the adenylyl cyclase stimulant forskolin. Conversely, 11beta-HSD2 activity was diminished in the presence of the Ca2+ ionophore A-23187 or the adenylyl cyclase inhibitor SQ-22536. mRNA levels for 11beta-HSD2 were not changed by any of the treatments. Proinflammatory cytokines inhibit human placental 11beta-HSD2 activity through a mechanism that involves increased intracellular Ca2+ and inhibition of adenylyl cyclase. This could result in excessive fetal exposure to maternal cortisol. This mechanism might mediate part of the increased risk of metabolic and cardiovascular disease in adult offspring.
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PMID:Proinflammatory cytokines inhibit human placental 11beta-hydroxysteroid dehydrogenase type 2 activity through Ca2+ and cAMP pathways. 1617 54

Stromal cells such as fibroblasts play an important role in defining tissue-specific responses during the resolution of inflammation. We hypothesized that this involves tissue-specific regulation of glucocorticoids, mediated via differential regulation of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Expression, activity and function of 11beta-HSD1 was assessed in matched fibroblasts derived from various tissues (synovium, bone marrow and skin) obtained from patients with rheumatoid arthritis or osteoarthritis. 11beta-HSD1 was expressed in fibroblasts from all tissues but mRNA levels and enzyme activity were higher in synovial fibroblasts (2-fold and 13-fold higher mRNA levels in dermal and synovial fibroblasts, respectively, relative to bone marrow). Expression and activity of the enzyme increased in all fibroblasts following treatment with tumour necrosis factor-alpha or IL-1beta (bone marrow: 8-fold and 37-fold, respectively, compared to vehicle; dermal fibroblasts: 4-fold and 14-fold; synovial fibroblasts: 7-fold and 31-fold; all P < 0.01 compared with vehicle). Treatment with IL-4 or interferon-gamma was without effect, and there was no difference in 11beta-HSD1 expression between fibroblasts (from any site) obtained from patients with rheumatoid arthritis or osteoarthritis. In the presence of 100 nmol/l cortisone, IL-6 production--a characteristic feature of synovial derived fibroblasts--was significantly reduced in synovial but not dermal or bone marrow fibroblasts. This was prevented by co-treatment with an 11beta-HSD inhibitor, emphasizing the potential for autocrine activation of glucocorticoids in synovial fibroblasts. These data indicate that differences in fibroblast-derived glucocorticoid production (via the enzyme 11beta-HSD1) between cells from distinct anatomical locations may play a key role in the predeliction of certain tissues to develop persistent inflammation.
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PMID:Differential expression, function and response to inflammatory stimuli of 11beta-hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue-specific regulation of inflammation. 1684 35

Glucocorticoids (GC) are important steroid hormones that regulate metabolism, development, and the immune system. GC are produced continuously, and maximal levels are reached following stress-related stimuli. Previous studies have demonstrated that increased GC production following thermal injury was responsible for thymic involution. Although GC are mainly synthesized by the adrenal glands, there is increasing evidence that GC may also be produced in nonadrenal tissues. The thymus was reported to express steroidogenic enzymes and to release GC. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is predominantly a reductase in cells and is essential for the local reactivation of GC. Here, we report that increased GC-induced apoptosis in thymocytes from burn-injured mice is related to increased glucocorticoid receptor (GR) expression and 11beta-HSD1 expression in thymocytes at day 1 postburn injury. In vitro, thymocytes were able to convert 11-dehydrocorticosterone (DHC) to corticosterone (CORT), which induced their apoptosis, and this was pharmacologically inhibited by 18beta-glycyrrhetinic acid, a specific 11beta-HSD inhibitor. Moreover, 11beta-HSD1 expression was confirmed in the 267S3 thymoma-derived cell line, and its activity was responsible for greater sensitivity of these cells to CORT-induced apoptosis. Finally, proinflammatory cytokines [tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6] increased thymocyte sensitivity to DHC-induced apoptosis through a mechanism involving 11beta-HSD1. Overall, we have shown that burn injury induced 11beta-HSD1 expression in thymocytes, which led to a greater sensitivity of these cells to CORT-induced apoptosis. Increased expression of 11beta-HSD1 and GR may play a role in intrathymic T cell development and can be major determinants of GC sensitivity after a trauma.
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PMID:Regulation of glucocorticoid sensitivity in thymocytes from burn-injured mice. 1900 48

To study the effects of immune cell activation by a protein antigen or lymphoid tissue derived cytokines on peripheral steroidogenesis activities of 3beta HSD and 17beta HSD was measured in lymphoid organs of control and BSA immunized mice after 3 weeks treatment. We demonstrated the presence of 3betaHSD and 17betaHSD in the lymphoid organs after active immunization. We found elevated serum corticosterone after 3 weeks of antigen administration in presence of CFA and a higher serum IL-6 level that also alter lymphoid tissue cytokine responses like TNF-alpha, IL-12p70, and IL-6, among which IL-12p70 and TNF-alpha down-regulate the activity of steroidogenic enzymes in the thymus during an immune response.
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PMID:Modulation of steroidogenic enzymes in murine lymphoid organs after immune activation. 1917 83

Glucocorticoids (GCs) are widely used for the treatment of hormone refractory prostate cancer. However, few data are available on the expression and regulation of glucocorticoid and mineralocorticoid receptors (GR and MR) and 11beta-hydroxysteroid dehydrogenase (11beta-HSD) 1 and -2 activities in prostate cancer cells. Here we show that GR is expressed in both the androgen-independent PC-3 cell line and, at very low levels, in the androgen-dependent LNCaP cells, and MR is expressed in both cell lines. IL-1beta increased GR expression in both cell lines. In LNCaP cells IL-1beta also increased MR expression. Significant 11beta-HSD oxidase activity and 11beta-HSD2 protein were found in LNCaP cells, but not in PC3 cells, and no ketoreductase activity was detected in either cell lines. GR function was assessed by measuring the inhibitory effect of dexamethasone on constitutive and IL-1beta-inducible IL-6 and osteoprotegerin (OPG) production. In PC-3 cells, IL-1beta stimulated IL-6 and OPG release, and dexamethasone dose-dependently inhibited IL-1beta-inducible IL-6 release, and constitutive and IL-1beta-inducible OPG release. In LNCaP cells, IL-1beta stimulated only OPG release. While dexamethasone was ineffective, cortisol dose-dependently inhibited IL-1beta-inducible OPG release. Eplerenone (Epl), a selective mineralocorticoid antagonist, reverted this effect. We conclude that different patterns of expression of receptors and 11beta-HSD activity were associated with different responsiveness to GCs in terms of regulated gene expression. GR and MR expression may vary as a function not only of the malignant phenotype, but also of local conditions such as the degree of inflammation. Inhibition of IL-6 and OPG release by GCs may contribute to the antitumor efficacy in prostate cancer.
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PMID:Differential expression of determinants of glucocorticoid sensitivity in androgen-dependent and androgen-independent human prostate cancer cell lines. 1940 40


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