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, and Hormonal Changes during Late Pregnancy and Early Postpartum: Implications for Autoimmune Disease Activity during These Times
Arthritis and Rheumatism Branch (I.J.E., R.L.W., M.C., K.S.K.), National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pediatric and Reproductive Endocrinology Branch (I.J.E., A.A.L., S.F., G.P.C.), National Institute of Child Health and Human Development, Developmental Endocrinology Branch (V.K.B.), National Institute of Child Health and Human Development, and Laboratory of Experimental and Computational Biology (M.D.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Dr. Ilia J. Elenkov, Division of Rheumatology, Immunology, and Allergy, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, D.C. 20007-2197. E-mail: ije{at}gunet.georgetown.edu
Abstract
Clinical observations indicate that some autoimmune diseases, such
as rheumatoid arthritis and multiple sclerosis, frequently remit during
pregnancy but exacerbate, or have their onset, in the postpartum
period. The immune basis for these phenomena is poorly understood.
Recently, excessive production of IL-12 and TNF-
was causally linked
to rheumatoid arthritis and multiple sclerosis. We studied 18 women
with normal pregnancies in their third trimester and during the early
postpartum period. We report that during the third trimester pregnancy,
ex vivo monocytic IL-12 production was about 3-fold and
TNF- production was approximately 40% lower than postpartum values.
At the same time, urinary cortisol and norepinephrine excretion and
serum levels of 1,25-dihydroxyvitamin were 2- to 3-fold higher than
postpartum values. As shown previously, these hormones can directly
suppress IL-12 and TNF- production by monocytes/macrophages
in vitro. We suggest that a cortisol-, norepinephrine-,
and 1,25-dihydroxyvitamin-induced inhibition and subsequent rebound of
IL-12 and TNF- production may represent a major mechanism by which
pregnancy and postpartum alter the course of or susceptibility to
various autoimmune disorders.
IL-12, PRODUCED by antigen-presenting
cells, is a major inducer of T helper 1 (Th1) responses by stimulating
Th1 lymphocyte proliferation and differentiation and by inducing
interferon (IFN)-
production from natural killer and T cells
(1, 2). Antigen-presenting cell-derived IL-12 and TNF-,
in concert with Th1 cell-derived IFN-, stimulate the activity of T
cytotoxic and natural killer cells, and monocytes/macrophages,
i.e. the major components of cellular immunity. IL-12 and
TNF- are considered major proinflammatory cytokines because they
stimulate the synthesis of nitric oxide and other inflammatory
mediators that drive chronic delayed-type inflammatory responses
(2). On the other hand, the antiinflammatory cytokine
IL-10 produced by monocytes/macrophages and Th2 cells promotes humoral
immunity and inhibits monocyte/macrophage activation and the production
of proinflammatory cytokines (1). Excessive production of
IL-12 and TNF- and a deficit of IL-10 appears to play a key role in
the inflammatory activity and the tissue damage observed in
organ-specific autoimmune diseases, such as rheumatoid arthritis (RA)
and multiple sclerosis (MS) (3, 4, 5). Moreover, excessive
IL-12 production is the pivotal factor in the proliferation and
differentiation of pathogenic autoreactive Th1 effector cells in the
experimental models of these diseases (6).
Some autoimmune diseases, such as RA and MS, often remit during pregnancy, particularly in the third trimester, but have an exacerbation or their onset during the postpartum period (7, 8, 9, 10). The risk of developing new onset RA during pregnancy, compared with nonpregnancy, is decreased by about 70%. In contrast, the risk of developing RA is markedly increased in the postpartum period, particularly the first 3 months (odds ratio of 5.6 overall and 10.8 after first pregnancy) (10). Moreover, a substantial fraction (20–30%) of premenopausal onset RA develops within 1 yr of pregnancy (R. Wilder, unpublished observations). In women with multiple sclerosis, the rate of relapse declines during pregnancy, especially in the third trimester, increases during the first 3 months postpartum, and then returns to the prepregnancy rate (8). Although documented extensively, these observations remain poorly understood.
The third trimester of pregnancy and the early postpartum period are
also known to be associated with abrupt changes of several hormones,
including in tandem increases and decreases, respectively, of E2,
progesterone, cortisol, and 1,25-dihydroxyvitamin
D3 (9, 11). Recently, we and others
demonstrated that cortisol, catecholamines (norepinephrine and
epinephrine), and 1,25-dihydroxyvitamin D3 are
potent inhibitors of IL-12 and TNF- production by
monocytes/macrophages ex vivo and in vitro
(12, 13, 14, 15, 16). We hypothesized that during late pregnancy the
increase of these hormones, and their rapid decline in the early
postpartum period, may induce opposite changes in both IL-12 and
TNF- production (17). Therefore, we examined the
production of IL-12 and TNF- after lipopolysaccharide (LPS)
stimulation of whole blood cultures ex vivo and measured the
levels of E2, progesterone, cortisol, 1,25-dihydroxyvitamin
D3, and catecholamines in women during gestation
wk 33–36 and 3–6 wk after delivery.
Materials and Methods
Subjects
Eighteen healthy pregnant women between the ages of 20 and 40 yr and 18 age-matched, healthy, nonpregnant women participated in the study, which was approved by the institutional review board of the NIH. The pregnant women underwent testing during gestation wk 33–36 and 3–6 wk after delivery. They were enrolled in the study with the approval of their obstetricians. We screened each participant at the NIH Clinical Center by history, physical examination, and routine laboratory tests. All signed informed consents. The controls had their tests during the early and mid follicular phases of their menstrual cycle (d 3–8). All participants abstained from taking medications (except prenatal vitamins and iron supplements in pregnancy) during the week before the study. Blood specimens for hormone measurements were drawn after 1 h of rest between 1300 and 1400 h. Urine samples were collected for two 24-h periods during the preceding 2 d to measure free cortisol and catecholamine excretion rates.
Whole blood cultures
Ex vivo whole blood cytokine production assays were performed as described elsewhere (12). Blood was drawn into sodium-heparin-containing sterile tubes (Vacutainer, Becton Dickinson and Co., Lincoln Park, NJ) and processed within 45 min. The blood, diluted 1:5 with RPMI 1640 (supplemented with 1% glutamine and 50 µg/ml gentamicin) with no added exogenous serum, was divided into aliquots (1.0 ml) in 24-well cell culture plates (Costar, Cambridge, MA). To induce cytokine production, bacterial LPS was added at 1 µg/ml final concentration, and the samples were incubated in 5% CO2 at 37 C for 18 h. After incubation, the blood was centrifuged, and the supernatant plasma was separated and stored in polypropylene tubes at -70 C until assayed.
The whole blood ex vivo cytokine assay, which has recently
found favor elsewhere (18), has several advantages. This
method avoids the isolation of leukocytes from whole blood that may
cause activation and artifactual differences not present in
vivo. The method also preserves the "natural environment"
(including hormones) of cytokine-producing cells. Importantly, in
comparison to methods using isolated peripheral blood mononuclear
cells, the whole blood assay also shows less intraindividual variation.
Less than 15% intraindividual variation of whole blood cytokine
production is reported when subjects are sampled over time (18, 19) (Elenkov, I. J., R. L. Wilder, and G. P. Chrousos,
unpublished observations). This contrasts with the wide (but stable)
range of IL-12, TNF-, and IL-10 secretion levels seen across healthy
individuals (interindividual variation) (18, 19, 20, 21),
demonstrating that this test forms a good basis for the study of
genetically or hormonally defined variation.
Monocytes/macrophages are the main IL-12-, TNF--, and
IL-10-producing cells in LPS-stimulated whole blood
(22). In view of the observed changes of
monocyte/macrophage numbers during pregnancy (see
Results), the whole blood cytokine production was
corrected for monocyte/macrophage counts (pg per
106 monocytes/macrophages).
Cytokine assays
IL-12 p70, TNF-, and IL-10 were measured using ELISA
employing the multiple antibody sandwich principle (Quantikine, R&D
Systems, Inc., Minneapolis, MN). IL-12 p70 ELISA recognizes
specifically the biologically active IL-12 heterodimer without
cross-reactivity with the individual subunits of the dimer (p35 and
p40). The detection limits of the IL-12 p70 and the high sensitivity
IL-12 p70 ELISA were 7.5 and 0.5 pg/ml, respectively, whereas they were
15.0 and 2.0 pg/ml for the TNF- and IL-10 ELISA. The quality control
parameters of these ELISAs were as follows: intraassay coefficient of
variation (CV), 1.1–1.5%; interassay CV, 3.3–7.1%. Plates were read
by a microplate reader (model 550, Bio-Rad Laboratories, Inc., Richmond, CA), and absorbance was transformed to cytokine
concentration (pg/ml) using a standard curve computed by Microplate
Manager III (Macintosh Data Analysis Software, Bio-Rad Laboratories, Inc.).
Hormonal measurements
E2 was measured by RIA after extraction and LH20 column chromatography. Intraassay CV was 4.5%, and interassay CV was 11%. Normal values for the follicular phase are 0.38–367 nmol/l. Progesterone was measured by RIA after extraction with hexane. Interassay CV was 6.7%, and intraassay CV was 4.5%. Normal values for the follicular phase are 0.003–0.03 nmol/l. 1,25-Dihydroxyvitamin D3 was measured by cartridge extraction and RRA. Intraassay and interassay CVs were 10%. Normal values are 53–161 pmol/l (Mayo Clinical Laboratories, Rochester, MN). Twenty-four-hour urinary excretion of free cortisol was measured after extraction by chemiluminescent competitive protein binding assay. Intraassay and interassay CVs were 4.4%. Normal values are 66–298 nmol/24 h (Mayo Clinic Laboratories). Twenty-four-hour urinary excretion of epinephrine and norepinephrine (NE) were measured by HPLC with electrochemical detection. Intraassay and interassay CVs were 3.5 and 4.0, respectively. Normal values are 0–109 and 89–473 nmol/24 h, respectively (Mayo Clinic Laboratories).
Data analysis
All data are presented as means ± SE. ANOVA was done with Statistica (version 5.5, StatSoft, Inc., Tulsa, OK). Pregnancy and postpartum values of the same individuals were compared by repeated measures ANOVA. Values from healthy age-matched control subjects were compared with those of pregnancy and postpartum subjects using one-way ANOVA.
Results
Blood count changes during pregnancy and postpartum
Pregnancy was associated with an increase of white blood cell counts compared with healthy, nonpregnant controls and the postpartum state (8.8 ± 0.5 x 103 mm3 vs. 6.0 ± 0.3 x 103 mm3, both in controls and postpartum; P < 0.001). This was attributable to a significant increase of polymorphonuclear leukocytes and monocytes (mean, 6.6 ± 0.5 x 103/µl and 0.62 ± 0.04 x 103/µl, respectively) during pregnancy compared with healthy matched nonpregnant controls (mean, 3.3 ± 0.3 x 103/µl and 0.38 ± 0.03 x 103/µl, respectively; P < 0.001) and the postpartum state (mean, 3.4 ± 0.2 x 103/µl and 0.4 ± 0.02 x 103/µl, respectively; P < 0.001). Pregnancy was also associated with a moderate but significant decrease (P < 0.05) of lymphocytes and eosinophil counts (mean, 1.8 ± 0.1 x 103/µl and 0.09 ± 0.01 x 103/µl, respectively) compared with control age-matched nonpregnant women (mean, 2.2 ± 0.1 x 103/µl and 0.16 ± 0.03 x 103/µl, respectively).
Decrease of IL-12 and TNF- production during pregnancy
During pregnancy, whole blood IL-12 production was decreased
2-fold compared with the postpartum period (61.0 ± 10.5
vs. 120.7 ± 31.8 pg/ml, respectively). When corrected
for monocyte count, the decrease of IL-12 production was more
pronounced (>3 fold; Table 1
). The
individual changes of IL-12 production corrected for monocyte count in
18 women during pregnancy and their follow-up in the postpartum period
are shown in Fig. 1. During pregnancy, 15
of the women had lower IL-12 production than postpartum. Of interest,
we found a large interindividual variation of the "effect of
pregnancy" on IL-12 production, i.e. 5 individuals had
dramatic changes of IL-12 production, whereas others had moderate or
minimal changes.
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per monocyte was decreased by 40% during
pregnancy compared with the postpartum period and narrowly failed to
reach statistical significance (P = 0.07; Table 1
).
However, we observed similar levels of TNF- production in pregnant
vs. nonpregnant women (Table 1). There were no significant
differences of LPS-induced IL-10 production by monocytes among the
control, pregnant, and postpartum groups (data not shown). Normal pregnancy is characterized by marked hormonal changes
The 24-h urinary cortisol excretion was increased about
4-fold during pregnancy compared with the nonpregnant state (Table 1),
and in all cases it exceeded the upper limit of the reference values.
After delivery, the cortisol excretion returned to normal levels. No
changes in 24-h urinary excretion of epinephrine and dopamine were
observed (data not shown), but we found that the 24-h urinary NE
excretion was significantly increased during pregnancy and returned to
baseline or lower levels in the postpartum period (Table 1).
As expected, the serum levels of E2 and progesterone were markedly
increased during pregnancy. Postpartum, the ovarian hormone levels
returned to normal follicular phase levels (Table 1). During pregnancy,
plasma 25-hydroxyvitamin D3 was increased by
50%, whereas 1,25-dihydroxyvitamin D3 increased
more than 2-fold (Table 1).
Cytokine production and hormone levels in a single individual before, during, and after pregnancy
We had the opportunity to follow the cytokine and hormonal changes
of one woman (subject 4 in Fig. 1) as nonpregnant, during pregnancy,
and postpartum (Fig. 2). She had a
substantial decline in IL-12 production during pregnancy compared with
the nonpregnant state. Three weeks after delivery, when cortisol, NE,
E2, progesterone, and 1,25-dihydroxyvitamin D3
returned to prepregnancy levels or lower, there was a notable rebound
of LPS-induced IL-12 and TNF- production.
|
, and IL-10
production
No data are available regarding whether E2 and progesterone are
able to modulate the production of IL-12 by monocytes/macrophages. The
significant changes of E2 and progesterone during pregnancy prompted us
to study their direct effects in our assay system. Neither E2 nor
progesterone at 10-5 to
10-11 M modulated the production of
IL-12, TNF-, or IL-10 in the LPS-stimulated human whole blood from
five normal, nonpregnant individuals and three pregnant individuals
(data not shown).
Discussion
We demonstrated that during late pregnancy, compared with the
postpartum period, the capacity of monocytes to produce IL-12 was
reduced more than 3-fold, whereas the capacity for TNF- production
was reduced by 
40%. The decreased production of these
proinflammatory cytokines was paralleled by significant increases of
cortisol, NE, 1,25-dihydroxyvitamin D3, E2, and
progesterone.
The pregnant women also had lower LPS-induced IL-12 production compared
with age-matched controls, although the difference did not reach
statistical significance (Table 1). The lack of significance in this
case may reflect the large interindividual variability of monocytic
IL-12 production across healthy individuals (Table 1). However, we
observed a clear suppression of IL-12 production during pregnancy and a
rebound in the postpartum when we followed a single individual through
the nonpregnant, pregnant, and postpartum states (Fig. 2). Thus,
because of the substantial interindividual variability of IL-12
production, larger and more extended longitudinal studies are needed to
address the differences between pregnancy and the nonpregnacy
state.
Like others (23), we did not observe a difference of
TNF- production in pregnant vs. nonpregnant women. This
might reflect the same factors described above for IL-12 production and
an increase of soluble TNF receptors p55 and p75 in the third trimester
of pregnancy, documented by Russell et al.
(23). We did not find significant differences of
LPS-induced IL-10 production by monocytes among the control, pregnant,
and postpartum groups. Previous studies have shown increased production
of IL-10 by peripheral blood mononuclear cells and placenta during
pregnancy (24, 25). This discrepancy with our observations
most likely reflects methodological differences. In the LPS-stimulated
whole blood assay used by us, the primary source of IL-10 is the
monocyte (22), whereas in the isolated peripheral blood
mononuclear cell assay, which involves stimulation by mitogens, the
primary source of IL-10 most likely is the lymphocyte.
The substantially increased urinary free cortisol excretion during the third trimester of pregnancy that returned to normal levels 3 wk after delivery indicates that late pregnancy is a state of adrenocortical activation, probably caused by the large amounts of CRH secreted by the placenta (11). We also found a significant increase of 24-h NE urinary excretion during pregnancy with a return to low normal levels in the postpartum period. This is consistent with observations in pregnant rats, in which a more than 2-fold increase of 24-h urinary excretion of NE has been described (26). Further studies are needed to elucidate whether these observations are linked to increased sympathetic nerve activity and/or reduced NE uptake during pregnancy, although, most likely, both take place (see also below).
The moderate increase of serum 25-hydroxyvitamin D3 during pregnancy probably reflects the increased levels of serum vitamin D-binding proteins (27, 28). Like Seely et al. (28), we observed a more than 2-fold increase of the highly regulated serum 1,25-dihydroxyvitamin D3 in the third trimester of pregnancy. These changes most likely result from increased conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 in the human placenta, in addition to the increase of vitamin D-binding proteins (27, 28).
Recent evidence indicates that glucocorticoids, NE, and
1,25-dihydroxyvitamin D3 potently inhibit the
production of IL-12 and TNF- by human monocytes/macrophages in
vitro and ex vivo (12, 13, 14, 15, 16, 29). These
hormones also inhibit the production of IL-2 and IFN- by Th1 cells
(15, 29). In contrast, glucocorticoids do not affect the
production of IL-10 by monocytes, but they potentiate IL-10 and IL-4
production by Th2 cells (12, 29, 30). Thus, the observed
hormonal changes during pregnancy may explain the inhibition of
monocytic IL-12 and TNF- production. Furthermore, because IL-12 is
extremely potent in enhancing IFN- and inhibiting IL-4 synthesis by
T cells, the inhibition of IL-12 production may represent an important
mechanism by which these hormones mediate a Th2 shift during pregnancy
(Fig. 3).
|
, or IL-10 by human monocytes ex
vivo. However, estrogens may affect cytokine production indirectly
by enhancing the activity of the stress system, i.e. via
increases in the secretion of cortisol and catecholamines
(11). In addition, estrogens are potent inhibitors of the
extraneuronal uptake of NE (uptake 2) (31), which may also
explain the increased NE excretion in pregnancy demonstrated in our
study. Therefore, estrogens may amplify the IL-12/TNF--inhibitory
and Th2-facilitatory activities of cortisol and NE in vivo
(Fig. 3). Furthermore, progesterone and estrogens up-regulate the
production of IL-4 and IL-10 by Th2 cells in vitro
(32, 33). Thus, an increase of estrogens and progesterone
may also facilitate a Th2 shift during pregnancy by directly
stimulating the production of IL-4 and IL-10 by Th2 cells (Fig. 3).
This is consistent with recent data documenting increased IL-4 and
IL-10 production by lymphocytes and the placenta during the third
trimester of pregnancy (24, 25).
In conclusion, we demonstrated that human third trimester pregnancy,
compared with the early postpartum period, is characterized by a
reduction of the monocytic production of the Th1 type/proinflammatory
cytokines IL-12 and TNF- and by an increase of the secretion of
cortisol, NE, and 1,25-dihydroxyvitamin D3.
Postpartum, when these hormones return to normal or low normal levels,
the removal of their inhibitory effects may induce a rebound of IL-12
and TNF- production and a Th1 shift.
The changes of Th1 type/proinflammatory cytokine production observed in
this study may provide new understanding of the clinical observations
that Th1-related diseases such as RA and MS frequently remit during
pregnancy but exacerbate or have their onset in the postpartum period.
Our study also suggests that some individuals have exaggerated
postpartum Th1 type/proinflammatory cytokine rebound, raising the
question of the factors that control this phenomenon. These individuals
could be at greater than average risk for developing or exacerbating
already existing autoimmune diseases. Thus, further studies of the role
of neuroendocrine factors in the regulation of IL-12, TNF-/IL-10,
and Th1/Th2 balance may suggest novel diagnostic and therapeutic
approaches for these diseases.
Acknowledgments
Footnotes
1 These authors contributed equally to this work. 
Abbreviations: IFN, Interferon; LPS, lipopolysaccharide; MS, multiple sclerosis; NE, norepinephrine; RA, rheumatoid arthritis; Th, T helper.
Received October 27, 2000.
Accepted June 6, 2001.
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