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Medical Research Council Group in Fetal and Neonatal Health and Development (K.S., J.R.G.C.), Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and Departments of Obstetrics and Gynaecology and Physiology, University of Western Ontario (K.Y.), Ontario, Canada
Address all correspondence and requests for reprints to: Kang Sun, Department of Physiology, University of Toronto, Faculty of Medicine, 1 King’s College Circle, Toronto, Ontario, M5S 1A8, Canada. E-mail: kang.sun{at}utoronto.ca
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Introduction |
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Several studies have demonstrated that 11 ß-HSD type 1 and 2 are regulated by sex steroids and the cAMP pathway (16, 17, 18). However, no studies have addressed the regulation of 11 ß-HSD by nitric oxide (NO), an important messenger in the human placenta and fetal membranes. The vascular endothelium and syncytiotrophoblast of the placenta, the fetal membranes and myometrium are able to synthesize NO (19, 20). In pregnancy, NO may contribute to the local regulation of placental hormones, for example inhibition of CRH release (21), as well as the maintenance of myometrial quiescence (22). It may also affect basal vascular tone in the fetal-placental circulation (23). Glucocorticoids exert positive feedback on CRH production in the placenta (24, 25). They can also induce hypertension through either a direct effect on blood vessels or by binding to the mineralocorticoid receptor (12, 26), in addition to the their effects on fetal organ maturation and growth retardation. Therefore, both NO and glucocorticoids are involved in the regulation of vascular tone and CRH release. We hypothesized that NO might also regulate the enzyme 11 ß-HSD, which in turn could influence local levels of bioactive glucocorticoid in the placenta, fetal membranes and myometrium, as well as the passage of maternal glucocorticoids into the fetal circulation. Therefore, we examined the catalytic properties, and determined the effects of different NO donors, on 11 ß-HSD type 1 and 2 activities or mRNA expression in cultured human placental trophoblast and chorionic trophoblast cells prepared from patients in late gestation.
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Materials and Methods |
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Preparation of 3H-cortisol and
3H-cortisone
3H-cortisol (specific activity: 64.0 Ci/mmol)
(Amersham Life Science, Buckinghamshire, UK) was purified by thin layer
chromatography (TLC) in the solvent system chloroform/ethanol (95/5,
vol/vol) for each separate measurement of 11 ß-HSD activity.
3H-cortisone was prepared by oxidizing
3H-cortisol with chromium trioxide (29) and was purified by
TLC before it was used for the enzyme activity assay.
Treatment of cells and 11 ß-HSD activity assay
On the day of an experiment, the cells were washed with FCS free
culture medium (pH 7.4) and preincubated in the same medium for 1
h. 11 ß-HSD type 2 oxidase activity was assayed using 100
nM cortisol containing 200,000 cpm 3H-cortisol;
11 ß-HSD type 1 oxidase and reductase activities were measured using
1 µM cortisol containing 200,000 cpm
3H-cortisol or 1 µM cortisone containing
200,000 cpm 3H-cortisone, respectively. The assays were
performed in the absence and presence of NO donors: sodium
nitroprusside (SNP) (Sigma), S-nitroso-N-acetylpenicillamine
(SNAP) (Sigma); soluble guanylate cyclase inhibitor: LY83583 (Sigma);
8-bromo-guanosine-3'5'-cyclic monophosphate (8-br-cGMP) (ICN) or
ADP-ribosylation inhibitor: N, N'-hexamethylene-bis-acetamide (HMBA)
(Sigma). Each treatment was performed in duplicate or triplicate for
each preparation of cells. Media were collected after 24 h
incubation at 37 C with the drugs. For representative cultures, cells
were washed twice with culture medium and lysed with 0.5% Triton
X-100. The cells were then scraped off the plate with a rubber
policeman and collected for the determination of intracellular uptake
of cortisol and cortisone. A time course study of both type 1 and 2
activities was conducted at 1, 2, 4, 8, 20, and 24 h incubation.
Cell viability before and after drug treatment was examined by trypan
blue exclusion study.
To measure conversions, a mixture of cortisol and cortisone (40 µg each) was added to the collected medium to allow localization of the steroids when subjected to TLC. Steroids in the media and cells were extracted with ethyl acetate. The extract from the medium was dried, reconstituted with ethyl acetate (100 µl) and applied to the TLC plate (Fisher Scientific). Cortisol and cortisone were separated in the solvent system chloroform/ethanol (95/5, vol/vol). Steroids were visualized under UV light, scraped off, and extracted with ethyl acetate. The solvent was dried, scintillation fluid added, and the radioactivity was counted in a liquid scintillation counter. The recovery rate of 3H-cortisol or 3H-cortisone was measured by adding 3H-cortisol or 3H-cortisone to culture medium and processing in the samples in identical fashion. The mean recovery rates of 3H-cortisol and 3H-cortisone were 86.7 ± 5.3%, 88.3 ± 4.3%, respectively. The 11 ß-HSD type 1 and 2 oxidase activity was expressed as the percent of cortisone formed from cortisol, whereas 11 ß-HSD type 1 reductase activity was expressed as the percent of cortisol formed from cortisone. Extracts of intracellular cortisol and cortisone was dried and counted for the determination of intracellular uptake of cortisol and cortisone.
Kinetic analysis
Kinetic analysis was performed as described previously (30) for
the respective oxidase and reductase activities. Conversion assays were
conducted using a fixed number of cells (106 cells) and
reaction time (3.5 h for placental cells, 8 h for chorionic
cells), but with varying amounts of substrates. The conditions were
chosen so that the initial velocity was linear with the reaction time.
In all cases, the conversion in the blank well (no cells) was
subtracted from that in the experimental wells before analysis. The
data were plotted as a straight line of s/v against
s according to the Michaelis-Menten Equation, and the
Km and Vmax values were calculated from the
intercepts of these plots.
RNA extraction and Northern blot analysis
Total cellular RNA was extracted with lithium chloride/urea from
placental trophoblast that had been treated with SNP and/or LY83583 for
24 h (31), except that the cells were grown in culture dishes at a
density of 15 x 106 cells/dish. After treatment of
cells, the cells were washed with PBS, and then 3 M lithium
chloride/6 M urea was added and the cells scraped off the
dish with a rubber policeman. The cells were stored at -80 C for later
extraction of total RNA. Northern blot hybridization was carried out
using specific human 11ß-HSD type 1 (32) and two complementary DNAs
(cDNAs) (courtesy of Dr. A. L. Albiston) (7). A cDNA for mouse 18S
ribosome RNA (rRNA) was used as an internal standard to determine the
relative amounts of RNA loaded into each well and the transfer
efficiency.
The autoradiographs were scanned using a densitometer (Ultrascan XL LKB 222—2-, LKB Produkter, Bromma, Sweden) to determine the relative optical densities of 11ß-HSD type 2 and 18S rRNA hybridization signals. For each RNA sample, the signal for the transcripts was measured within the linear range of the densitometer, and the ratio of 11ß-HSD type 2 mRNA signals to 18S rRNA was calculated.
Statistical analysis
All data are shown as mean ± SEM Student’s
t test; linear regression analysis or two-way ANOVA test
were used to assess statistical differences. Statistical significance
was set at P < 0.05.
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Results |
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). Trypan
blue exclusion study also showed that the percentage of viability of
the cells before and after treatment were both more than 95%.
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, a
and b). These Km values of placental 11ß-HSD oxidase
activity and chorionic 11ß-HSD reductase activity compare favorably
with previously published values for 11ß-HSD 2 and 11ß-HSD 1
(4).
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). Under the same conditions, chorionic
trophoblast showed mainly type 1 reductase activity with only barely
detectable oxidase activity. The conversion of cortisone (1
µM) to cortisol by chorionic trophoblast increased
linearly during the 24 h incubation (r = 0.992)
with an average conversion of 71.1 ± 7.7% at 24 h (n =
4) (Fig. 3b), whereas the conversion of either 1 µM or
100 nM cortisol to cortisone was very low, reaching only
2.2 ± 0.3% and 3.1 ± 0.2%, respectively, during the 24-h
incubations (Fig. 3b).
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Effects of SNP and SNAP on 11 ß-HSD oxidase and reductase
activities
SNP, an NO donor, potently inhibited the conversion of cortisol
(100 nM) to cortisone in cultured placental trophoblast
(n = 7) in a dose-dependent manner (1–400 µM)
(P < 0.01, Fig. 4a). The
same doses of SNP did not affect the conversion of cortisone (1
µM) to cortisol either in the placental (n = 3) or
chorionic trophoblasts (n = 5) (P > 0.05, Fig. 5, a and b). LY83583 (1
µM), an inhibitor of soluble guanylyl cyclase, partially
blocked the inhibitory effect of SNP on the placental conversion of
cortisol to cortisone (n = 7, P < 0.01, Fig. 4a).
HMBG (10 mM), an inhibitor of ADP-ribosylation, did not
affect the inhibitory influence of SNP on the conversion of cortisol to
cortisone by placental trophoblast (P > 0.05, n =
3, Fig. 4b). Another donor of NO, SNAP (1 mM), also
significantly inhibited the conversion of cortisol (100 nM)
to cortisone in the placental syncytiotrophoblast (P <
0.01), an effect that was partially blocked by LY83583 (n = 4,
P < 0.05). SNAP did not affect the conversion of
cortisone (1 µM) to cortisol in the chorionic cell
preparations (P > 0.05, n = 3, Fig. 6). 8-br-cGMP (100– 400
µM), a synthetic analog of cGMP also inhibited the
conversion of cortisol (100 nM) to cortisone in the
placental syncytiotrophoblast (P < 0.05 or 0.01,
n = 3, Fig. 7).
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). However, signals for 11 ß-HSD type
1 mRNA were not detected in placental syncytiotrophoblast by northern
analysis following one month exposure.
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Discussion |
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We used immunostaining to characterize the cells present at the conclusion of the culture period. The placental trophoblast aggregated to form an apparent syncytium that was cytokeratin positive. Chorionic cells also formed clumps and remained as isolated cells; a characteristic that appears to depend on the initial plating density. These cells had been partially purified by Percoll density gradient before culture and were >90% cytokeratin positive. Our previous work using IHC demonstrated that immunoreactive 11 ß-HSD type 1 was present intensely in the chorionic trophoblast and abundant 11 ß-HSD type 1 mRNA was observed in the chorion/decidual tissues as well (10). We have therefore assumed the activity of these cultures to be predominantly chorion (trophoblast) cells but certainly recognize that there may be some contamination with decidual cells. Lopez Bernal et al. demonstrated that both 11 ß-HSD dehydrogenase and reductase activities was found in the human choriodecidual tissues with the dehydrogenase activity predominating. Their work also suggested that the activity in the choriodecidua was of decidual, rather than chorionic, origin (36). Recently, Arcuri et al. reported both 11 ß-HSD type 1 and 2 to be present in endometrial stromal cells; expression of the enzyme was were enhanced during decidualization (37). Therefore, the observed 11 ß-HSD type 1 reductase activity in our chorionic cell culture could be contributed in part by decidual cells, but this seems unlikely as a primary source because a predominant reductase activity was observe in the chorion cell, which is in contrast to the predominately oxidase activity reported for the decidual cell. Additional studies will be required to resolve this issue. In vivo, the close proximity of chorion trophoblast and decidual stromal cells suggests close functional interaction. Although the affinity of 11 ß-HSD type 1 is too low to exclude maternal glucocorticoids from the fetus effectively, the unique cortisol regenerating function of 11 ß-HSD type 1 could also provide a coordinated mechanism whereby the amount of maternal glucocorticoids reaching the fetus is precisely controlled. However, the mechanism by which the placental syncytiotrophoblast and chorionic trophoblast, the cells of same origin, express different types of 11 ß-HSD is unknown at present.
In this study, the percent recoveries of 3H-cortisol and 3H-cortisone were 86.7% and 88.3%, respectively, suggesting that very little 3H-steroid was taken up by the cells. In addition, we found that only 0.33% of total 3H-steroid was taken up by the cells, which further suggests that the determination of conversion of cortisol and cortisone in the medium reflected the intracellular enzyme activity.
NO donors, both SNP and SNAP, inhibited 11 ß-HSD type 2 oxidase activity in the placental trophoblast but did not affect 11 ß-HSD type 1 reductase activity, suggesting that the inhibitory effect of NO is specific for type 2 activity. Furthermore, SNP also reduced the levels of type 2 mRNA in the placental syncytiotrophoblast, indicating that NO may affect transcriptional regulation of the 11 ß-HSD type 2 gene. We accept, however, that the present studies do not exclude an effect of the NO donor on RNA stability. NO formed from L-arginine by NO synthase (NOS), can act in a paracrine manner and as an intracellular messenger. The main pathway of NO effects is stimulation of the soluble guanylyl cyclase (GC-S) (38). GC-S forms guanosine cyclic 3',5'-monophosphate (cGMP), which in turn specifically regulates protein phosphorylation, ion channel conductivity, and phosphodiesterase activity (38). In the present study, we found that the soluble guanylyl cyclase inhibitor, LY83583, partially blocked the inhibitory effect of SNP and SNAP on 11 ß-HSD type 2, suggesting that the effect of NO on 11 ß-HSD type 2 is mediated in part through the cGMP pathway. In an earlier study, we also demonstrated that similar doses of SNP stimulated the accumulation of cGMP in cultured human placental trophoblast (21). The synthetic cGMP analog, 8-br-cGMP, also mimicked the inhibitory effect of NO donors on placental 11 ß-HSD type 2 activity further suggesting a cGMP-mediated effect of NO on placental 11 ß-HSD type 2. On the other hand, as 8-br-cGMP was less potent than the NO donor, and the guanylyl cyclase inhibitor, LY83583, could only partially blocked the effect of NO, we propose that there may exist alternative pathways interacting with cGMP pathway resulting in more pronounced inhibition with NO donors.
When NO reaches high levels, it has been shown to have inhibitory effects on protein activities through ADP-ribosylation (38, 39). Because the ADP-ribosylation inhibitor, HMBG, was unable to block the effect of NO on 11 ß-HSD type 2 in this study, it is unlikely that this pathway plays a role in NO-induced inhibition of 11 ß-HSD type 2. Furthermore, it is also unlikely that the inhibitory effects of SNP and SNAP are a result of toxic effects on the cells, as the effects are specific on 11 ß-HSD type 2 activity, but not 11 ß-HSD type 1 reductase activity in the same cell type. The cells were more than 95% viable before and after drug treatment, which also excludes the possibility of toxic effects of the drugs tested in this study. Moreover, it has been recently reported that NO influences glyceraldehyde-3-phophate dehydrogenase (GADPH) activity by covalent linkage of NAD+ to the enzyme through ADP-ribosylation (40), which in turn would decrease the NAD+ available for steroid dehydrogenation. This may contribute in part to the inhibitory effect of NO on 11 ß-HSD type 2 activity. It is unlikely, however, to be the primary cause of the inhibition because SNP also suppressed the expression of 11 ß-HSD type 2 mRNA. In addition, the guanylyl cyclase inhibitor, LY83583, partially reversed the inhibitory effect of NO on 11 ß-HSD type 2 activity. Moreover, the inhibitory effect of NO was not affected by ADP-ribosylation inhibitor. We have interpreted our results to suggest that the specific inhibitory effect of NO on 11 ß-HSD type 2 is at least partially mediated by cGMP, although other pathways rather than ADP-ribosylation could also exist.
NO synthase is present in umbilical arteries and veins, myometrium, fetal membranes, and placental syncytiotrophoblast (19, 20). NO generated in the feto-placental circulation contributes to the local regulation of activities such as inhibition of CRH release, relaxation of basal vascular tone, and myometrial quiescence during pregnancy (21, 22, 23, 41). On the contrary, glucocorticoids induce hypertension either through a direct effect on the blood vessel or by binding to the minerolocorticoid receptor (12, 26), with positive feedback on the production of CRH and prostaglandins in trophoblast-derived cells in a manner that might facilitate myometrial contraction (24, 25, 42). The inhibitory effect of NO on 11 ß-HSD type 2 activity could result in more bioactive cortisol in the placenta. In turn, this could balance or override the effects of NO on the fetal-placental circulation, CRH production, and myometrial quiescence.
In conclusion, the results presented in this paper show that 11 ß-HSD type 2 activity predominates in cultured placental trophoblast, whereas 11 ß-HSD type 1 predominates in the chorion, mainly as a reductase. NO specifically inhibits placental 11 ß-HSD type 2 activity and its mRNA expression, but not 11 ß-HSD type 1 reductase activity. This effect is mediated at least partially through the cGMP pathway, although an alternative pathway not involving ADP-ribosylation may exist.
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Acknowledgments |
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Footnotes |
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Received April 21, 1997.
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F. A. Patel, V. L. Clifton, K. Chwalisz, and J. R. G. Challis Steroid Regulation of Prostaglandin Dehydrogenase Activity and Expression in Human Term Placenta and Chorio-Decidua in Relation to Labor J. Clin. Endocrinol. Metab., January 1, 1999; 84(1): 291 - 299. [Abstract] [Full Text]
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Y.-L. Dong, P. R.R. Gangula, L. Fang, and C. Yallampalli Nitric oxide reverses prostaglandin-induced inhibition in ovarian progesterone secretion in rats Hum. Reprod., January 1, 1999; 14(1): 27 - 32. [Abstract] [Full Text] [PDF]
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