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Original Studies |
Decreases, and Interleukin-10 Increases, the Sensitivity of Human Monocytes to Dexamethasone: Potential Regulation of the Glucocorticoid Receptor
Laboratory of Radio-Immunology and Neuroendocrine-Immunology (D.F., H.M., M.-T.H., W.D., V.G.), Institute of Pathology, Department of Gastroenterology CHU (D.F., E.L., J.B.), University of Liège, Belgium; and Developmental Endocrinology Branch (D.F., G.P.C.), NICHD, National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Denis Franchimont, M.D., Developmental Endocrinology Branch, NICHD, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, Bethesda, Maryland 20892.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF, a proinflammatory cytokine) and
interleukin (IL)-10 (an anti-inflammatory cytokine) to differentially
regulate the sensitivity of human monocytes/macrophages to
glucocorticoids. To accomplish this, we first analyzed the pattern of
TNF and IL-10 inhibition by dexamethasone in LPS-stimulated
whole-blood cell cultures. Second, we studied the modulation of the
sensitivity of these cells to dexamethasone by preincubation with
TNF or IL-10 and measurement of LPS-stimulated IL-6 secretion. In
addition, we evaluated the effect of dexamethasone on
phorbol-myristate-acetate-stimulated IL-1 receptor antagonist secretion
by the human monocytic cell line U937. Finally, we investigated whether
the modulation of corticosensitivity in TNF- and IL-10-pretreated
U937 cells was related to a change of the glucocorticoid receptor
concentration and affinity. Dexamethasone had different effects on
LPS-induced TNF and IL-10 secretion; whereas it suppressed TNF in
a dose-dependent fashion, its effect on IL-10 secretion was biphasic,
producing stimulation at lower, and inhibition at higher doses. The
concentration of LPS employed influenced the effect of dexamethasone on
IL-10 secretion (P < 0.001). Pretreatment with
TNF diminished, and with IL-10 improved, the ability of
dexamethasone to suppress IL-6 secretion in whole-blood cell cultures
(P < 0.01 for both) and to enhance IL-1 receptor
antagonist secretion by U937 cells (P < 0.05 for
both). TNF decreased (P < 0.001), while IL-10
increased (P < 0.001), the concentration of
dexamethasone binding sites in these cells, with no discernible effect
on their binding affinity. We conclude that glucocorticoids
differentially modulate TNF and IL-10 secretion by human monocytes
in a LPS dose-dependent fashion and that the sensitivity of these cells
to glucocorticoids is altered by TNF or IL-10 pretreatment; TNF
blocks their effects, whereas IL-10 acts synergistically with
glucocorticoids. This is accompanied by opposite glucocorticoid
receptor changes, respectively opposing and favoring glucocorticoid
actions. This study suggests that the pattern of pro-/antiinflammatory
cytokine secretion may alter the response of patients to glucocorticoid
therapy. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B (2, 3). The glucocorticoid resistance observed in inflammatory
diseases may be induced by the inflammatory process and/or be
genetically or constitutionally determined (4, 5). Cytokines, the main
endocrine, paracrine, and autocrine factors of the immune/inflammatory
response, have been reported to modulate the sensitivity of immune
cells to glucocorticoids (6, 7, 8, 9, 10).
Tumor necrosis factor (TNF, a proinflammatory cytokine) and
interleukin (IL)-10 (a T helper 2-type and antiinflammatory cytokine)
are secreted by activated macrophages and play opposite roles in both
innate and specific immune responses (11, 12, 13, 14, 15). Monocytes/macrophages,
as antigen-presenting cells, are of major importance in the
decision for differentiation of naive Th0 CD4+ cells toward Th1-
directed cellular immunity or Th2-directed humoral immunity.
Glucocorticoids promote a shift from Th1-type and proinflammatory to
Th2-type and antiinflammatory cytokine secretory pattern. This is
because the former is strongly inhibited by glucocorticoids, whereas
the latter is not or positively affected (16, 17, 18, 19). In this study, we
hypothesized that cytokines could differentially regulate the
sensitivity of normal human monocytes/macrophages from healthy subjects
to glucocorticoids in a fashion that could be influenced by the balance
of proinflammatory/antiinflammatory cytokine secretion. To test this
hypothesis, we first analyzed the pattern of dexamethasone-mediated
inhibition of TNF and IL-10 secretion by LPS-stimulated
whole-blood cell cultures; and, second, we studied the modulation of
the dexamethasone responses of human LPS-stimulated whole-blood cell
cultures or of a phorbol-ester-stimulated human monocytic cell line by
preincubation with TNF or IL-10.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Ten healthy male volunteers (age range, 25–45 yr old) served as
blood donors. The blood was treated as previously described (20). The
whole-blood cell cultures were treated as follows: 1) LPS (endotoxin
from Salmonella enteritidis, Sigma Chemical Co., St.
Louis, MO) was added at a final concentration of either 100 pg/mL, 1
ng/mL, or 10 ng/mL. In whole-blood cell cultures, the mononuclear cells
activated by LPS are mainly monocytes/macrophages. Dexamethasone was
added at a final concentration ranging from
10-9–10-6 mol/L in separate wells containing
LPS. Plates were incubated at 37 C in 5% CO2. The
incubation periods for LPS-stimulated whole blood were 24 h and
48 h. 2) LPS was added at a final concentration of 1 ng/mL.
Twenty-four hours and 48 h before LPS stimulation, the whole-blood
cell culture was incubated alone or either in the presence of TNF (1
ng/mL) or IL-10 (50 pg/mL). Dexamethasone was added at a final
concentration of 10-8 mol/L in separate wells containing
LPS. Plates were incubated at 37 C in 5% CO2. The
incubation period for LPS-stimulated whole blood was 24 h. The
contents of the wells were then collected and centrifuged at 900
x g for 10 min. Supernatants were then recovered and stored
at -20 C before analysis.
Cell line cultures
Two types of clones (plus and minus) of the myeloid monocytic
cell line, U937 cells, were a generous gift from Priscilla Biswas and
Guido Poli (Ospedale San Raffaele, Immunopathogenesis Unit, Milano,
Italy). Cells were maintained in RPMI 1640 (BioWhittaker, Inc. Belgium) with 10% steroid-free heat-inactivated
FCS, 100 U/mL penicillin, 100 µg/mL streptomycin sulfate, and 2
mmol/L glutamine (BioWhittaker, Inc.) at 37 C in 5%
CO2. The FCS was treated with 1% dextran-coated charcoal
to remove endogenous sex steroids and glucocorticoids. Cells were
counted and cultured in medium alone or in the presence of TNF (10
ng/mL) or IL-10 (250 pg/mL) (R&D Systems, UK) for 24 h and
48 h. The cells were then treated as follows: 1) The cells were
removed, counted, and prepared for whole-cell dexamethasone binding
assay; 2) The cells were stimulated with phorbol-myristate-acetate
(PMA), at a final concentration of 10 ng/mL, for 24 h, in medium
alone or in the presence of dexamethasone (10-8 and
10-6 mol/L). The supernatants were then recovered and
stored at -20 C before further analyses.
Whole-cell dexamethasone binding assay
A whole-cell dexamethasone binding assay was used to quantify GR
number and to determine GR affinity in untreated and TNF- or
IL-10-treated cells. Cells were incubated, in a waterbath at 37 C, for
2 h, at a final concentration of 107 cells/mL in RPMI
1640 buffer solution containing 0.5% BSA (Sigma,
Belgium) supplemented with seven different concentrations of
[3H]-dexamethasone (Amersham International,
Arlington Heights, IL) ranging from 2.5–50 nmol/L (SA, 82 Ci/mmol), in
the presence or in the absence of 1000-fold excess of unlabeled
dexamethasone (Sigma). After incubation, cells were
cooled, centrifuged, and washed before the supernatant was carefully
aspired. Cells were resuspended in an equal volume of scintillation
cocktail for counting. Dissociation constant (Kd) values
and receptor binding capacity were determined on the basis of
saturation curves using nonlinear regression computed with the Prism
2.0 program (GraphPad Software, Inc.). Statistical
analyses were performed on the Scatchard analysis of the same
curves.
Immunoassays
Specific enzyme-linked immunosorbent assays were used
to measure human TNF, IL-10, and IL-6 (Biosource Technologies, Inc./Medgenix, Belgium) and IL-1 Ra (receptor antagonist)
(R&D Systems) and were performed according to the manufacturer’s
instructions. Absorbency was transformed to cytokine concentration
using a standard curve computed with Medgenix enzyme-linked
immunosorbent assay software.
Statistical analyses
The relative changes of cytokine production were computed for each dexamethasone dose. A logarithmic transformation was used for the percentage of response, to normalize the distribution. A generalized linear mixed model (SAS PROC MIXED) was used to analyze the dexamethasone general effect and the specific-dose effect on cytokine secretion. All results were considered to be significant at the 5% critical level (P < 0.05). Statistical analyses were carried out using the SAS software package (SAS Institute, Inc., Cary, NC). Nonparametric (Mann Withney and Wilcoxon tests) and parametric tests (Student’s t and ANOVA tests) were also used for comparisons, as appropriate.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-10 secretion in
LPS-stimulated whole-blood cell cultures (Fig. 1
)
TNF and IL-10 secretion were significantly increased in
LPS-stimulated whole-blood cell cultures (P < 0.001).
Although both absolute and percent baseline values are shown, only the
statistical comparisons between cytokine levels expressed as mean
percent baseline are reported (Fig. 1, right panels). TNF
secretion was uniformly suppressed in a dose-dependent fashion by
dexamethasone (10-9–10-6 mol/L) after three
different concentrations of LPS (Fig. 1, middle and
right panels). Nevertheless, the dexamethasone-induced
inhibition of TNF at 10-8 and 10-7 mol/L
was less marked after 1 and 10 ng than after 0.1 ng LPS stimulation
(P < 0.001) (Fig. 1, right panels). In
contrast, the effect of dexamethasone on IL-10 secretion was biphasic,
characterized by stimulation at the lower doses employed and inhibition
at the higher doses (Fig. 1, left and right
panels). LPS dose effects on dexamethasone-induced changes in IL-10
secretion were observed; IL-10 was strongly suppressed by dexamethasone
(10-8–10-6 mol/L) after 0.1 ng LPS
stimulation, whereas its secretion was biphasic after 1 and 10 ng of
LPS stimulation (P < 0.001). After exposure to 1 and
10 ng LPS, there was no difference in IL-10 modulation by dexamethasone
at 10-9 and 10-8 mol/L; however, a
significant difference appeared at 10-7 and
10-6 mol/L glucocorticoid (P < 0.01 and
P < 0.05, respectively) (Fig. 1, right
panels). At each of the three concentrations of LPS employed, the
dexamethasone-induced modulation (10-9–10-6
mol/L) was significantly different between IL-10 and TNF
(P < 0.05–0.001). After 0.1 ng LPS, however, no
difference was observed in the dexamethasone-induced modulation of
IL-10 and TNF secretion at 10-7 and 10-6
mol/L glucocorticoid (Fig. 1, right panels). The results
were similar at both 24- and 48-h incubations (Fig. 1, right
panels).
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and IL-10 modulate dexamethasone-mediated IL-6 suppression
in whole-blood cell cultures (Fig. 2)
We used the same TNF and IL-10 concentrations that
were observed in LPS-stimulated whole-blood cell cultures (1 ng/mL and
50 pg/mL, respectively) (Fig. 1
) and investigated whether TNF or
IL-10 preincubation could change the sensitivity to dexamethasone
assessed by dexamethasone-mediated IL-6 inhibition in whole-blood cell
cultures from 10 healthy subjects. The whole-blood cell cultures
exposed to TNF or IL-10 did not produce IL-6. After LPS stimulation,
however, whole-blood cell cultures not exposed to either cytokine
secreted more IL-6 (399.8 ± 29.2 pg/mL) than when exposed to
TNF (155.7 ± 24.2 pg/mL, P < 0.01) or IL-10
(232.6 ± 44.8 pg/mL, P < 0.01). Preincubation
with TNF was associated with a lower IL-6 secretion than
preincubation with IL-10 (P < 0.01). A longer
pretreatment, up to 48 h before LPS stimulation, was associated
with poor IL-6 secretion and did not enable us to assess
corticosensitivity. The dexamethasone-mediated IL-6 inhibition was
stronger after preincubation with IL-10 (18.9 ± 1.5%,
P < 0.01) and weaker after preincubation with TNF
(58.5 ± 2.1%, P < 0.01) than with medium alone
(41.1 ± 1.83%).
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and IL-10 modulate dexamethasone-induced IL-1 Ra secretion
by a human monocytic cell line (Fig. 3)
We examined whether TNF and IL-10 preincubation could
change the sensitivity to dexamethasone assessed by
dexamethasone-induced IL-1 Ra secretion in the human monocytic cell
line U937. In the baseline condition, IL-1 Ra secretion was increased
after both TNF (16.4 ± 0.9 pg/mL, P < 0.01)
and IL-10 (10.1 ± 0.6 pg/mL, P < 0.01)
preincubation; no significant difference in the IL-1 Ra level was
observed after these two preincubations. After PMA stimulation,
however, dexamethasone-induced IL-1 Ra secretion at 10-6
mol/L was higher with IL-10 preincubation (55.7 ± 3.5 pg/mL,
P < 0.05) and weaker with TNF preincubation
(14.7 ± 1.7 pg/mL, P < 0.05) than with medium
alone (23.5 ± 3.1 pg/mL). No significant difference was observed
between the IL-1 Ra responses of plus and minus clones of U937
cells.
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decreases, and IL-10 increases, the GR concentration (but
not binding affinity) in a human monocytic cell line (Fig. 4)
To assess the effect of TNF and IL-10 on the GR number and
binding affinity, we used dexamethasone radioligand binding in the
human monocytic cell line U937. This was done to avoid the high
variability observed in studies of isolated peripheral blood
mononuclear cells. U937 cells were cultured, in the absence or presence
of TNF or IL-10, for up to 48 h; and dexamethasone binding was
assessed. No change in proliferation rate was observed between the
different preincubations (data not shown). Both TNF and IL-10 failed
to induce a significant modulation of the GR number at time periods
less than 48 h. However, 48-h exposure to TNF resulted in a
60% decrease of the GR number (4,834 ± 246 sites/cell
vs. 11,709 ± 544 sites/cell, P <
0.001) without any change of the binding affinity (11.4 ± 1.5
nmol/L vs. 16.1 ± 1.8 nmol/L), whereas exposure to
IL-10 resulted in a 50% increase of the GR numbers (17,734 ± 87
sites/cell vs. 11,709 ± 544 sites/cell,
P < 0.001), also without any change of the binding
affinity (21.5 ± 2.4 nmol/L vs. 16.1 ± 1.8
nmol/L). The results are summarized on Table 1.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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secretion was
always suppressed by dexamethasone in a classic sigmoidal fashion.
Thus, the degree of monocyte/macrophage activation modulates the effect
of dexamethasone on IL-10 secretion, whereas the direction of the
TNF response to glucocorticoids remains unchanged. cAMP-elevating
drugs increase IL-10 and decrease TNF secretion (24), and
cAMP-responsive elements have been described in both the IL-10 and
TNF promoters (25, 26). The GR interacts with cAMP-responsive
element-binding protein, and this interaction may play a role in the
differential modulation of IL-10 and TNF secretion by
glucocorticoids (27). IL-1Ra is a receptor-level natural antagonist of IL-1 that was isolated from monocytes and monocytic cell lines (28). Glucocorticoids inhibit IL-1 Ra secretion by LPS-stimulated human peripheral monocytes (29) but potentiate the IL-1ß secretory response of monocytic cells to PMA (30). The PMA-differentiated monocytic cell line U937 produces IL-1Ra (31). Here, we demonstrated that dexamethasone increased IL-1 Ra secretion by these cells, providing an additional explanation for an indirect antiinflammatory action for glucocorticoids.
Preincubation with TNF or IL-10 modulated the sensitivity to
dexamethasone in both normal leukocytes present in whole-blood cell
cultures and U937 cells. Both TNF and IL-10 inhibited IL-6 and
enhanced IL-1 Ra secretion in the absence of dexamethasone; however,
their effects were in opposite directions in the presence of
dexamethasone. Thus, whereas IL-6 was more inhibited by TNF than by
IL-10 at the baseline state, dexamethasone-mediated IL-6 inhibition was
less prominent after TNF incubation than after IL-10 incubation.
Similarly, whereas IL-1 Ra secretion was slightly more stimulated by
TNF than by IL-10 at the baseline state, in the presence of
dexamethasone, it was blocked by TNF and dramatically enhanced by
IL-10 preincubation.
IL-10 increased, and TNF decreased, the GR concentration of U937
cells without modifying its binding affinity for dexamethasone.
Previously, some cytokines (such as IFN
) were shown to increase
sensitivity of cells to glucocorticoids by increasing the receptor
concentration (6), whereas other cytokines (such as IL-2, IL-4, and
IL-13) decreased sensitivity by decreasing its binding affinity (7, 8).
MIF, the macrophage migration inhibitory factor, is regulated by
glucocorticoids like IL-10; however, unlike IL-10, it blocks
dexamethasone-mediated inhibition of cytokine production by
LPS-stimulated monocytes (10). Our study suggests that IL-10 may
enhance glucocorticoid action by increasing the GR concentration,
whereas TNF may exert the opposite effect by decreasing the GR
concentration. Changes in the receptor may be one of several mechanisms
for altering tissue sensitivity to glucocorticoids (3). Indeed, the
modulation of dexamethasone response by cytokines may also be related
to NF-B, which is involved in the transcription of many
proinflammatory cytokines, including IL-6, and is highly expressed in
inflamed tissues (5). Glucocorticoids and IL-10 inhibit NF-B
activation, whereas TNF activates NF-B (32, 33, 34). The opposite
effect on NF-B modulation exerted by TNF and IL-10 may also
provide an additional explanation for the opposite effects of these
cytokines on glucocorticoid sensitivity described here.
In Crohn’s disease, blocking TNF with humanized antibody (cA2) or
administering IL-10 were found to be useful adjunctive therapies (35, 36). Because TNF decreases, and IL-10 increases, sensitivity to
dexamethasone, this study provides evidence for another potential
beneficial indirect effect of these cytokine therapies. This also
suggests that the balance of TNF/IL-10 secretion during the course
of an inflammatory disease may determine changes in sensitivity to
glucocorticoids. Thus, a patient with a high or low TNF/IL-10 ratio
would, respectively, be less or more sensitive to endogenous and
exogenous glucocorticoids and more or less susceptible to develop
corticosteroid-resistant and -sensitive inflammatory disease.
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Footnotes |
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Received October 21, 1998.
Revised March 12, 1999.
Accepted April 30, 1999.
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