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European Institute for Peptide Research (IFRMP 23), Department of Endocrinology, INSERM U413, University Hospital of Rouen, (H.L., J.M.K.) 76031 Rouen, France; Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U413, Unite Associée Centre National de la Recherche Scientifique, University of Rouen, (H.L., V.C., C.D., H.V., J.M.K.) 76821 Mont-Saint-Aignan, France; and Department of Pharmacology, INSERM E 9920, University Hospital of Rouen, (P.C., C.T.) 76031 Rouen, France
Address all correspondence and requests for reprints to: Dr. Hervé Lefebvre, IFRMP 23, Department of Endocrinology, INSERM U413, Hospital of Boisguillaume, University Hospital of Rouen, 76031 Rouen cedex, France. E-mail: herve.lefebvre{at}chu-rouen.fr
Abstract
In the human adrenal cortex, serotonin (5-HT) is contained in mast-like cells, and we have shown that 5-HT stimulates aldosterone secretion, suggesting that 5-HT may control glomerulosa cells through a paracrine mechanism. Concurrently, the presence of 5-hydroxyindolacetic acid in human adrenocortical extracts indicates that 5-HT may be metabolized after local release by mast cells. The aim of the present study was to investigate in vitro the production and metabolism of 5-HT by the human adrenal cortex. Perifused adrenal slices released spontaneously detectable amounts of 5-HT (0.74 ± 0.38 fmol/mg wet tissue·min). The mast cell-depleting drug compound 48/80 induced a burst of 5-HT secretion followed by a gradual increase in aldosterone production. Administration of the specific 5-HT4 receptor antagonist GR 113808 (10-6 M) did not affect compound 48/80-induced 5-HT release but abolished the stimulatory effect of compound 48/80 on aldosterone secretion, indicating that 5-HT released locally is responsible for a paracrine control of steroidogenesis.
Incubation of cells from the human adrenal cortex with 5-HT (10-5 M) provoked the formation of the 5-HT metabolite 5-hydroxytryptophol. The type A monoamine oxidase (MAO) inhibitor clorgyline (10-6 M) suppressed the metabolism of 5-HT into 5-hydroxytryptophol. Immunocytochemical staining of cultured cells revealed the presence of a subpopulation of MAO-A-positive cells. Double labeling with an antiserum against chromogranin A showed that MAO-A was actually contained in chromaffin cells. Similarly, immunohistochemical staining of adrenal slices showed that MAO-A was expressed in chromaffin cells located both in the medulla and in intracortical rays.
In conclusion, the present study shows that, in the human adrenal cortex, 5-HT, released by mast-cells, may stimulate aldosterone secretion in a paracrine manner. Our data also indicate that 5-HT is metabolized by MAO-A located in intracortical chromaffin cells.
VARIOUS BIOLOGICALLY ACTIVE substances (including classical neurotransmitters and neuropeptides) are released within the adrenal cortex by chromaffin cells, nerve endings, endothelial cells, or cells of the immune system. These regulatory factors, which are produced in the vicinity of steroidogenic cells, are capable of modulating steroid production in a paracrine manner (for a review, see Ref. 1). The presence of serotonin (5-HT) has been demonstrated by immunohistochemical and biochemical approaches in the adrenal gland of the frog, mouse, rat, and human (2, 3, 4, 5); 5-HT-like immunoreactivity (5-HT-LI) has been found in adrenochromaffin cells of frogs, mice, and rats (2, 3, 4, 6). In the frog adrenal gland, 5-HT-LI is only detected in chromaffin tissue; whereas, in the rat adrenal gland, 5-HT-LI is also present in mast cells located in the wall of adrenal arterioles and throughout the cortex (7, 8). In humans, 5-HT is exclusively detected in perivascular mast cells and, therefore, may be released during inflammation and allergic responses (5). However, production of 5-HT by the human adrenal gland has not yet been studied.
It is now well established that 5-HT is able to stimulate gluco- and mineralocorticoid production from adrenocortical cells in various species, including humans, suggesting that the indolamine may exert a paracrine control of the secretory activity of the adrenal cortex (9, 10, 11, 12, 13, 14). The type of receptor involved in the corticotropic effect of 5-HT has been investigated in frogs, rats, and humans. A recent study has shown that 5-HT-induced aldosterone secretion from the rat adrenal gland is mediated by activation of 5-HT7 receptors (15). In frog and man, the action of 5-HT on adrenocortical tissue can be accounted for by recruitment of 5-HT4 receptors positively coupled to adenylyl cyclase and calcium influx (5, 16, 17, 18, 19). Interestingly, 5-HT4 receptor agonists seem to be much more potent in stimulating aldosterone than cortisol secretion from human adrenocortical cells. In agreement with this observation, in vivo studies have shown that the 5-HT4 receptor agonists zacopride and cisapride stimulate aldosterone secretion in healthy volunteers and various groups of patients, including patients with primary and/or secondary hyperaldosteronism (20, 21, 22, 23).
In the central nervous system and in peripheral organs, 5-HT is preferentially metabolized by type A monoamine oxidase (MAO) into 5-hydroxyindolacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTOL) (for a review, see Ref. 24). Significant amounts of 5-HIAA have been found in frog, rat, and man adrenocortical extracts, using HPLC combined with electrochemical detection (HPLC-ECD) (2, 3, 5). In addition, immunohistochemical and biochemical studies have shown the presence of types A and B MAO in the adrenal cortex and medulla of dog, cat, rat, and cattle (25, 26, 27). Type A MAO has also been characterized in rat phaeochromocytoma (PC 12) cells (28). In man, an immunohistochemical study, aimed at examining the distribution of MAOs in various endocrine glands, has shown the presence of type A MAO in the adrenal cortex (29). However, the metabolism of 5-HT has not yet been investigated in the normal human adrenal gland.
The aims of the present study were: 1) to determine whether 5-HT is produced by human adrenocortical tissue and to examine the effect of adrenal 5-HT on aldosterone secretion; and 2) to investigate the presence of MAOs in the human adrenal cortex by using biochemical and immunocytochemical techniques.
Materials and Methods
Test substances, reagents, and tissues
The 5-HT, 5-HTOL, 5-HIAA, homovanillic acid (HVA), clorgyline, and compound 48/80 (condensation product of N-methyl-p-methoxyphen-ethylamine with formaldehyde) were purchased from Sigma laboratories (St. Louis, MO). GR 113808 ([1-[2-methylsulphonylamino)ethyl]-4-piperidinyl]methyl 1-methyl-1H-indole-3-carboxylate, maleate) was provided by GlaxoSmithKline (Greenford, UK). DMEM, Ham’s F-12 medium, FCS, gentamycin solution (10 mg/ml), and the antibiotic solution (10,000 U/ml penicillin G sodium; 10,000 U/ml streptomycin sulfate; and 25 µg/ml Amphotericin B) were supplied by Life Technologies, Inc., (Grand Island, NY). Mouse monoclonal antibodies against human type A and B MAO (refer to MCA 616 and MCA 614, respectively) were obtained from Serotec (Kidlington, England, UK). Specific rabbit polyclonal antibodies to human chromogranin A (refer to WE 14-156333) were kindly provided by Dr. Y. Anouar (INSERM U 143, Mont-Saint-Aignan, France).
Human adrenal tissue was obtained, after informed consent, from patients undergoing expanded nephrectomy for kidney cancer. In the present study, 10 adrenal glands were used for perifusion, cell culture, and immunohistochemistry experiments. The protocol of collection of the tissue and the experimental procedures were approved by the regional ethics committee (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale de Haute-Normandie, Loi Huriet, January 1990).
Perifusion experiments
The effect of compound 48/80 on 5-HT and aldosterone production by human adrenal tissue was studied using a perifusion system technique, as previously described (5). Briefly, human adrenal fragments were transferred into 100 ml DMEM and rapidly transported to the laboratory. The adrenal cortex was carefully dissected, diced into small pieces (1–2 mm3), and preincubated in 5 ml DMEM. The adrenocortical fragments were rinsed three times with fresh medium, mixed with biogel P2, and transferred into perifusion chambers. Each chamber consisted of a polystyrene column (inside diameter, 10 mm) delimited by two Teflon pestles. The adrenal tissue (500 mg/chamber) was perifused with DMEM supplemented with sodium metabisulfite (3 mg/100 ml, Sigma) to avoid spontaneous oxidative degradation of 5-HT released by the tissue. DMEM was continuously gassed with a 95% O2-5% CO2 mixture at a constant flow rate (300 µl/min), temperature (37 C), and pH (7.40). The tissues were allowed to stabilize for 2 h; and then test substances, dissolved in gassed DMEM, were administered at the same flow rate as DMEM alone. Effluent fractions were collected at 5-min intervals, immediately frozen, and kept at -80 C until assays.
HPLC-ECD was used to measure 5-HT concentrations (see below). Aldosterone concentrations were determined by RIA, as previously described (30). GR 113808 had no intrinsic effect on aldosterone production from human glomerulosa cells (personal unpublished data) and did not interfere in the aldosterone assay at concentrations up to 10-6 M. In contrast, compound 48/80 gave rise to a 30% elevation in antibody-bound counts, leading to artifactually lowered aldosterone levels. For this reason, aldosterone concentration was not measured in the four fractions of perifusate after compound 48/80 administration. Results are expressed as mean ± SD, and statistical significance was assessed with Dunnett’s test, after ANOVA.
Cell culture
Adrenal fragments were immediately immersed in culture medium (50% DMEM-50% Ham’s F-12) supplemented with 0.2% antibiotic-antimycotic solution and 0.2% gentamycin, and rapidly transported to the laboratory. As for perifusion experiments, the adrenal cortex was dissected from fat and medullary tissues and minced with scissors, and adrenal cells were enzymatically dispersed, as previously described (31). Briefly, tissue samples were stirred for 45 min at 37 C in culture medium containing protease (2 mg/ml), collagenase (2 mg/ml), and deoxyribonuclease I (70 µg/ml). The cell suspension was centrifuged (100 x g; 37 C; 20 min). The pellet was resuspended in culture medium containing 80 µg/ml deoxynuclease I, and the cells were dispersed by gentle aspiration with a siliconized Pasteur pipette with a flame-polished tip. The dispersion procedure was repeated twice. Isolated cells were then transferred into culture medium supplemented with 5 µg/ml insulin, 10 µg/ml transferrin, vitamin C (20 mg/ml), and 5% FCS. Adrenocortical cells were cultured in Petri dishes (at a density of 106 cells/dish) and incubated at 37 C, in 100% relative humidity, in a 5% CO2-95% air atmosphere. For immunocytochemical experiments, cells were cultured on coverslips. The culture medium was changed, 24 h after plating, and thereafter was renewed every 48 h. Incubation experiments of cells with 5-HT were conducted after 2–4 days in culture.
Incubation experiments
Before each experiment, culture medium was removed; and cells were incubated with fresh DMEM (control experiments), DMEM with 5-HT (10-5 M), or DMEM with 5-HT (10-5 M) and the MAO-A inhibitor clorgyline (10-6 M). In all cases, DMEM was supplemented with 3 mg/100 ml Na metabisulfite. To determine the time-course of 5-HTOL accumulation, cells were incubated with 5-HT (10-5 M) for 15 min, 30 min, and 1, 2, 4, 6, 12, and 24 h at 37 C. After each incubation period, aliquots of the culture medium were taken and immediately frozen at -80 C until HPLC analysis. Under the experimental conditions used for the characterization of 5-HT metabolites by HPLC-ECD, synthetic 5-HIAA was undetectable after incubation in DMEM. In contrast, 5-HTOL concentration was measurable, with a high reproducibility (interassay coefficient of variation lower than 7%), and spontaneous degradation of synthetic 5-HTOL in DMEM was negligible (lower than 10% over 24 h). For this reason, the metabolism of 5-HT by cells derived from the adrenal cortex was investigated by measuring the formation of 5-HTOL in the culture medium. Results are expressed as mean ± SD, and statistical significance was assessed by Bonferroni test, after one-way ANOVA.
HPLC analysis
Characterization and quantitation of 5-HT in the effluent perifusate and measurement of 5-HT metabolites, i.e. 5-HTOL and 5-HIAA, in incubation medium were carried out by HPLC-ECD. A sample (50 µl) of culture medium was directly injected into a Spherisorb ODS-2, 3-µm (150 x 4.6 mm) column. Separation of 5-HT, 5-HTOL, and 5-HIAA was achieved by using a mobile phase of KH2PO4 (25 mM), sodium EDTA (10 mM), and methanol (9.3%, vol/vol), adjusted to pH 3.3, at a flow rate of 0.9 ml/min. Fifty nanograms of HVA was added to each sample and used as an internal standard. Under these conditions, the retention times of 5-HT, 5-HTOL, 5-HIAA, and HVA were 9.7, 21.3, 27.7, and 37.5 min, respectively. Quantitation was achieved with an electrochemical detector (Bioanalytical Systems, Inc., West Lafayette, IN) equipped with a glass carbon working electrode and an Ag/AgCl reference electrode. The potential was set at + 0.7 V; and the sensibility, at 1 nAmp.
Immunohistochemistry
Adrenal fragments were immersed in 50 ml McLean’s fixative
solution immediately after surgery and maintained in the fixative for
8 h. The tissues were rinsed in 0.1 M PBS containing
15% sucrose, for 12 h, and transferred into a 30% sucrose-PBS
solution for 24 h. The tissue fragments were coated with an
embedding medium (O.C.T. Tissue Tek, Reichert Jung, Nussloch, Germany)
and frozen onto an electric fast-cooling sample carrier. Adrenal
sections were cut at 10 µm on a cryostat (Frigocut 2700, Reichert
Jung). Adrenal cells on coverslips were immersed in a 4%
paraformaldehyde/PB (vol/vol) solution for 90 min. After fixation,
cells were rinsed three times in PBS before incubation with antibodies.
Adrenal cells and/or tissue sections were incubated overnight at 4 C in
a humid atmosphere with either MAO-A or MAO-B antibodies diluted 1:10
in PBS containing 1% human serum albumin and 0.3% Triton (staining
buffer) or staining buffer alone. The sections and/or cells were rinsed
in three different baths of PBS (10 min each) and incubated at room
temperature for 1 h with fluorescein isothiocyanate
(FITC)-conjugated goat antimouse 
-globulins (Nordic Immunological
Laboratories, Tilburg, The Netherlands) at a working dilution of 1:100.
For double staining, cultured cells were incubated overnight at 4 C
with both mouse antibodies to MAO-A diluted 1:10 in staining buffer and
rabbit antiserum to chromogranin A diluted 1:200 in staining buffer.
After rinsing in three different baths of PBS, cells were incubated at
room temperature with both FITC-conjugated goat antimouse -globulins
diluted 1:100 and Texas-red-conjugated donkey antirabbit -globulins
(Nordic Immunological Laboratories) diluted 1:30. Finally, sections
and/or cells were rinsed in PBS for 1 h, mounted in PBS-glycerol,
and coverslipped. The preparations were examined on a
Leitz (Rockleigh, NY) Orthoplan microscope equipped
with a Vario Orthomat photographic system. Selected sections were
analyzed using a confocal laser scanning microscope (Leica Corp., Heidelberg, Germany) equipped with a Diaplan optical
system and an argon/krypton ion laser. Confocal laser
scanning-microscope analysis was performed using a band-pass filter
(
= 535 ± 7 nm) for detection of FITC and a long-pass
filter ( > 610 nm) for detection of Texas-red.
Results
Production of 5-HT by the human adrenal cortex
Human adrenocortical slices were perifused as described in
Materials and Methods. HPLC-ECD revealed the presence of
significant amounts of 5-HT in the effluent perifusate. Basal
adrenocortical production of 5-HT (mean ±
SD) was 0.74 ± 0.38 fmol/mg wet
tissue·min. Administration of one pulse of compound 48/80 (0.67
mg/ml, 5 min) to perifused human adrenocortical slices induced a marked
increase in 5-HT release, which reached a maximum of +
509%, 10 min after the infusion of compound 48/80. Then, 5-HT levels
gradually declined and became undetectable, 45 min after the beginning
of the stimulation (Fig. 1
). In the same
experiments, a significant increase in aldosterone production occurred
30 min after the peak of 5-HT (Fig. 2A).
As illustrated in Fig. 2B, prolonged administration of the specific
5-HT4 receptor antagonist GR 113808
(10-6 M, 150 min), did not
affect the stimulation of 5-HT induced by compound 48/80 but totally
abolished the stimulatory effect of compound 48/80 on aldosterone
secretion.
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The HPLC-ECD conditions made it possible to resolve 5-HT, 5-HTOL,
5-HIAA, and HVA, the latter being used as an internal standard (Fig. 3A). After a 2-h incubation of 5-HT in
culture medium alone, no 5-HT metabolite was observed (Fig. 3B). In
contrast, a 2-h incubation of 5-HT (10-5
M) in the presence of cells from the adrenal cortex
provoked the formation of 5-HTOL (Fig. 3C). Time-course studies
revealed that the content of 5-HTOL in the DMEM medium of cells
incubated with 5-HT increased linearly over a 24-h period (Fig. 4A). The MAO-A inhibitor clorgyline
(10-6 M) suppressed the metabolism
of 5-HT into 5-HTOL (Fig. 4B).
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Labeling of cultured cells derived from the human adrenal cortex
with a monoclonal antibody against MAO-A revealed the presence of
clusters of immunoreactive cells. In these cells, the immunoreactive
material was located in the cytoplasm and exhibited a granular aspect
(Fig. 5A). In contrast, no MAO-B
immunoreactivity could be observed in cultured cells. MAO-A-positive
cells were also labeled by the chromogranin A antiserum (Fig. 5B).
Incubation of human adrenal slices with the monoclonal MAO-A antibody
produced intense labeling of the medulla (Fig. 6A). MAO-A immunoreactivity was
also detected in a subpopulation of cells in the cortex. These
MAO-A-containing cells were arranged in rays stretching from the
medulla through the cortex and reaching the capsule (Fig. 6, A and B).
Small clusters or isolated MAO-A-immunopositive cells were also
observed in the three zones of the cortex. Incubation of adrenal slices
with the monoclonal MAO-B antibody produced only moderate labeling of
the adrenal medulla (Fig. 6C). When the primary antibodies were
substituted with PB, no immunofluorescence was observed (Fig. 6D).
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We have previously shown the presence of significant amounts of 5-HT in human adrenocortical extracts (5), and we have found that the amine is stored in the cytoplasm of perivascular adrenocortical cells exhibiting the morphological characteristics of mast cells (5). In addition, we have demonstrated that 5-HT stimulates aldosterone secretion from the human adrenal cortex through activation of 5-HT4 receptors positively coupled to adenylyl cyclase and calcium influx (9), suggesting that 5-HT may control aldosterone secretion in a paracrine manner.
Here, we show that perifused human adrenocortical slices release spontaneously detectable amounts of 5-HT. Exposure of adrenal explants to compound 48/80, a drug that specifically induces degranulation of mast cells, evoked a robust increase of 5-HT output followed by a rapid collapse in 5-HT secretion, indicating that, in the human adrenal cortex, 5-HT is exclusively produced by mast cells. Administration of compound 48/80 subsequently induced a marked increase in aldosterone secretion. The fact that the stimulation of aldosterone production occurred 30 min after the peak of 5-HT suggested that adrenal steroidogenesis evoked by compound 48/80 could be ascribed to the release of 5-HT by mast cells. However, it is well demonstrated that mast cells can release various cytokines, such as IL-6 (for a review, see Ref. 32), which (like 5-HT) can stimulate corticosteroid secretion (33). In addition, it might have happened that compound 48/80 itself could directly activate aldosterone production. It was thus necessary to determine whether 5-HT was really involved in the mechanism of action of compound 48/80 on corticosteroidogenesis. The specific 5-HT4 receptor antagonist GR 113808 completely abolished compound 48/80-induced aldosterone secretion. This observation demonstrates that the stimulation of aldosterone production evoked by compound 48/80 can be accounted for solely by its effect on 5-HT release. Taken together, these data indicate that 5-HT released locally within the adrenal cortex can stimulate aldosterone secretion through a paracrine mode of action.
In the central nervous system and in peripheral organs, 5-HT is preferentially metabolized by type A MAO into acid and alcohol metabolites, i.e. 5-HIAA and 5-HTOL, respectively (34). We have previously demonstrated that human adrenocortical extracts contain significant amounts of 5-HIAA (5), suggesting that 5-HT is locally metabolized after release from intraadrenal mast cells. In agreement with this hypothesis, the presence of types A and B MAOs has been demonstrated by biochemical approaches in the adrenal cortex and medulla of rat and cattle (26, 27). The present data show that incubation of cells derived from the human adrenal cortex with 5-HT causes the appearance of 5-HTOL in the culture medium. Spontaneous degradation of 5-HT could be excluded, because 5-HTOL was undetectable when 5-HT was incubated in culture medium in the absence of cells. In addition, the formation of 5-HTOL by cells incubated with 5-HT was virtually suppressed by the MAO-A inhibitor clorgyline, demonstrating the occurrence of MAO activity in the human adrenal cortex. In agreement with this observation, immunocytochemical labeling showed that a subpopulation of cultured cells derived from the cortex contained MAO-A immunoreactivity. These MAO-A-positive cells were also labeled by antibodies to chromogranin A, a selective marker of chromaffin cells (35). The presence of chromaffin cells among cultured cells derived from the adrenal cortex is consistent with previous observations showing that adrenomedullary cells penetrate into the cortical zones in the rat and human adrenal glands (36, 37). Labeling of adrenal slices with the MAO-A antibody showed that not only the medullary zone but also clusters of cells in the adrenal cortex were immunoreactive. Similarly, types A and B MAOs have previously been detected in the adrenal cortex of rat, cat, dog, and cattle by immunohistochemistry (25). Intracortical chromaffin cells are in close contact with steroidogenic cells (38) and are thus capable of modulating corticosteroidogenesis through the release of various factors, including catecholamines and neuropeptides (for a review, see Ref. 39). The present data indicate that chromaffin cells may also indirectly participate in the local regulation of adrenocortical function by inactivating bioactive signals produced by cells of the immune system.
The present results, together with previous findings (9),
show that, in man, paracrine regulation of adrenocortical cell activity
by 5-HT involves interactions between three types of cells (Fig. 7). Released by mast cells in the
vicinity of glomerulosa cells, 5-HT stimulates aldosterone secretion
through activation of 5-HT4 receptors positively
coupled to adenylyl cyclase and calcium influx. Concurrently, 5-HT can
be metabolized by type A MAO present in the cytoplasm of intracortical
chromaffin cells. Collectively, these data provide evidence for a
physiological role of 5-HT in the regulation of aldosterone secretion
in humans.
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Acknowledgments
We thank Drs. P. Grise, D. Pavard, and O. Rousseau, who kindly provided human adrenal tissue; and M. Guervin for technical assistance.
Footnotes
This work was supported by grants from Institut National de la Santé et de la Recherche Médicale (U413), IFRMP 23, and the Conseil Régional de Haute-Normandie.
Abbreviations: FITC, Fluorescein isothiocyanate; 5-HIAA, 5-hydroxyindolacetic acid; HPLC-ECD, HPLC combined with electrochemical detection; 5-HT, serotonin; 5-HT-LI, 5-HT-like immunoreactivity; 5-HTOL, 5-hydroxytryptophol; HVA, homovanillic acid; MAO, monoamine oxidase.
Received April 5, 2001.
Accepted June 15, 2001.
References
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) and aldosterone (
)
responses to a single pulse of compound 48/80 (0.67 mg/ml, 5 min) in
the absence (A) or presence (B) of GR 113808
(10-6 M, 150 min). The data are
representative of three independent experiments.
