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Original Studies |
Departments of Internal Medicine I (R.H.S., L.K., S.H., J.S., W.F., B.L.), Laboratory Medicine and Clinical Chemistry (G.R.), and Hematology and Oncology (M.K.), University Medical Center, D-93042 Regensburg, Germany
Address all correspondence and requests for reprints to: Dr. Rainer H. Straub, Laboratory of Neuroendocrinoimmunology, Department of Internal Medicine I, University Medical Center, D-93042 Regensburg, Germany. E-mail: rainer.straub{at}klinik.uni-regensburg.de
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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, or IL-2 with age in 120 female and male healthy subjects
(15–75 yr of age). Serum DHEA, DHEAS, and ASD levels significantly
decreased with age (all P < 0.001), whereas serum
IL-6 levels significantly increased with age (P <
0.001). DHEA/DHEAS and IL-6 (but not tumor necrosis factor- or IL-2)
were inversely correlated (all patients: r = -0.242/-0.312;
P = 0.010/0.001). In female and male subjects, DHEA
and ASD concentration dependently inhibited IL-6 production from
peripheral blood mononuclear cells (P = 0.001). The
concentration-response curve for DHEA was U shaped (maximal effective
concentration, 1–5 x 10-8 mol/L), which may be the
optimal range for immunomodulation. In summary, the data indicate a
functional link between DHEA or ASD and IL-6. It is concluded that the
increase in IL-6 production during the process of aging might be due to
diminished DHEA and ASD secretion. Immunosenescence may be directly
related to endocrinosenescence, which, in turn, may be a significant
cofactor for the manifestation of inflammatory and age-related
diseases. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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However, until now a link between low serum levels of DHEA or DHEAS in
systemic inflammatory diseases or during the process of aging and the
pathogenesis of the above-mentioned disorders was not demonstrated in
humans. DHEA has immunomodulatory properties, such as induction of
mitogen-stimulated IL-2 secretion from murine lymphocytes (31, 32), but this effect is inconsistent in other studies (33, 34). In
addition, mitogen-stimulated rodent lymphocyte or thymocyte
proliferation was markedly suppressed by DHEA (33, 35), but DHEA
attenuated dexamethasone-induced inhibition of rodent lymphocyte
proliferation (36). DHEA inhibits murine natural killer cell
differentiation (37) and endotoxin-induced tumor necrosis factor-
(TNF) production in mice in vivo (38) and in human
peripheral blood mononuclear cells (PBMC) in vitro (39). As
TNF is an important mediator of IL-6 secretion, it can be assumed
that DHEA inhibits IL-6 production, which was demonstrated in mice (14, 32).
Hence, the aim of the study was to investigate the correlation between
serum levels of DHEA, DHEAS, or the second major androgen precursor
4-androstene-3,17-dione (ASD) and serum concentrations of TNF, IL-6,
or IL-2 in well defined, normal male and female Caucasian subjects of
ages between 15–75 yr. Furthermore, we investigated the effects of
DHEA and ASD on stimulated IL-6, TNF, and IL-2 production of PBMC
and stimulated IL-6 production of isolated monocytes of normal male and
female subjects.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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One hundred and twenty Caucasian subjects were recruited, and health status was verified by means of a 33-item questionnaire. The questionnaire addressed known diseases in the past and at present, current symptoms of diseases, current medication, alcohol intake, smoking habits, family history, and operation history. Sixty were men, and 60 were women (10 female and 10 male subjects for each decade: 15–24, 25–34, 35–44, 45–54, 55–64, and 65–80 yr). The mean age of female subjects was 45.1 ± 2.2 yr, and that of the male subjects was 43.8 ± 2.1 yr. All subjects were informed about the purpose of the study and gave written consent to participate. Fertile female subjects were not taking contraceptives. Blood was drawn between 1000–1200 h, and serum was immediately stored at -80 C in adequate aliquots. For cell culture experiments, heparinized blood was drawn from 6 additional male and 6 additional female subjects (25–35 yr, first 10 days of the menstrual cycle) between 1600–1800 h.
Laboratory parameters in normal subjects
Immunometric enzyme immunoassay for the quantitative
determination of serum DHEA (Diagnostic Systems Laboratories, Webster,
TX), DHEAS (IBL, Hamburg, Germany), serum IL-2 (Quantikine, R&D
Systems, Minneapolis, MN; sensitivity, 7 pg/mL), serum IL-6 (high
sensitivity Quantikine, R&D Systems; sensitivity, 0.1 pg/mL), and serum
TNF (high sensitivity Quantikine, R&D Systems; sensitivity, 0.2
pg/mL) were used. ASD was measured by radioimmunometric assay (DPC
Biermann, Bad Nauheim, Germany).
Isolation of PBMC and culture
PBMC were isolated from heparinized whole blood by Ficoll-Paque (Pharmacia Biotech, Freiburg, Germany) gradient centrifugation (840 x g, 20 min, 20 C). The interphase containing PBMC was collected and washed twice (440 x g, 5 min, 18 C) in RPMI 1640 (Sigma, Munich, Germany). PBMC were incubated in RPMI 1640 supplemented with 10% heat-inactivated FCS, 100 IU/mL penicillin, and 100 µg/mL streptomycin (all additions from Sigma, Munich, Germany) at about 106 cells/mL overnight and washed again on the next morning (440 x g, 5 min, 18 C). Then, PBMC were seeded at 105 cells/mL into 24-well (1-mL) microtiter plates (Costar, Bodenheim, Germany) in RPMI 1640 with 10% heat-inactivated FCS, 100 IU/mL penicillin, and 100 µg/mL streptomycin and then stimulated with DHEA or ASD (stimulation see below). For superfusion experiments, PBMC were transferred to minisuperfusion chambers and treated as detailed below.
Isolation of monocytes
Monocytes were isolated from PBMC by countercurrent elutriation (J6 M-E centrifuge, Beckman, Munich, Germany) using a large volume chamber (50 mL), a JE-5 rotor at 2500 rpm, and a flow rate of 110 mL/min in Hanks’ Balanced Salt Solution supplemented with 2% human albumin. Elutriated monocytes were more than 90% pure, as determined by morphology and antigenic phenotyping. Purified monocytes were cultured on Teflon foils (Biofolie 25, Heraeus, Hanau, Germany) at a cell density of 106 cells/mL in RPMI 1640 supplemented with 5% pooled human AB group serum for 12 h. Thereafter, 8 x 105 monocytes were placed into microsuperfusion chambers and superfused for 8 h (for superfusion experiments, see below).
Drugs, stimulation, and production of supernatants in cell culture experiments
For experiments to study IL-6 or TNF production after 12
h of incubation, PBMC were stimulated with 1 ng/mL lipopolysaccharide
(Salmonella typhimurium, Sigma). For experiments to study
IL-2 production, anti-CD3 was used as a T cell stimulator (HIT3a,
PharMingen, Hamburg, Germany; also, anti-CD3 Dynabeads antibody, Dynal,
Hamburg, Germany). At the same time, DHEA or ASD was added to final
concentrations of 1 x 10-6, 5 x
10-7, 1 x 10-7, 5 x
10-8, 1 x 10-8, 5 x
10-9, or 1 x 10-9 mol/L. DHEA and ASD
were dissolved in dimethylsulfoxide (DMSO; Serva, Heidelberg, Germany)
and diluted to the final concentrations in culture medium at the day of
the experiment. RU 30486 was provided by Roussel UCLAF (Romainville,
France). After 24 h, supernatants were harvested for measurement
of IL-6, TNF, and IL-2 and stored at -20 C until assayed.
Cell superfusion experiments
Cell superfusion experiments were performed to minimize autocrine or paracrine feedback mechanisms in the intercellular space. After cell isolation and incubation for 12 h (see above), PBMC or monocytes were placed in minisuperfusion chambers under sterile conditions. The minisuperfusion chambers consisted of two 0.22-µm sterile filters (Minisart, Sartorius, Gottingen, Germany), which were put together after loading 8 x 105 PBMC or monocytes between the filters. The chambers were superfused with RPMI 1640 supplemented with 10% heat-inactivated FCS, 100 IU/mL penicillin, and 100 µg/mL streptomycin. Superfusion was performed for 8 h at a temperature of 37 C and a flow rate of 33 µL/min (12 chambers in parallel; Ismatec pump, Wertheim-Mondfeld, Germany). During the first 4 h of the superfusion period, all chambers were superfused with culture medium without any added drug. Between 225–240 min, superfusate was collected to determine the IL-6 level at 4 h [IL-64 h; picograms per mL; enzyme-linked immunosorbent assay (ELISA) technique, see below]. During the second part of the superfusion period (4–8 h), DHEA was applied to modulate IL-6 secretion. Between 465–480 min, superfusate was collected to determine IL-68 h. As spontaneous IL-6 secretion at 4 and 8 h correlated closely, IL-64 h was used to standardize the IL-6-secreting capacity of the superfused cells. The dimensionless ratio [100 x (IL-68 h/IL-64 h)] was used to standardize the IL-6 secretion of each chamber at 8 h. This standardization technique was necessary because IL-6 production in different chambers, despite similar cell numbers, varied significantly.
Detection of cytokines in culture supernatants and superfusate
Human IL-6, TNF, and IL-2 were quantified by immunometric
enzyme immunoassay (Endogen, Boston, MA). Using these ELISAs, the
sensitivities for IL-6, TNF, and IL-2 determinations were less than
1, less than 5, and 7 pg/mL, respectively. In our hands, intra- and
interassay coefficients of variation were below 10%.
Presentation of the data and statistical analysis
All data are given as the mean ± SEM. Correlations between serum concentrations of hormones, cytokines, or age were demonstrated by linear regression lines, and significance was tested by Spearman rank correlation analysis (SPSS/PC for Windows version 7.5, SPSS, Chicago, IL). All incubations in cell culture experiments were performed at least in quadruplicate. In one superfusion experiment with DHEA, two different conditions were investigated: 1) six controls, and 2) six chambers with the indicated concentration of DHEA. In superfusion experiments, an average of one experiment varied from subject to subject. Hence, the effects are demonstrated as a percentage of the control (the control is 100%) of each subject. One-way ANOVA (SPSS/PC for Windows version 7.5) was used to compare the control vs. drug-induced effects, and P < 0.05 was the significance level.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, and
IL-2
The mean DHEAS serum concentration in male subjects was 5.9
± 0.39 µmol/L (DHEA, 16.8 ± 1.68 nmol/L), and that in female
subjects was 4.62 ± 0.41 µmol/L (DHEA, 16.2 ± 0.17
nmol/L; with respect to DHEAS, P = 0.028 for the
differences between male and female subjects). The mean ASD serum
concentration in male subjects was 2.50 ± 0.19 ng/mL (8.75
nmol/L), and that in female subjects was 2.29 ± 0.24 ng/mL (8.02
nmol/L; no significant difference between male and female subjects). In
male subjects, mean serum concentrations of IL-6 and TNF were
1.70 ± 0.16 and 2.07 ± 0.10 pg/mL, respectively, and in
female subjects, these levels were 1.70 ± 0.09 and 1.72 ±
0.07 pg/mL, respectively. The serum TNF concentration in female
subjects was significantly lower compared to that in male subjects
(P = 0.004). IL-2 was not measurable in the serum of
normal subjects.
Interrelation between age and hormones or age and cytokines
In both gender groups, serum DHEA levels (male:
rRank = -0.416; P = 0.002; female:
rRank = -0.609; P < 0.001), serum DHEAS
levels (male: rRank = -0.752; P < 0.001;
female: rRank = -0.569; P < 0.001), and
serum ASD levels (male: rRank = -0.437; P
= 0.001; female: rRank = -0.648; P <
0.001) were negatively correlated with age. Serum DHEA levels
correlated linearly with serum DHEAS levels [DHEAS (micromoles per L)
= 3.16 + 0.125 x DHEA (nanomoles per L); r = 0.492;
P < 0.001]. In contrast, the serum IL-6 concentration
was positively correlated with age in both gender groups (male:
rRank = 0.411; P = 0.001; female:
rRank = 0.480; P < 0.001; all subjects are
shown in Fig. 1
). However, serum TNF
levels correlated with age only in female subjects and not in male
subjects (female: rRank = 0.331; P = 0.009;
male: rRank = 0.106; P = 0.425).
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serum
levels
Serum levels of DHEAS (in both gender groups) and DHEA (only in
female subjects) were significantly negatively correlated with serum
IL-6 (Table 1). Furthermore, in females,
serum ASD levels were also negatively correlated with serum IL-6
concentrations (Table 1). DHEA, DHEAS, or ASD serum concentrations did
not correlate with TNF in male and female subjects. Figure 2 illustrates the interrelation of DHEAS
and IL-6 serum concentrations in all subjects (rRank =
-0.312; P < 0.001). Serum DHEA correlated negatively
with serum IL-6 in all subjects (rRank = -0.242;
P = 0.010). Healthy subjects with high DHEA or DHEAS
serum levels had low IL-6 serum levels and vice versa.
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Figure 3 demonstrates a
U-shaped modulation of IL-6 production by DHEA in male and female
subjects (similar effects in both gender groups only in about 70% of
the tested subjects). At serum concentrations of 5 x
10-9 to 5 x 10-8 mol/L, DHEA
significantly inhibited IL-6 secretion (Fig. 3). Under the same
conditions, ASD inhibited IL-6 secretion in concentrations of 1 x
10-9 mol/L and 5 x 10-9 mol/L (similar
effects in both gender groups only in about 70% of the tested
subjects; Table 2). DHEA and ASD did not
modulate endotoxin-stimulated TNF production or anti-CD3-stimulated
IL-2 production of PBMC (data not shown). In additional experiments
using PBMC, we found that ethanol, which is normally used to solubilize
DHEA, was able to significantly induce IL-2 production by PBMC at
concentrations of 0.1–0.0001 parts/1000. This effect was not observed
when DMSO was used as solvent (data not shown). Ethanol or DMSO did not
affect IL-6 and TNF measurements or IL-6 and TNF production by
PBMC.
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Superfusion experiments were conducted to reduce autocrine or
paracrine feedback mechanisms due to other secreted mediators. Under
these conditions, DHEA again significantly inhibited IL-6 production by
PBMC (Fig. 4, A and B) and monocytes
(Fig. 5). The concentration-response
curve was U shaped, with a maximal effective concentration of 5 x
10-8 mol/L (for PBMC and monocytes: P <
0.001). The DHEA-induced inhibition of IL-6 production by PBMC was not
changed by the progesterone/cortisol receptor blocker RU 30486 (Table 3). The sulfated derivative DHEAS also
had no effect on IL-6 secretion in concentrations ranging from 1
x 10-8 to 1 x 10-4 mol/L
(P > 0.2; data not shown).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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IL-6 is thought to be the most important cytokine in several
age-dependent diseases (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). This may be due to the increase in
serum IL-6 levels with age observed in animals (14, 40, 41) and humans
(42, 43). We were able to confirm the age-associated increase in serum
IL-6 levels in male and female subjects. In addition, serum TNF
concentrations increased with age, but only in female subjects. In
aging mice, the altered regulation of IL-6 production was corrected by
the administration of DHEA (14), and a linkage was proposed between the
age-dependent decrease in DHEA and the increase in serum IL-6
concentrations (14). In our cross-sectional approach in healthy human
subjects, serum DHEA (DHEAS in male and female subjects) concentrations
were significantly negatively correlated with IL-6 serum levels in
female subjects. Serum levels of ASD, another adrenal androgen
precursor, were inversely correlated with serum IL-6 concentrations in
female, but not male, subjects. This may depend on the different
processing of DHEA and ASD in male and female subjects. In males, these
hormones are predominantly metabolized to androgens, whereas in
females, these hormones are mainly metabolized to estrogens (reviewed
in Ref.44), which both may then exert different effects on IL-6
production by PBMC or monocytes. However, serum TNF and IL-2 levels
were not correlated with serum DHEA, DHEAS, or ASD concentrations,
indicating a direct effect of DHEA on IL-6 production. One can
speculate that the negative interrelation between DHEA or ASD and IL-6
only in female subjects may lead to a higher susceptibility to
age-associated diseases. This may be relevant in rheumatoid arthritis,
polymyalgia rheumatica, and osteoporosis, in which the female to male
preponderance is obvious.
In further experiments, we found an inhibiting effect of DHEA on
endotoxin-stimulated IL-6 production by PBMC and monocytes and also an
inhibiting effect of ASD on endotoxin-stimulated IL-6 production by
PBMC. DHEA inhibition of IL-6 was found at concentrations of 5 x
10-8 to 5 x 10-9 mol/L, which is the
serum concentration in our normal subjects (range, 1–44 nmol/L). The
inhibiting effect of DHEA was not found for TNF production, again
indicating a direct and specific effect of DHEA and ASD on IL-6
synthesis. Furthermore, anti-CD3-stimulated IL-2 secretion by PBMC was
not influenced by DHEA. Superfusion experiments using PBMC and
monocytes revealed the same inhibiting effect of DHEA on IL-6 secretion
in the same concentration range. In superfusion experiments, feedback
mechanisms due to accumulation of mediators are ruled out because
cellular products are immediately removed by the constant superfusate
flow. The suppression of IL-6 production was not due to the effects of
cortisol and/or progesterone because RU30486 was not able to attenuate
the inhibiting effect of DHEA.
These experiments demonstrate the narrow concentration range at which DHEA or ASD is able to inhibit IL-6 secretion. The U-shaped concentration-response curve is probably due to the presence of more than one cofactor in the regulation of IL-6 secretion by DHEA and indicates that hormonal DHEA metabolites, such as estrogens or androgens, could have additional stimulating and inhibiting effects. Hence, decreased DHEA serum concentrations during aging or inflammatory diseases will be paralleled by a significant increase in IL-6 production. In autoimmune diseases such as systemic lupus erythematosus, enhanced IL-6 concentrations may lead to increased autoantibody production (45). Thus, we conclude that the decrease in DHEA levels is a deleterious process, in particular during chronic inflammatory diseases. However, therapeutic correction of serum DHEA levels, which was proposed several times (23), needs careful observation and monitoring during the therapy, because substantially elevated DHEA may also have negative effects on IL-6 secretion and thus on inflammatory processes and disease outcome.
Received October 24, 1997.
Revised March 2, 1998.
Accepted March 3, 1998.
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