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Experimental Studies |
Department of Internal Medicine III, University of Leipzig, 04103 Leipzig, Germany
Address all correspondence and requests for reprints to: Stefan R. Bornstein, Department of Internal Medicine III, University of Leipzig, Philipp-Rosenthal-Straße 27, 04103 Leipzig, Germany.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, interferon-, interferon-
, IL 1, IL-2, and IL-6, are
known to influence the interactions between the
hypothalamic-pituitary-adrenocortical (HPA) axis and the immune system
(3, 4, 5, 6). Several studies have demonstrated that IL-6 stimulates the HPA axis in vitro and in animals at different levels (7, 8, 9, 10, 11, 12, 13). IL-6 has been shown to exert T-cell-mediated antitumor activity (14) and, therefore, has been tested as a potential therapy in patients with advanced malignancies (15). IL-6 was found to be a potent activator of the HPA axis, stimulating cortisol and ACTH release in patients with cancer. It was suggested that this cytokine could be a useful tool in testing the HPA axis as an alternative for the insulin tolerance test (16). A current study could confirm these results in patients with metastatic renal carcinomas. Interestingly, after long-term application of IL-6, the ACTH plasma level decreased, whereas IL-6 still led to a significant stimulation of glucocorticoid release (16, 17).
Recently, much interest has been focused on the adrenal gland as the
target organ of the HPA axis and on how it interacts with the immune
system. In adrenalectomized rats, stress-induced IL-6 levels were found
to be substantially reduced, demonstrating that the adrenal is the main
source of IL-6 (18). In vitro data revealed a direct
influence of IL-6 on rat adrenal steroidogenesis (8) and that the
release of IL-6 from rat adrenal zona glomerulosa cells could be
enhanced by several agents, for example: IL-1, IL-1ß, angiotensin
II, and ACTH (19, 20, 21). Although these data gave only indirect evidence
for the presence of IL-6 in the adrenal gland, we were able to
demonstrate by combination of immunohistochemistry and in
situ hybridization that IL-6 messenger RNA (mRNA) is expressed in
the human adrenal gland by steroid-producing cells and macrophages,
which were found in direct contact with catecholamine producing cells
(22). This suggests a local immunoadrenal interaction between the
immune system and adrenocortical cells.
However, there are, as yet, no data on the presence of the IL-6 receptor (IL-6R) on adrenal cells or the effects of IL-6 on adrenal steroidogenesis. Therefore, we designed this study to address the following questions: 1) Are IL-6 and its receptor expressed by adrenal cells in vitro? 2) Where is the IL-6R located within the adrenal gland? 3) Does IL-6 affect adrenal steroidogenesis in vitro? To avoid confounding results by the participation of macrophages in our in vitro experiments, dispersed human adrenal cells were depleted from CD68-positive cells before culture.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell culture
Directly after surgery, adrenals were transported in ice-cold Dulbecco’s phosphate-buffered saline (PBS) into the laboratory, where preparation immediately began. After removing the adipose tissue, the adrenals were cut into small pieces with sharp scissors and washed three times in DMEM/F12 medium (GibcoBRL/Life Technologies GmbH, Eggenstein, Germany) with 2.438 g/L NaHCO3, 10 mmol/L HEPES, 100 U/mL penicillin G, and 100 µg/mL streptomycin sulfate, pH 7.4. Dispersed cells were obtained by digestion in medium with 1 mg/mL collagenase (Serva/Boehringer Ingelheim Bioproducts Partnership, Heidelberg, Germany) and 0.1 mg/mL deoxyribonuclease I (Sigma-Aldrich Chemie GmbH, Deisenhofen, Germany). The cell suspension was filtered through 60-µm nylon gauze and washed by centrifugation. Pellets were resuspended in culture medium [medium, as described above, with 50 U/mL penicillin G and 50 µg/mL streptomycin sulfate and additional 10% FCS (GibcoBRL/Life Technologies GmbH)]. The cells were counted, depleted of CD68-positive cells, and seeded in: 1) 8-well LabTek chamberslides (Nunc GmbH, Wiesbaden-Biebrich, Germany) at a density of 25,000 cells/well in 250 µL for immunohistochemistry; 2) 24-well plates (Nunc) at a density of 100,000 cells/well in 1 mL for incubation; and 3) 6-well plates (Nunc) at a density of 106 cells per well in 5 mL for isolation of RNA. After a 72-h period of culture with exchange of medium every 24 h, cells were incubated for 6 h, 12 h, or 24 h with recombinant human IL-6 (Peprotek/Biozol Diagnostica Vertrieb GmbH, Eching, Germany) or ACTH1–24 (Synacthen; Ciba-Geigy GmbH/Ciba Pharma, Wehr, Germany) in serum-free medium containing 50 U/mL penicillin G and 50 µg/mL streptomycin sulfate, 5 mg/L insulin, 10 mg/L transferrin, 5 mg/L sodium selenite, 20 mg/L ascorbic acid, and 0.01% (wt/vol) bacitracin. Cells that were used as controls were treated in the same way without addition of secretagogues. For light microscopy, unstimulated cells in the chamberslides were fixed after 72 h of culture. Cell culture and incubation were kept at 37 C in a humidified atmosphere of 5% CO2.
Depletion of CD68-positive cells
Cells were counted after digestion, centrifuged, resuspended in culture media (107 cells/mL), and dispersed by pipetting. Monoclonal mouse antihuman CD68/KP1 (Dako Diagnostika GmbH, Hamburg, Germany) was added to the heterogeneous cell suspension (1:100 = 10 µL/mL) and incubated for 30 min at 4 C, gently agitating the cell suspension. The stock solution of magnetic sheep antimouse IgG Dynabeads M-450 (Deutsche Dynal GmbH, Hamburg, Germany) was then vortexed. Beads (4/cell or 1–2 x 107/mL cell suspension) were washed twice with PBS. The tube with the beads and the PBS was vortexed and placed for 2 min in the MPC-1 (magnetic particle concentrator; Deutsche Dynal GmbH), PBS was discarded and the procedure repeated. Finally, Dynabeads were resuspended in the same volume of culture media as calculated for the cells. The cell suspension was washed twice, resuspended in culture media containing the Dynabeads, and incubated for 30 min at 4 C with gentle agitation. The tube with the Dynabeads/cell suspension was placed in the MPC-1 for 2 min. At the end, purified cell suspension was removed for further work.
Determination of steroid hormones
The supernatants of the incubated cells were measured with commercial RIAs for aldosterone and cortisol (DPC Biermann GmbH, Bad Nauheim, Germany) or dehydroepiandrosterone (DHEA) (Diagnostics Systems Laboratories Deutschland GmbH, Sinsheim, Germany) according to the manufacturer’s instructions.
Immunohistochemistry
After removing the medium, the chamberslides were shock-frozen using precooled isopentane in liquid nitrogen, dried briefly, fixed in acetone for 10 min, and dried again. If the staining process was not performed directly after the acetone-fixing, the slides were wrapped in tin foil and stored, frozen at -80 C. Paraffin-fixed sections of complete adrenal glands were used for staining IL-6R in tissue. The cells were immunostained using the LSAB Kit (Dako Diagnostika GmbH), according to the manufacturer’s protocol, with a polyclonal rabbit antihuman IL-6 antibody (Genzyme Virotech GmbH, Rüsselsheim, Germany) or a polyclonal goat antihuman IL-6R antibody (R&D/DPC Biermann GmbH). Visualization was achieved by incubating the slides with AEC Chromogen System (Dianova-Immunotech GmbH, Hamburg, Germany) as described in the manufacturer’s protocol. Slides were counterstained with hematoxylin, rinsed in water, and mounted with glycerin gelatine. As control, the specific antisera were replaced by nonimmune pig or rabbit serum. No nonspecific staining was noticed.
RNA extraction, screening for DNA contamination, and complementary DNA (cDNA) synthesis
Total RNA from 0.1 g tissue or 1 x 106
cultured cells was isolated by a single-step method using RNAzol B (AGS
Angewandte Gentechnologie Systeme GmbH, Heidelberg, Germany) according
to the manufacturer’s protocol. The resulting total RNA was washed
twice with 80% ethanol, dried, and dissolved in DEPC-treated water.
Determination of OD 260/280 and native gel electrophoresis served as
quality controls for the isolated RNA. Before RT, RNA samples
containing 0.1–5.0 µg total RNA were incubated for 10 min at 37 C
with 1.5 µL DNase I (Boehringer Mannheim GmbH, Mannheim, Germany) to
avoid DNA contamination. The obtained RNA was screened in a control PCR
with specific primers for glyceraldehyde-3-phosphate-dehydrogenase
(GAPDH) (23) to determine probes containing genomic DNA. Only RNA
samples without DNA contamination were used in PCR experiments. After
incubation with DNase I, the probes were denatured at 65 C for 10 min,
and then 0.1–5 µg total RNA/reaction mix tube was used to synthesize
cDNA with the Ready To Go T-Primed First Strand Kit (Pharmacia Biotech,
Uppsala, Sweden). Resulting cDNA samples were screened with PCR using
specific primers for GAPDH (as control for RT), IL-6 (23) and IL-6R
(24), and the PrimeZyme DNA Polymerase Kit (Biometra, Göttingen,
Germany). Each 25 µL amplification contained 2.5 µL 10 x
concentrated buffer, 0.25 U PrimeZyme, 2.5 mmol/L of each dNTP , 0.5
µmol/L of each primer, and 1 µL cDNA in adjusted dilution. PCR was
performed in a thermal cycler with the following program sets: initial
denaturing for 3 min/94 C, one cycle: denaturing 30 sec/94 C, annealing
30 sec/primer specific, and elongation 30 sec/72 C, final elongation
for 7 min. Primer sequences, primer specific PCR conditions, and number
of cycles were listed in Table 1
. Peripheral blood
lymphocytes (PBL) were used as positive control and H2O as
negative control. Reaction products were added to a 1.5% agarose gel,
stained with ethidium bromide (0.5 µg/mL), and photographed under
ultraviolet light. A 100-bp ladder (GibcoBRL/Life Technologies
GmbH) was used as standard (600-bp band is 2–3 x
pronounced).
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The identity of PCR products was confirmed by restriction mapping and sequencing (data not shown). For sequencing, the ABI PRISM Dye Terminator Cycle Sequencing Ready Reaction Kit and AmpliTaq DNA Polymerase (Perkin Elmer, Weiterstadt, Germany) was used according to the manufacturer’s instructions.
Number of investigated adrenals and statistical analysis
Three adrenals were used for RT-PCR and measuring aldosterone release, six were for measuring cortisol and DHEA in the supernatants of cultured cells, and four were for immunohistochemistry. In every cell culture experiment, the mean was calculated from four cell wells/data point. Results and the corresponding SEM were calculated by using the mean values from the independent experiments. Because of the differences in basal secretion, data are expressed as percent means of basal level. Statistical significance was evaluated by ANOVA and Dunnett’s post test using the single data points from all experiments.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RT-PCR analysis of IL-6 (Fig. 1B) and IL-6R (Fig. 2D) revealed mRNA expression in complete adrenal tissue,
human adrenal cells in culture including all cell types, and human
adrenal cells in culture depleted of CD68-positive cells. The results
provide evidence for IL-6 and IL-6R mRNA expression in vivo
and in vitro in the presence and absence of macrophages. All
screened probes were tested to be void of DNA contamination before RT
(see Materials and Methods).
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Protein expression of IL-6 (Fig. 1A
) and IL-6R (Fig. 2C) were
detected in primary cultures of human adrenal cells depleted of
macrophages (CD68-positive cells) by immunohistochemical staining with
specific antibodies. Figure 2A shows the distribution of IL-6R within a
paraffin-fixed section of the adrenal gland (Fig. 2B, negative
control). Positive signals were predominantly given in the zona
reticularis and the inner zona fasciculata but also in single cells
within the zona glomerulosa and the medulla. The intensity of staining
and the staining patterns varied interindividually in the four
different adrenals investigated.
Depletion of CD68-positive cells
Adrenal cells were immunostained against CD68 to control the
depletion of macrophages from primary cultures (Fig. 3).
Staining of macrophages was observed in cultures including all cell
types (Fig. 3A), but not in cultures depleted of CD68-positive cells
(Fig. 3B). This demonstrated the successful depletion and the absence
of macrophages in such cultures.
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The effects of IL-6 and ACTH on steroidogenesis were
investigated with human adrenal cell cultures depleted of macrophages
(CD68-positive cells). IL-6 at a concentration of 10-8
mol/L had a time-dependent effect on hormone secretion in
vitro (Fig. 4). The amount of steroids in the
supernatants was weak within the first 12 h, reaching its maximum
after 24 h of incubation. This indicates that IL-6 is a long-term
stimulator of steroidogenesis with no acute effects. The stimulation of
hormone production by IL-6 in the range of 10-8
mol/L-10-12 mol/L was dose-dependent (Fig. 4). Hormone
releases \ SEM after 24 h of incubation with
IL-6 at a concentration of 10-8 mol/L were: aldosterone
172 \ 28% (n = 3, P < 0.01), cortisol
177 \ 27% (n = 6, P < 0.01), and DHEA
153 \ 20% (n = 6, P < 0.01). For a
vitality control, human adrenal cells in culture were incubated with
ACTH at a physiological concentration of 10-10 mol/L for
24 h. This led to the following hormone secretions
\ SEM: aldosterone 320 \ 76%, cortisol 194
\ 19%, and DHEA 167 \ 14%.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The presence of IL-6 in the rat adrenal gland has been well
established. IL-6 release by rat adrenal zona glomerulosa cells can be
stimulated by several agents such as IL-1, IL-1ß, angiotensin II,
and ACTH (19, 20, 21). Later investigations revealed that IL-6 mRNA
expression occurs in the adrenal cortex and medulla of rats (25). In a
former study, we were able to demonstrate that in humans, adrenal
derived IL-6 is expressed by steroid-producing cells and macrophages
but not by chromaffin cells (22).
We present here the first data revealing the expression of the IL-6R in the human adrenal gland. The IL-6R was detected at the mRNA level in both complete tissue and complete cultures, including all cell types and those depleted of macrophages. Immunohistochemical staining provided evidence that the IL-6R is distributed all over the entire adrenal gland with a predominant expression in the zona reticularis and the inner zona fasciculata. Similar data were reported from animal experiments, in which IL-6R mRNA was detected in the cortex and the medulla of rat adrenals by in situ hybridization (25).
IL-6 exerts its activity by binding to a receptor complex consisting of two subunits, an 80-kDa IL-6-binding protein (IL-6R) and a 130-kDa signal-transducing protein (gp130). IL-6R binds IL-6 with low affinity but cannot signal, whereas gp130 cannot bind IL-6. The IL-6/IL-6R molecule binds gp130 by noncovalent association, together forming the high-affinity IL-6R complex. The antibody used in this study detects the membrane-bound IL-6R subunit and its soluble form (26). Because the IL-6R can be demonstrated on human adrenocortical cells, systemic, as well as local, IL-6 may act directly on the steroid production via this receptor.
IL-6 is known to activate the HPA axis by stimulation of the AVP neuron (27), the CRH neuron (7), the median eminence (28), anterior pituitary cells (29, 30), and adrenal cells in rats (8). There is increasing evidence supporting the concept of an extrapituitary regulation of the adrenal cortex. Original findings have shown that diurnal variations in adrenal steroidogenesis do not seem to be directly related to plasma ACTH concentrations (31, 32, 33). It has been reported that, in cases of patients with severe trauma such as burns or bone fractures, the plasma level of ACTH decreases after several days, while cortisol is still present in high concentrations (34, 35). Two recent clinical studies have investigated the effects of IL-6 on patients with metastatic carcinomas. In those patients, plasma concentrations of ACTH and cortisol reached their maximum between 1–4 h after injection. After chronic treatment with IL-6, the ACTH release measured on day 7 or day 21, respectively, attenuated while the cortisol level could still be stimulated by IL-6 (16, 17). Glucocorticoids are able to inhibit cytokine-induced ACTH secretion by acting at the hypothalamic level (36). Therefore, the lack of ACTH after chronic administration of IL-6 may be either the result of inhibiting cortisol feedback. The data may also suggest a direct chronic effect of IL-6 on the human adrenal in vivo.
Within the adrenal, there is a close cellular interaction of tissue macrophages with cortical cells (37). Thus, it is important to exclude a macrophage-mediated effect of IL-6 on adrenocortical cells. The analysis of cultures depleted of CD-68 positive cells provides evidence for a stimulation of human steroidogenesis by IL-6 in vitro, which is not mediated by secretory products of macrophages. Because IL-6 is produced locally in the adrenal gland, concentrations of 10-8 mol/L can be considered physiological. The responses of aldosterone, cortisol, and DHEA after stimulation with IL-6 at 10-8 mol/L were weak within the first 12 h and clearly elevated after 24 h of incubation. The findings that IL-6 exerts its action in a nonacute manner are supported by data from animal experiments, in which incubation of rat adrenal cells in vitro with IL-6 had no effect after 3 h or 12 h but increased corticosterone secretion after 24 h (8). This lack in short-term stimulation of adrenal cells in vitro was also observed in our investigations of isolated perfused porcine adrenals (38, 39, 40). In this system, suited to measure prompt effects on steroidogenesis, IL-6 showed no effect on hormone release (unpublished data). Therefore, we postulate that the acute regulation of the HPA axis by IL-6 is mediated via the hypothalamus and/or the pituitary, whereas the long-term effect can be attributed to a stimulation of adrenal steroidogenesis via the IL-6R.
Given the fact that IL-6 is produced in the zona reticularis and zona fasciculata (22) and that IL-6R is expressed primarily in the same inner cortical zones as IL-6 but also with lower density in the zona glomerulosa, it is likely that cortisol and DHEA production is mediated by autocrine mechanisms, whereas aldosterone secretion seems to be caused in a more paracrine manner. Indirect effects of IL-6 on steroidogenesis via secretion products from the medulla can not be excluded, because the IL-6R occurs in this region.
The effect of IL-6 on DHEA secretion is of interest for two reasons. First, considering the fact that there is a discrepancy in ACTH levels in plasma and androgen release in the time of adrenarche and in several other clinical situations (41), IL-6 seems to be a local factor in the production of C19-steroids. Second, because IL-6 is expressed in the zona reticularis and stimulates DHEA secretion, it may be involved in local immune adrenal interactions.
The ability of IL-6 to stimulate mineralcorticoid, androgen, and
glucocorticoid production indicates IL-6 as a factor that coordinates
the responses of all adrenocortical zones. This is supported by the
fact that IL-6 release can be regulated by completely different
stimulators, for example: ACTH, angiotensin II, or immune derivates
such as IL-1/ß (20, 21). Therefore, IL-6 seems to play a role in
integrating the adrenal responses to the endocrine and immune
system.
In conclusion, we demonstrated that: 1) IL-6 and IL-6R are expressed in vitro by adrenal cells in the presence and absence of macrophages; 2) IL-6R expression is distributed in the entire adrenal gland but occurs predominantly in the zona reticularis and the inner zona fasciculata; 3) IL-6 leads to long-term stimulation of adrenal steroidogenesis in vitro. With these observations, combined with data from other studies, we postulate that the acute regulation of the HPA axis by IL-6 is mediated via the hypothalamus, whereas at the level of the adrenal gland, IL-6 exerts its action in a nonacute manner. Because IL-6 acts on steroidogenesis in all zones of the adrenal cortex and can be stimulated by several agents of different origin, IL-6 seems to participate in integrating adrenal responses to stimuli from the immune and endocrine system.
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Acknowledgments |
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Footnotes |
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Received January 10, 1997.
Revised April 4, 1997.
Accepted April 16, 1997.
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) and ACTH (#). The
left-hand graphs demonstrate the time-dependent hormone
responses of aldosterone (top), cortisol
(middle), and DHEA (bottom), after 6
h, 12 h, and 24 h of incubation with IL-6 10-8
mol/L. The graphs on the right show the dose dependency
of 24-h incubation with IL-6 in the range of 10-8
mol/L-10-12 mol/L. Incubation with ACTH 10-10
mol/L for 24 h was performed as a control for vitality of the
cells in culture. Data are expressed as percentage means ±
SEM of basal level. Statistical significance of IL-6
stimulation, compared with basal secretion, was evaluated by ANOVA and
Dunnett’s post test (*, P < 0.05; **,
P < 0.01; ***, P < 0.001).