Human Reproduction, Vol. 17, No. 9, 2300-2306,
September 2002
© 2002 European Society of Human Reproduction and Embryology
Regulation of 11ß-hydroxysteroid dehydrogenase type 1 gene expression in human ovarian surface epithelial cells by interleukin-1
1 Assisted Conception Programme, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA and 2 Department of Reproductive and Developmental Sciences, University of Edinburgh Centre for Reproductive Biology, 49 Little France Crescent, Edinburgh EH16 4SB, UK
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Abstract |
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BACKGROUND: Local modulation of 11ß-hydroxysteroid dehydrogenase (11ßHSD) activity, to promote increased availability of anti-inflammatory glucocorticoids, is proposed as a compensatory response to inflammatory stimuli. Human 11ßHSD type 1 (11ßHSD1) is principally an 11-oxoreductase that reversibly reduces cortisone to cortisol. METHODS: Since ovulation is an acute inflammatory process, we examined the influence of pro-inflammatory cytokines on expression of 11ßHSD1 mRNA and metabolism of cortisone to cortisol by human ovarian surface epithelium (HOSE) in vitro. RESULTS: Northern analysis showed an
1.5 kb-sized 11ßHSD1 mRNA transcript in total RNA that was up-regulated 3-fold by interleukin (IL)-1
(0.5 ng/ml) at 24 h. By real-time RT–PCR, induction of 11ßHSD1 mRNA by IL-1 was measurable at 6 h and maximal at 12 h. Primary HOSE cell cultures also showed low-level 11-oxoreductase activity that was stimulated time- and dose-dependently by IL-1 and IL-1ß. The 11ßHSD1 mRNA and 11-oxoreductase responses to 0.5 ng/IL were both suppressed by IL-1 receptor antagonist (25 ng/ml). CONCLUSIONS: Cultured HOSE cells express IL-1-responsive 11ßHSD1 and 11-oxoreductase activity mRNA in vitro. An 11ßHSD1-catalysed increase in anti-inflammatory glucocorticoid activity caused by pro-inflammatory cytokines could contribute to the local resolution of inflammation during ovulation.
Key words: cytokines/inflammation/ovarian surface epithelium/ovulation
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Introduction |
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Mammalian ovulation is a natural inflammatory reaction (Espey, 1994
; Morris and Richards, 1995; Hellberg et al., 1996). The ovulation-inducing gonadotrophin surge triggers target ovarian cells to undergo profound structural and metabolic changes including mobilization of thecal fibroblasts, increased leukocyte migration, release of inflammatory media tors and loosening of connective tissue elements in the follicle wall and overlying tunica (Murdoch et al., 1999; Bukulmez and Arici, 2000). Within the ovulatory follicle, luteinising granulosa cells divert from estrogen biosynthesis to predominantly progesterone biosynthesis, anticipating formation of the corpus luteum. Simultaneously, granulosa cells increasingly express 11-oxoreductase (Tetsuka et al., 1997; Smith et al., 2000), the activity of which favours the accumulation of cortisol over cortisone within the follicular fluid (Andersen and Hornnes, 1994; Harlow et al., 1997; Andersen et al., 1999; Yong et al., 2000). Since cortisol is a potent anti-inflammatory agent (van der Burg and van der Saag, 1996; McKay and Cidlowski, 1999), locally activated cortisol may play a role in the resolution of this natural inflammatory event (Andersen and Hornnes, 1994; Hillier and Tetsuka, 1998; Irahara et al., 1999).
The ovarian surface epithelium (OSE) is the outermost cellular layer breached during ovulation and is therefore intimately involved in the tissue remodelling that occurs (Auersperg et al., 2001; Murdoch et al., 2001). OSE cells near the site of stigma formation undergo apoptosis followed by inflammatory necrosis and slough off before the surface is ruptured (Murdoch et al., 1999). After which, adjacent OSE cells proliferate and recolonize the affected area (Osterholzer et al., 1985; Gillett et al., 1992). Repeated episodes of ovulation-associated injury and repair are presumed to underlie the high frequency of ovarian carcinoma arising from the OSE (Fathalla, 1971; Salazar et al., 1995), which account for 90% of all ovarian cancers (Ozols et al., 1991). Since factors related to inflammation of the OSE have been associated with increased risk of ovarian cancer (Ness and Cottreau, 1999; Ness et al., 2000), it is critically important to understand how inflammatory cell damage is normally resolved in the OSE.
Exposure to inflammatory stimuli increases 11ß -hydroxysteroid dehydrogenase type 1 (11ßHSD1) gene expression and enzymic activity in various epithelial cell types (Schleimer, 1991; Escher et al., 1997; Feinstein and Schleimer, 1999; Cai et al., 2001), including ovarian granulosa cells (Tetsuka et al., 1999). Since 11ßHSD1 is predominantly an 11-oxoreductase that reversibly metabolizes cortisone to cortisol (Tannin et al., 1991; Stewart and Mason, 1995), its increased expression at sites of inflammation has been proposed as part of a compensatory mechanism that promotes anti-inflammatory actions of glucocorticoids (Andersen and Hornnes, 1994; Escher et al., 1997; Hillier and Tetsuka, 1998). The ovulation-inducing LH surge triggers local production of inflammatory cytokines (Adashi, 1998), to which the OSE is inevitably exposed during ovulation. Thus, we sought to determine if cultured human OSE (HOSE) cells undertake cytokine-responsive 11ßHSD1 gene expression and 11-oxoreduction of cortisone to cortisol in vitro, focusing on founder members of the interleukin (IL)-1 gene family: IL-1, IL-1ß and IL1-receptor antagonist (IL1-RA) (Sims et al., 2001).
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Subjects and methods |
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Patients
OSE cells were obtained from normal ovaries of premenopausal women (age range 33–46 years) undergoing laparotomy for benign gynaecological conditions, and in whom there had not been exposure to exogenous hormones in the 2 months prior to surgery. Sampling was random with respect to stage of menstrual cycle (Table I). The specimens were obtained at the start of the operation before any surgical dissection so as to minimize blood contamination and devascularization. If oophorectomy was planned, the specimen was obtained before removal of the ovary. All specimens were obtained with informed consent, and local ethics committee approval was granted for the study. Experiments on HOSE cells collected and cultured from 15 patients are reported.
Collection and culture of HOSE cells
The exposed ovarian surface was gently scraped using a sterile Ayres spatula to remove a portion of the OSE layer, taking great care to avoid follicular rupture during handling. The specimen comprising `flakes' of OSE in peritoneal fluid, as a consequence of the sampling technique, was rinsed from the spatula into sterile culture medium, before being transported to the laboratory. The culture medium consisted of Medium 199:MCDB105 (1:1, v/v) supplemented with fetal calf serum (15% v/v), streptomycin (50 µg/ml), penicillin (50 IU/ml), nystatin (500 IU/ml) and 1mmol/l L-glutamine (Kruk et al., 1990). All culture materials were from Gibco BRL (Life Technologies Ltd, Renfrewshire, UK) or Sigma Chemical Co. (Poole, Dorset, UK). The HOSE cells in culture medium were transferred to a serum-precoated 75 cm2 culture flask (Corning Inc. Glass Works, Corning, NY, USA) and incubated at 37°C in a humidified tissue culture incubator gassed with 95% air–5% CO2, for up to 28 days. The culture medium was renewed every 7 days. In this primary culture system, HOSE cells typically develop into cell monolayers within 24 days (Hillier et al., 1998). Immunocytochemical staining with an anti-human cytokeratin (CAM 5.2) monoclonal antibody (kit no. 92-0005; Becton Dickinson Immunocytometry Systems Europe, Erembodegem, Belgium), which recognizes cytokeratin proteins 8 and 18, confirmed the epithelial origin of the HOSE cell cultures (Van Niekerk et al., 1993; Tsao et al., 1995; Auersperg et al., 2001).
Confluent HOSE cell monolayers were trypsinized using a solution of 0.05% (w/v) Trypsin and 0.02% EDTA in modified Puck's saline A (Gibco). The resulting cell suspension was washed in culture medium, then centrifuged at 800 g for 5 min, and resuspended in fresh culture medium. Cell counting was performed in a haemocytometer, using Trypan Blue exclusion to estimate viability, which ranged from 80 to 97%. The mean cellular yield was 3.9x106 viable cells per culture flask trypsinized. Replicate portions of the cell suspension containing 105 cells in 0.5 ml medium were then distributed into 24-well polystyrene culture dishes (Corning) and incubated for 24 h. The serum-containing medium was then replaced with serum-free culture medium containing 0.1% bovine serum albumin and incubated for a further 24 h.
To start experiments, human recombinant IL-1 or IL-1ß (R&D Systems, Europe Ltd, Abingdon, Oxon, UK) was added to the culture medium at a final concentration of 0.02–50 ng/ml. IL-1 receptor antagonist (R&D Systems) was used at a concentration of 25 ng/ml. Incubation was at 37°C for 24 h, unless time (6–48 h) was the dependent variable. All treatments were in triplicate or duplicate, depending on available cell numbers. After removing spent culture medium, total RNA was extracted for analysis of 11ßHSD1 mRNA or prewarmed (37°C) medium (0.5 ml) containing substrate [1,2,6,7-3H]cortisone was added to HOSE monolayers to initiate the 11-oxoreductase assay, as described below.
Northern analysis
Total RNA for Northern analysis was extracted from HOSE cell monolayers using RNAzol BTM (Tel-Test, Friendswood, TX, USA) following the manufacturer's recommendations. Total RNA (20 µg) was size-fractionated on a 1.0% agarose gel containing 2.2 mol/l formaldehyde and transferred onto nylon membrane (Hybond-N; Amersham Pharmacia Biotech, Little Chalfont, Buckhamshire, UK) by capillary transfer. An 11ßHSD1 cDNA probe encompassing the entire coding region of 11ßHSD1 was excised with HindIII and XbaI from pcDNA I-11ßHSD1 cDNA, which was constructed (Mason and Stewart, 1995) from a 11ßHSD1 cDNA generously provided by Dr Perrin White, Dallas, TX, USA. The probe was labelled with 32P-dCTP (Redivue; Amersham) using the Prime-It II (Stratagene Europe, Amsterdam, The Netherlands) random primer labelling kit, and then passed through a NICK column (Amersham) to remove unincorporated 32P-labelled nucleotides. Hybridization was carried out overnight at 42°C using UltrahybTM (Ambion Europe Ltd, Huntingdon, Cambs, UK) containing ~1x106 cpm cDNA probe/ml.
Membranes were washed in stringency wash solution containing 2x standard saline citrate (SSC) and 0.1% sodium dodecyl sulphate (SDS) for 2x5 min at 42°C, then washed in stringency wash solution containing 0.1xSSC and 0.1% SDS for 2x15 min at 42°C. The membranes were exposed to autoradiographic film (Kodak XAR-5; Eastman Kodak, Rochester, NY, USA) for 6 days at –70°C against an intensifying screen. The radioactivity of each signal was then quantified by electronic autoradiography (Instant Imager; Packard, Downers, Grove, IL, USA). The membranes were then stripped and the process repeated using a 32P-labelled human 18S ribosomal RNA cDNA probe donated by Dr G.Scobie (MRC Human Reproductive Sciences Unit, Edinburgh, UK), as an index of uniformity of RNA gel loading and transfer to the membrane. Total RNA from human luteinising granulosa cells (Tetsuka et al., 1997) was the 11ßHSD1 mRNA positive control.
Real-time quantitative RT–PCR
Real-time quantitative RT–PCR was used to quantify the effects of interleukins on 11ßHSD1 mRNA expression, since insufficient total RNA from treated HOSE cells was available for replicate Northern analyses. Tri Reagent (Sigma) was used to obtain total RNA for this purpose. The abundance of 11ßHSD1 mRNA was quantified using the TaqMan RT–PCR system (ABI PRISM 7700 Sequence Detection System; Applied Biosystems, Warrington, UK), in which a specific PCR product is generated using a 5' nuclease fluorogenic probe and primers (Livak et al., 1995). Commercial reagents (TaqMan PCR Reagent Kit; Perkin-Elmer) and conditions were used according to the manufacturer's instructions. Total RNA (1 µg) from each sample was reverse-transcribed for subsequent PCR analysis. A total of 1 µl of the resulting RT reaction mixture with oligonucleotides at a final concentration of 300 nmol/l of primers and 200 nmol/l of TaqMan hybridization probe were analysed in a 25 µl volume. Primer Express software (Perkin-Elmer) was used to design the oligonucleotides using uniform selection parameters that allow application of standard cycle conditions. Target (11ßHSD1) mRNA was quantified in relation to 18S ribosomal RNA abundance in each sample, using placental 11ßHSD1 mRNA as the internal standard. The 11ßHSD1 primers and TaqMan probes used were as follows. 11ßHSD1 forward: AGCTCTGCGCCAAGAAGAAGT; 11ßHSD1 reverse: AGGATCTTCCTGCATG-GATTTC; 11ßHSD1 TaqMan probe: TGACAGCTCACTCTGGACCACTCTTCTGA.
11-Oxoreductase assay
Conversion of [1,2,6,7-3H]cortisone to [1,2,6,7-3H]cortisol was the index of 11-oxoreductase activity, measured as previously described (Thomas et al., 1998). In brief, culture medium containing substrate cortisone (50 pmol), including 0.1 µCi [3H]cortisone, was added to each well giving a final volume of 0.5 ml. Control incubations containing no cells were also set up. Incubation was for 4 h at 37°C in a humidified atmosphere of 5% CO2 in air. Media from individual wells were then pipetted into glass tubes and vortexed with diethyl ether (3 ml) for 1 min to extract steroids. The extracts were then evaporated under nitrogen in tubes containing 10 nmole carrier, unlabelled cortisone and cortisol. The dried etheric extracts were then transferred in ethyl acetate to silica gel-precoated plastic sheets (PE SIL G; Whatman Ltd, Maidstone, Kent, UK) for thin-layer chromatographic separation of precursor cortisone and product cortisol in the solvent system chloroform:ethanol (92:8 by vol) (BDH Laboratory Supplies, Poole, Dorset, UK).
Cortisone and cortisol bands were identified by visualization under direct UV light, and the corresponding areas were cut out and transferred to a counting vial for determination of radioactivity by ß-scintillation spectrophotometry. Consistently >90% of the total radioactivity added to the incubations was accounted for in the cortisone and cortisol bands. Enzymic activity was expressed as percentage total radioactivity [(product cpm/substrate cpm + product cpm)x100] after correction for values from control (no cell) incubations.
Statistical analysis
Results are expressed as mean ± SEM. Data were analysed by analysis of variance and Student's-t test, taking P < 0.05 to indicate statistically significant differences between mean values.
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11ßHSD1 mRNA expression
Northern blotting revealed a ~1.5 kb-sized human 11ßHSD1 mRNA transcript in cultured HOSE cell total RNA, the abundance of which was increased almost 3-fold by incubation with IL-1
(0.5 ng/ml) for 24 h. Results from two experiments are shown in Figure 1.
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Time-dependent stimulation of 11ßHSD1 mRNA expression by IL-1
(0.5 ng/ml) was confirmed by real-time RT–PCR. Combined data from four experiments are shown in Figure 2. Stimulation (2.9-fold relative to control) occurred at 6 h, increasing to 5.6-fold at 12 h (P < 0.01) and dropping to 2.3-fold at 24 h (P < 0.05).
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The effect of IL-1RA on IL-1
action was tested in two experiments, one of which is shown in Figure 3. On both occasions, the presence of IL-1RA in HOSE cell culture medium completely blocked IL-1-stimulated 11ßHSD1 mRNA expression.
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11-Oxoreductase activity
Consistent with the presence of 11ßHSD1 mRNA, cultured HOSE cells exhibited low-level 11-oxoreductase activity, which was increased time-dependently by treatment with IL-1
(0.5 ng/ml). Results from a typical experiment are given in Figure 4. In 4/4 experiments, IL-1 had no measurable action on 11-oxoreductase activity at 6 h, but at 12, 24 and 48 h it caused average fold increases (relative to control) of 1.34 (P < 0.05), 1.69 (P < 0.01) and 1.66 (P < 0.01) respectively.
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The presence of IL-1RA (25 ng/ml) in HOSE cell culture medium significantly suppressed the response to IL-1
(0.5 ng/ml), without affecting basal 11-oxoreductase activity, in 2/2 experiments. Results from one of these experiments are shown in Figure 5.
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Effects of IL-1
and IL-1ß on 11-oxoreductase activity were compared by treating HOSE cells for 24 h with increasing doses of either substance. Combined data from four experiments are shown in Figure 6. Both cytokines elicited similar effects, with maximal stimulation (average ~1.7-fold, relative to control) occurring at 0.5 ng IL-1/ml.
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Discussion |
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We show here that cytokine-activated HOSE cells increasingly express 11ßHSD1 mRNA and undertake metabolism of cortisone to cortisol in vitro. Of the two known human 11ßHSD isoforms, 11ßHSD1 is principally reductive (converts cortisone to cortisol) whereas 11ßHSD2 is strongly oxidative (converts cortisol to cortisone) (Stewart and Mason, 1995
). Thus the present data are consistent with cytokine-induced up-regulation of 11ßHSD1 enzymatic activity in HOSE cells. The results from HOSE cell specimens obtained in the follicular and luteal phases of the menstrual cycle did not obviously differ (data not shown) although the opportunistic sampling and need to establish primary HOSE cell cultures precluded meaningful comparisons. We do not know if prolonged culture alters the expression of the 11ßHSD system, but basal and IL-1-responsive 11-oxoreductase activity persist for at least 4 weeks, which is the time required to propagate enough cells from individual patients for experimental analysis in vitro.
Our results also show that HOSE cell IL-1 receptors are functionally coupled to 11ßHSD1 gene expression, since both 11ßHSD1 mRNA and enzyme activity stimulated by IL-1 were suppressed by the presence of IL-RA. HOSE cells are an established site of IL-1 synthesis (Ziltener et al., 1993), and stimulatory effects of IL-1 on HOSE cell proliferation have been described previously (Marth et al., 1996). Under the short-term, serum-depleted conditions of IL-1 exposure used here, we saw no IL-1-induced increase in HOSE cell number. However, IL-1 did cause morphological changes tending to a fibroblastic phenotype, which were also reversible by IL-RA (data not shown). Thus our results are consistent with both paracrine and autocrine modes of regulation of the OSE by IL-1 signalling via IL-1 receptors.
The ability of IL-1 to alter steroid metabolism in HOSE extends existing evidence that the development and function of the OSE is influenced by multiple extracellular stimuli (Auersperg et al., 2001), including GnRH (Kang et al., 2000), gonadotrophins (Zheng et al., 2000; Ivarsson et al., 2001b; Kuroda et al., 2001; Parrott et al., 2001) and locally produced growth/differentiation factors (Gordon et al., 1995; Choi et al., 2001a,b; Nilsson et al., 2001; Wong et al., 2001). Cultured HOSE cells also produce estradiol and progesterone (Ivarsson et al., 2001a), and express receptors for both of these steroid hormones (Karlan et al., 1995; Brandenberger et al., 1998; Hillier et al., 1998). Thus any or all of these factors have the potential to interact with IL-1 in the regulation of HOSE 11ßHSD gene expression and enzymatic activity.
We have previously demonstrated that induction of ovulation by treatment with hCG, as a surrogate LH, causes up-regulation of 11ßHSD1 and down-regulation of 11ßHSD2 gene expression in luteinising granulosa cells (Tetsuka et al., 1997), and that this is associated with increased metabolism by these cells of cortisone to cortisol (Yong et al., 2000). The results presented here suggest that cytokine-mediated induction of 11ßHSD1 expression in the OSE is part of a co-ordinated ovarian response to LH/hCG. The likely physiological significance is that the OSE is exposed to multiple inflammatory mediators during ovulation, including cytokines (IL-1 and Il-6) that up-regulate the inducible cyclo-oxygenase isozyme prostaglandin-H synthase (PGHS)-2, responsible for prostaglandin (PG)-E2 formation (Morris and Richards, 1995; Hellberg et al., 1996). PGE2 formed via PGHS-2 initiates the acute cellular events associated with inflammation and is the product responsible for ovulation (Smith and Langenbach, 2001). The subsequent biochemical cascade leads to collagen breakdown, apoptotic cell death at the ovarian surface and follicular rupture (Murdoch et al., 1999). It follows that a compensatory anti-inflammatory mechanism is an obligatory component of this natural injury–repair process, as summarized in Figure 7.
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Glucocorticoids exert anti-inflammatory effects via the ligand-activated glucocorticoid receptor (GR) signalling pathway in inflamed tissues, to antagonise the induction of the pro-inflammatory transcription factor nuclear NF-
B (van der Burg and van der Saag, 1996; McKay and Cidlowski, 1999). A growing body of evidence suggests that sites of inflammation express relatively high levels of 11ßHSD1, which presumably promotes ligand access to GR through its 11-oxoreductive catalytic activity (Escher et al., 1997). Stimulation of 11ßHSD1 mRNA expression by pro-inflammatory cytokines has been observed in cultured glomerular mesangial (Escher et al., 1997), aortic smooth muscle cells (Cai et al., 2001), bronchial airway epithelial cells (Feinstein and Schleimer, 1999), ovarian granulosa cells (Tetsuka et al., 1999), and now HOSE cells. Thus an up-regulation of 11ßHSD1-associated 11-oxoreductase activity may be a generalized response to inflammation that ensures maximal accessibility of anti-inflammatory glucocorticoids to sites of tissue injury. It remains to be determined if the increased 11ßHSD1 mRNA response of HOSE to IL-1 is associated with a corresponding down-regulation of 11ßHSD2 expression, as occurs in IL-1-treated granulosa cells. If so, the attendant reduction in cortisol inactivation by 11ßHSD2 would be expected to reinforce the proposed anti-inflammatory function of 11ßHSD1.
Finally, these results cast new light on steroid signalling in the OSE. Until recently, the HOSE was seen as a relatively inert ovarian steroidogenic compartment. However, it seems increasingly likely that locally produced steroids and related molecules play significant roles in co-ordinating the cyclic waves of cellular proliferation, differentiation and death that naturally occur in the OSE. Glucocorticoid metabolism and signalling may hold particular relevance to the pathophysiology of the OSE, not least because of the inflammatory basis of ovulation (Espey, 1994) and the epidemiological evidence that ovarian epithelial inflammation may play a role in ovarian cancer (Ness and Cottreau, 1999; Ness et al., 2000).
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Acknowledgements |
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We are grateful to Ms Pawlina Largue for expert technical assistance, and the nursing staff of the Royal Infirmary of Edinburgh gynaecology theatres for assistance with the collection of HOSE specimens. Supported by MRC Programme Grant G0000066 to S.G.H.
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3 To whom correspondence should be addressed. E-mail: s.hillier{at}ed.ac.uk
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Submitted on February 25, 2002; accepted on May 15, 2002.
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