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Original Studies |
Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, Private Bag, 92109 Auckland, New Zealand
Address all correspondence and requests for reprints to: Dr. J. A. Keelan, Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, Private Bag, 92109 Auckland, New Zealand. E-mail: j.keelan{at}auckland.ac.nz
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(100 ng/mL), lipopolysaccharide (5 µg/mL), dexamethasone
(1 µmol/L), or an appropriate vehicle control (n = 3
wells/treatment) for 24 h. Media were harvested, and IL-10, IL-6,
and PGE2 concentrations were determined by immunoassay.
Basal choriodecidual production rates of IL-10 were significantly
decreased with labor (P < 0.001), whereas
PGE2 and IL-6 production rates increased. The production of
all three substances was increased by IL-1ß, tumor necrosis
factor-, and lipopolysaccharide, but inhibited by dexamethasone. In
contrast to PGE2 and IL-6, there was significantly
increased responsiveness of IL-10 production to inflammatory stimuli
after labor, but decreased responsiveness to the inhibitory effects of
dexamethasone. These data indicate that IL-10 could play a role in
modulating or promoting resolution of the inflammatory processes
associated with labor at term and with intrauterine
infection-associated preterm labor. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF), IL-6, and IL-8] and PGs, both basally and in
response to inflammatory stimuli and bacterial products (1, 2, 3, 4, 5, 6, 7).
Parturition, both at term and preterm, is associated with an increased
production of these proinflammatory mediators by gestational tissues,
whereas in the setting of intrauterine infection this response is
greatly amplified (3, 4, 8, 9).
In addition to proinflammatory cytokines, gestational tissues also
produce antiinflammatory cytokines, such as IL-10. Originally
identified as cytokine synthesis inhibitory factor based on its ability
to suppress cytokine synthesis by type 1 T helper cells, this 18-kDa
polypeptide is produced by T cells, B cells, and macrophages (10, 11, 12).
IL-10 is also produced by cells of human chorion, decidual, and
placental tissues (13, 14, 15, 16, 17, 18, 19) and has been measured in human amniotic
fluid during late gestation (20, 21, 22). In vitro production of
IL-10 by macrophages and monocytes is enhanced by proinflammatory
stimuli such as IL-1ß, TNF, and LPS, but is suppressed by
glucocorticoids (10, 23). IL-10 production by decidual cells in culture
has also been reported to be stimulated by IL-1ß and bacterial
products (13, 14, 15, 16).
Although stimulatory actions have occasionally been reported, IL-10
displays predominantly inhibitory effects on inflammatory reactions
(11). For example, the production of IL-1, IL-6, IL-8,
granulocyte-macrophage colony-stimulating factor, granulocyte
colony-stimulating factor, and TNF by monocytes and macrophages is
inhibited by IL-10 (11). With respect to the tissues of pregnancy,
cytokine and PG production by human chorion, decidual, and placental
cells in culture is also inhibited by IL-10 (24, 25, 26, 27, 28, 29, 30). Interestingly,
administration of IL-10 has been shown to prevent lipopolysaccharide
(LPS)-induced preterm delivery in mice (31).
As parturition has been likened to an inflammatory response with associated changes in the production of several proinflammatory mediators, it is probable that there are also labor-associated changes in the production of the antiinflammatory cytokine IL-10. Recently, Jones et al., using monolayer decidual cultures, reported that basal decidual IL-10 production rates did not change significantly with the onset of labor (16). However, the use of dispersed cell cultures to draw conclusions about changes in production rates of tissues during different physiological changes is questionable in the light of the manipulations associated with the preparation and maintenance of such cultures. In contrast to this, the production rates of the proinflammatory mediators IL-6 and PGE2 by choriodecidua and amnion are known to increase with the onset of labor, accompanied by increases in their concentrations in amniotic fluid (3, 4, 32, 33, 34, 35, 36).
It was the aim of this study to examine the characteristics of IL-10 production by choriodecidual tissues before and after the onset of labor using a tissue explant system. This system was chosen in preference to dispersed cell culture in an attempt to maintain tissue integrity and responses as much as possible, and hence closer approximate the situation in vivo. Furthermore, with the involvement of proinflammatory cytokines and PGs in the pathogenesis of infection-associated preterm labor and also possibly in the progression of normal term labor, this system enabled an assessment to be made of the labor-associated changes in the responsiveness of IL-10 production by gestational tissues to immunomodulatory agents.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Culture medium (DMEM-medium 199) was obtained from Irvine
Scientific (Santa Ana, CA). FCS was purchased from Life Technologies Ltd. (Auckland, New Zealand). Bovine 
-globulin
was purchased from Sigma Chemical Co. (St. Louis, MO).
Human IL-1ß was obtained from Immunex Corp. (Seattle,
WA). Human TNF was provided by Dr. John Fraser of the University of
Auckland. LPS and dexamethasone were obtained from Sigma Chemical Co. Recombinant human IL-6, anti-IL-6 antiserum, and human
recombinant IL-10 were obtained from R & D Laboratories
(Minneapolis, MN), and anti-IL-10 antisera were purchased from
PharMingen (San Diego, CA). Streptavidin-alkaline
phosphatase was obtained from Life Technologies, and
phosphatase substrate (p-nitrophenol phosphate) was obtained
from Sigma Chemical Co. Tritiated PGE2 for RIA
was purchased from Amersham (Aylesbury, UK), and nonradiolabeled
PGE2 was obtained from Cayman Chemicals (Ann Arbor, MI).
Enzyme-linked immunosorbent assay (ELISA) Easiwash 96-well plates were
obtained from Corning (Corning, NY), and all other disposable tissue
culture plasticware was purchased from Nunc (Copenhagen, Denmark).
Explant culture
Human term placentas were obtained at National Women’s Hospital
(Auckland, New Zealand) from women at term who gave informed consent,
either by elective cesarean section before the onset of labor (term,
not in labor) or after uncomplicated spontaneous vaginal delivery
(term, spontaneous labor). After removal of the amnion, identified as
the inner avascular membrane, the contiguous choriodecidua membranes
were washed in DMEM-medium 199. Tissue disks (6 mm) were excised using
a sterile cork borer, transferred to six-well culture plates (six disks
per well, three wells per treatment), and equilibrated for 24 h in
DMEM-medium 199 medium supplemented with 10% FCS and antibiotics (37)
at 37 C in a humidified atmosphere of 5% CO2-95% air.
Each of the six disks in a single well were cut from random areas of
the membranes to minimize the effects of any regional differences in
cytokine production within these tissues. After equilibration, media
were replaced with serum-free media containing 0.1% bovine
-globulin and antibiotics, and the following treatments or
appropriate vehicle controls were added: IL-1ß (10 ng/mL), TNF
(100 ng/mL), LPS (5 µg/mL), and dexamethasone (1 µmol/L; in ethanol
vehicle). These doses were chosen as maximal on the basis of
experiments in monolayer cultures. Three replicate wells per test
treatment were used. After 24 h the incubation was terminated, and
the media were stored at 4 C before immunoassay. Production rates were
normalized to the wet weight of tissue in each well.
Cytokine immunoassays
IL-10 and IL-6 were measured by ELISA. The ELISA for IL-6 was performed as described previously (37). The assay had a sensitivity of about 20 pg/mL and an intraassay precision of 5.5%. Interassay precision was 16.1%.
The IL-10 ELISA used monoclonal antihuman IL-10 as capture antibody and prebiotinylated rat antihuman IL-10 as secondary antibody. The signal was quantitated using streptavidin-alkaline phosphatase with p-nitrophenol phosphate. The standard curve for the IL-10 assay ranged from 0–2500 pg/mL. The assay had a sensitivity of about 15 pg/mL and an intraassay precision of 2.6%. Interassay precision was 11.2%.
PGE2 immunoassay
Media were assayed for PGE2 by direct RIA, similar
to that described previously (38) except that the antiserum used was
raised in-house in rabbits against PGE2-BSA and
PGE2-thyroglobulin conjugates. Medium samples or standards
prepared in medium (100 µL) were incubated overnight with
[3H]PGE2 tracer (
5000 cpm/tube) and
antisera (sufficient to give 25% maximal binding) at 4 C. Unbound
radiolabel was removed with cold dextran-coated charcoal, and the
radioactivity in the supernatant (bound fraction) was determined in a
scintillation counter. Curve fitting and data extrapolation were
performed using Ultraterm II software (Wallac Oy, Turku,
Finland). No significant cross-reaction (<0.02%) of the
antiserum was detected with the following eicosanoids:
PGF2, 6-keto-PGF1, PGA2,
thromboxane B2, 5-hydroxyeicosatetraenoic acid (HETE),
12-HETE, 15-HETE, leukotriene B4, leukotriene
C4, and arachidonic acid. None of the cytokines used in
this study cross-reacted with the antiserum. The assay sensitivity was
approximately 5 pg/mL, and the intraassay precision was 5.6%.
Interassay precision was 17.8%.
Representation of data and statistics
Prostanoid and cytokine production rates are expressed as either picograms per mg wet wt of tissue/24 h (median) or as a percentage of the control values (mean ± SEM). Values were derived from pooled data from experiments performed on triplicate samples from six to eight separate placentae. Significant differences between basal production rates before and after labor onset were determined by the Mann-Whitney U test for nonparametric data, whereas the significance of responsiveness to treatments, expressed as a percentage of the control values, was determined by ANOVA followed by Dunnett’s test. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Choriodecidual membrane explants produced detectable quantities of
IL-10, IL-6, and PGE2, as shown in Fig. 1
. IL-10 production rates were
significantly lower after labor onset compared to those before labor
(median, 0.21 vs. 0.82 pg/mg tissue/24 h; P
< 0.001). In contrast to this, PGE2 production was
significantly higher during labor than before labor onset (median, 26.9
vs. 9.0 pg/mg tissue/24 h; P = 0.026). IL-6
production after labor onset was also slightly higher than that before
labor (median, 963.4 ± vs. 786.3 pg/mg tissue/24 h),
although this difference was not statistically significant.
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Concentration-dependent effects of IL-1ß, TNF, and LPS on
IL-10 production were determined in tissues taken before and after
labor onset. These data are shown in Fig. 2, A–C, expressed as a percentage of the
control value. Before labor, the maximum response to treatment with
IL-1ß (10 ng/mL) was approximately 5-fold greater than the control
response (4.44 ± 1.12 pg/mg tissue/24 h) as shown in Fig. 2A.
Interestingly, this increase relative to the control value was
significantly greater after labor onset, reaching up to 30-fold higher
than control production rates. However, due to the labor-associated
decrease in basal IL-10 production, the increased response to IL-1ß
resulted in mean IL-10 production rates (3.68 ± 0.58 pg/mg
tissue/24 h) that were not significantly different from those produced
by membranes taken before labor onset and treated with IL-1ß.
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(100 ng/mL), with production
increasing approximately 7-fold over control production before labor,
but nearly 12-fold after labor onset (Fig. 2B
). However, despite this
large increase relative to control production, the mean absolute IL-10
production rates in response to TNF after labor onset remained
significantly below those before labor (1.97 ± 0.25
vs. 3.76 ± 0.37 pg/mg tissue/24 h).
Following the same trend, there was a significant labor-associated
increase in responsiveness of IL-10 production to treatment with LPS (5
µg/mL) as shown in Fig. 2C. Upon treatment with LPS, IL-10 production
from tissues obtained before labor was approximately 10-fold higher
than the control production rate, whereas after labor onset this
increase was nearly 80-fold. Unlike the responses to IL-1ß and
TNF, the LPS-stimulated IL-10 production rates increased from a mean
of 7.00 ± 0.73 pg/mg tissue/24 h before labor to 11.55 ±
1.32 pg/mg tissue/24 h after labor.
Regulation of IL-6 production by inflammatory mediators before and after labor onset
Concentration-dependent effects of IL-1ß, TNF, and LPS on
IL-6 production were also determined in tissues taken before and after
labor. All three stimuli increased IL-6 production by approximately 2-
to 3-fold, as shown in Fig. 3, A–C.
However, in contrast to the situation observed with IL-10 production,
there were no significant differences between the responsiveness of
tissues obtained before and after labor with respect to IL-6
production.
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The effects of IL-1ß, TNF, and LPS on PGE2
production rates by choriodecidual explants were qualitatively similar
to those on IL-6 production (Fig. 4, A–C). The three stimuli induced significant 2- to 4-fold increases in
PGE2 production rates both before and after labor onset.
Again, there were no significant differences between the responsiveness
of the tissues taken before and after labor. In addition, mean
PGE2 production rates in response to treatment reached
similar levels before and after labor onset.
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Treatment of tissues obtained before labor onset with the
glucocorticoid agonist dexamethasone resulted in significant inhibition
of IL-10 production by approximately 60%, as shown in Fig. 2D.
Remarkably, however, in tissues taken after labor onset, this
inhibition was no longer apparent. In contrast, dexamethasone
significantly inhibited PGE2 production by approximately
25–30% in tissues obtained both before and after labor onset (Fig. 4D). Interestingly, although IL-6 production from tissues obtained
before labor was not affected by dexamethasone, IL-6 production from
tissues obtained after labor was significantly inhibited by 70%.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This labor-associated decrease in IL-10 contrasts with an earlier report by Jones et al., who found no significant changes in IL-10 production by decidual cells with labor onset, although a mean decrease of approximately 25% was observed in this study (16). The differences are probably due to the use of dispersed cells in culture as opposed to the tissue explant model used in the present study. It has recently been documented that cytokine output by dispersed cells differs from that by tissue explants (39), probably in response to insults occurring during the isolation procedure. In addition, changes in cell phenotype associated with monolayer culture may confound intrinsic differences between pre- and postlabor tissues. Furthermore, the chorion cells in the choriodecidual explants may have some influence on the results presented here that was absent in the decidual cell cultures used by Jones et al. (16).
In contrast to the significant decline in the production rate of IL-10 with labor, production rates of PGE2 and IL-6 increased, although with IL-6 this did not reach significance. This finding contrasts with that of Laham et al. (34), who reported a significant 3-fold increase in IL-6 release from choriodecidual explants obtained after labor onset. The experiments performed by Laham et al., however, were conducted after only a 1-h wash-out period. As membranes are exposed to vaginal flora during normal delivery, a transient increase in cytokine production might explain these differences. We performed our experiments after a 24-h wash-out period to allow recovery of the tissues from the effects of exposure to stimuli associated with delivery. Nevertheless, the labor-associated increase in PGE2 production was more profound and statistically significant.
The reduction in IL-10 production we observed with labor onset has several implications. Although it is not yet clear whether this change occurs before or as a sequelae to labor onset, it is plausible to suggest that the decrease may be involved in the concurrent increase in the production of inflammatory substances (IL-6 and PGE2). IL-10 is well known for its ability to inhibit the production of inflammatory cytokines by T cells, monocytes, and macrophages (12). Furthermore, IL-10 has been shown to inhibit IL-1ß- and LPS-stimulated production of IL-6 and PGE2 by decidual and chorion cells (24, 25, 26, 27). A waning of the antiinflammatory influence of a cytokine such as IL-10 could lead to an uprising of inflammatory processes, as evidenced by increasing production of proinflammatory mediators, and therefore might be involved in the initiation or maintenance of parturition.
Previous studies in a variety of cell types have shown that IL-10 is
positively regulated by the inflammatory mediators upon which it exerts
its antiinflammatory effects (10). We also found that IL-10 production
by choriodecidual explants was increased by IL-1ß, TNF, and LPS,
in accordance with prior findings that IL-1ß and bacterial products
enhance IL-10 production by chorion and decidual tissues (13, 14, 15, 16).
TNF has also previously been shown to induce IL-10 production in a
variety of cell systems, including peripheral blood mononuclear cells
(40, 41) and human microglial cells (42), and during experimental
endotoxemia in nonhuman primates (43), although its effects on
choriodecidual IL-10 production have not been reported. The fact that
the antiinflammatory cytokine IL-10 is positively regulated by these
proinflammatory mediators indicates the presence of a negative feedback
loop regulating the inflammatory process within gestational tissues.
Under normal circumstances, this loop may function to contain
inflammatory events within certain "safe" limits or to promote
resolution of inflammatory processes after inciting stimuli have been
removed.
Despite an apparent marked reduction in IL-10 production rates after
labor, a heightened responsiveness to these inflammatory stimuli after
labor onset was observed, whereas there was little or no change in the
responsiveness of production of IL-6 and PGE2. Although
this increase in responsiveness might be explained by an influx of the
inflammatory cells that produce IL-10 or a labor-associated increase in
the receptors for IL-1ß, TNF, and LPS, the failure to observe a
similar increase in the responsiveness of IL-6 and PGE2
production renders these explanations unlikely. Our results would be
consistent with a selective alteration in the control of IL-10
transcription, translation, or secretion with labor. There has been
some evidence presented that IL-10 production is regulated at the
posttranslational level. For example, in monocytes, TNF and cAMP
both individually induced IL-10 messenger ribonucleic acid (mRNA)
expression, but an associated increase in protein production was only
observed when these two substances were added together (40, 44). In
addition, although TNF has been shown to be a potent stimulator of
microglial IL-10 production, this effect was not reflected in the
expression of IL-10 mRNA (42). More specifically, Trautman et
al. (13) have measured the levels of mRNA expression by
gestational membranes in response to IL-1ß and detected no changes
with labor onset. These findings support a role for posttranslational
modification in the labor-associated changes in the responsiveness of
IL-10 production to inflammatory stimuli observed here.
Unexpectedly, a labor-associated reduction in the inhibition of IL-10 production by glucocorticoids was observed. This apparent decrease in the effectiveness of glucocorticoids was not evident with IL-6 or PGE2 production, and its significance and mechanism remain unclear.
Overall, these data suggest that within human choriodecidua there is a specific labor-related refinement of IL-10 production at a time when there is a marked increase in the production of proinflammatory mediators. However, despite this, the inflammatory process continues, as evidenced by the increased basal production of the proinflammatory mediators with labor. There may exist a situation in which the decreased basal production of IL-10 allows inflammatory processes to proceed, whereas the increased responsiveness of IL-10 production to inflammatory stimuli coupled with the decreased responsiveness to the inhibitory effects of dexamethasone may represent a protective mechanism to ensure that these processes do not escalate to a point that becomes hazardous to the wellbeing of the mother or fetus.
Received June 18, 1998.
Revised September 1, 1998.
Accepted September 2, 1998.
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References |
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