Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294
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ABSTRACT |
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Hypoxemia depresses cell-mediated immune
functions in males, whereas proestrous females do not show such
a depression. We hypothesized that elevated systemic estradiol levels
in proestrous females prevent hypoxemia-induced immune depression. To
study this hypothesis, male C3H/HeN mice were pretreated with
17-estradiol (E2, 40 µg/kg body wt sc) or vehicle for
3 days before induction of hypoxemia and again immediately before
induction of hypoxia. The mice were subjected to hypoxemia (95%
N2-5% O2) or sham hypoxemia (room air) for 60 min, and plasma and spleen cells were collected 2 h later. In
vehicle-treated mice, splenocyte proliferation and interleukin-2 and
interleukin-3 production were depressed after hypoxemia.
E2-pretreated animals, however, displayed no such
depression in splenic T cell parameters after hypoxemia. Splenic
macrophage cytokine production was also depressed in vehicle-treated
mice subjected to hypoxia, whereas it was normal in
E2-pretreated mice. In summary, these findings indicate
that administration of E2 before hypoxemia prevented the
depression of cell-mediated immune functions. Thus administration
of 17
-estradiol in high-risk patients before major surgery might
decrease hypoxemia-induced immune depression under those conditions.
inflammation; cytokines; estradiol; gender
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INTRODUCTION |
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THERE IS A WEALTH OF
INFORMATION indicating that hormonal mechanisms play an important
role in regulating immune functions under stressful conditions, such as
trauma-hemorrhage and septic shock (2). Studies have also
demonstrated that severe hypoxemia in males, in the absence of blood
loss or tissue trauma, results in a profound systemic inflammatory
response and depressed immune responses similar to those observed after
trauma-hemorrhage, a condition associated with regional tissue
hypoxemia (10, 18). In contrast to male mice, no such
depression in immune functional parameters is observed in female mice
in the proestrous state of the estrous cycle after hypoxemia
(18). Similarly, although depressed cell-mediated immune
functions have been observed in males after trauma-hemorrhage, no
depression has been observed in proestrous females under such
conditions (15, 34). Several studies have provided
evidence that the hormonal environment is responsible for the
gender-specific inflammatory response after adverse circulatory
conditions. Testosterone has been shown to exert immunosuppressive
effects on immune functions, while estrogens appear to be
immunoprotective (1, 33). Recently, administration of
17-estradiol has been shown to exhibit beneficial effects on
posttraumatic immune responses in males after trauma-hemorrhage (16). Additional support for the protective role of
estrogens comes from studies in cardiovascular research indicating
gender differences in the susceptibility to hypoxia-induced or
oxidant-mediated organ and cell dysfunction (12, 22, 25,
31). In light of those findings, we hypothesized that
administration of 17
-estradiol in males should prevent the
depression of cell-mediated immune responses after severe hypoxemia.
The aim of the present study, therefore, was to determine whether
pretreatment of males with 17
-estradiol has any protective effects
on immune responses after hypoxemia.
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MATERIALS AND METHODS |
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Animals. Inbred male C3H/HeN mice (Charles River Laboratories, Wilmington, MA), 7-8 wk of age (24-27 g body wt), were used in this study. All procedures were carried out in accordance with the guidelines set forth in the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. This project was conducted at Rhode Island Hospital and was approved by the Institutional Animal Care and Use Committee of Rhode Island Hospital and Brown University.
Experimental groups.
Male mice were randomly assigned to the following two treatment groups:
mice in group 1 received a subcutaneous injection of 200 µl of corn oil vehicle (Sigma Chemical, St. Louis, MO), and animals
in group 2 received a subcutaneous injection of
17-estradiol (40 µg/kg dissolved in corn oil). In preliminary
studies, this dose of 17
-estradiol was found to increase plasma
17
-estradiol concentrations in male mice comparable to levels
observed in female mice in the proestrous state of the estrous cycle.
Animals were treated daily between 8 and 9 AM for 3 days before
experimentation and again immediately before the induction of hypoxemia
or sham hypoxemia. Animals from each treatment group were then randomly assigned to the hypoxemia or sham hypoxemia group (n = 7-8/group).
Murine model of hypoxemia. The hypoxemia model used in our experiments was previously described by Ertel et al. (10). Animals were placed in two plastic chambers (20 × 10 × 8 cm), each with an inlet and an outlet, through which the hypoxic gas mixture or room air flowed. Hypoxemia was induced by flushing one of the chambers with a gas mixture of 95% N2-5% O2 at a flow rate of 10 l/min for 60 min. At the same time, control (sham) animals were kept in the second chamber, which was flushed with room air for 60 min. The animals were constantly monitored during this period, and no immediate or late mortality was observed with the use of this hypoxemia model. Previous studies using this murine hypoxemia model have shown that, in male mice, arterial PO2 decreased significantly to ~40 mmHg throughout the duration of hypoxemia and returned to a baseline of 120 mmHg within minutes after the end of hypoxemia (10, 18). The mice were symptomatic for hypoxia, displaying rapid shallow breathing and minimal physical activity. The animals were killed by methoxyflurane overdose 2 h after hypoxemia to obtain the spleen and whole blood.
Plasma collection and storage.
Whole blood was obtained by cardiac puncture and placed in
microcentrifuge tubes (Microtainer, Becton Dickinson, Rutherford, NJ).
The tubes were then centrifuged at 16,000 g for 15 min at 4°C. Plasma was separated, placed in pyrogen-free microcentrifuge tubes, immediately frozen, and stored at 80°C until assayed.
Preparation of splenocyte cultures.
At 2 h after hypoxemia or sham hypoxemia, the spleens were removed
aseptically, and splenocytes were isolated as previously described in
detail (35). Splenocyte viability was tested using trypan
blue exclusion and found to be ~95% in all groups. The splenocytes
were then resuspended in RPMI 1640 (GIBCO-BRL, Grand Island, NY)
containing 10% heat-inactivated fetal bovine serum (GIBCO-BRL) at a
final concentration of 1 × 106 cells/ml. The ability
of the splenocyte cultures to produce cytokines in response to a
mitogenic challenge was assessed by incubation for 48 h (at
37°C, 5% CO2, and 90% humidity) in the presence of concanavalin A (2.5 µg/ml; Pharmacia/LKB Biotech, Piscataway, NJ).
After incubation, the cell suspension was centrifuged at 300 g for 15 min, and the supernatants were harvested and stored at 80°C until assayed. The cells' ability to proliferate in
response to mitogenic stimulation with 0 (negative control) or 2.5 µg/ml concanavalin A was measured by incorporation of
[3H]thymidine, as previously described (30).
Preparation of splenic macrophage cultures.
Splenic macrophage cultures were established by adherence, as
previously described in detail (36). The monolayers of
splenic macrophages (1 × 106 cells/ml) were
stimulated with 10 µg of lipopolysaccharide from Escherichia
coli 055:B5 (Difco Laboratories, Detroit, MI) per milliliter of
Click's medium containing 10% heat-inactivated fetal bovine serum for
48 h at 37°C, 5% CO2, and 90% humidity to assess the cells' ability to release cytokines. At the end of the incubation period, the culture supernatants were removed, centrifuged at 300 g for 15 min, divided into aliquots, and stored at 80°C
until assayed for cytokine concentrations.
Assessment of cytokine and prostaglandin E2
production.
The capacity of splenocyte cultures to produce interleukin (IL)-2
(CTLL-2) and IL-3 (FDC-P1) was assessed by determining the amount of
respective cytokines in the collected culture supernatant using
specific bioassays as previously described in detail (18, 20). IL-6 activity was determined by assessing the 72-h
proliferation of the IL-6-dependent murine hybridoma 7TD1 cells
stimulated by serial dilutions of plasma or supernatants, as described
in detail elsewhere (24). IL-1 (DuoSet, Genzyme
Diagnostics, Cambridge, MA) and IL-10 (OptEIA Set, Pharmingen, San
Diego, CA) levels in the supernatants were determined by ELISA
according to the manufacturer's recommendations. Prostaglandin (PG)
E2 levels in splenic macrophage supernatants were
determined using an ELISA kit (Cayman Chemical, Ann Arbor, MI)
according to the manufacturer's instructions.
Determination of plasma 17-estradiol concentrations.
17
-Estradiol concentrations were measured using a commercially
available radioimmunoassay (ICN Biomedicals, Costa Mesa, CA) as
recommended by the manufacturer.
Statistical analysis. Values are means ± SE. One-way ANOVA, followed by the Student-Newman-Keuls test as a post hoc test for multiple comparisons, was used to determine the significance of the differences between experimental means. P < 0.05 was considered significant.
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RESULTS |
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Effect of 17-estradiol pretreatment on plasma estradiol and IL-6
levels.
At 2 h after hypoxemia (i.e., 3 h after the last
administration of vehicle or 17
-estradiol), plasma
concentrations of 17
-estradiol were significantly increased in male
mice pretreated with 17
-estradiol in both treatment groups compared
with vehicle-pretreated male mice (P < 0.05; Table
1). Plasma concentrations of IL-6 were also markedly increased in vehicle-pretreated male mice
(P < 0.05); however, circulating IL-6 levels in
17
-estradiol-pretreated male mice subjected to hypoxemia were
similar those observed in sham animals (Table 1).
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Splenocyte responses after hypoxemia.
Splenocyte proliferative capacity was significantly depressed in male
mice pretreated with vehicle compared with the corresponding sham-treated animals (P < 0.05; Fig.
1A). In male mice pretreated with 17-estradiol for 3 days before hypoxemia, however, no
depression of splenocyte proliferative capacity was observed. At 2 h after hypoxemia, splenocyte IL-2 and IL-3 release was significantly depressed in vehicle-pretreated male mice compared with the
corresponding sham-treated animals (P < 0.05; Fig. 1,
B and C). In male mice pretreated with
17
-estradiol, splenocyte IL-2 and IL-3 production after hypoxemia
was comparable to that observed in sham animals.
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Splenic macrophage responses after hypoxemia.
After hypoxemia, splenic macrophage IL-1 production was decreased in
vehicle-pretreated male mice compared with corresponding sham-treated
animals; however, this decrease was not statistically significant (Fig.
2A). In male mice receiving
17
-estradiol before the experiment, IL-1
release after hypoxemia
was comparable to values in sham-treated animals. At 2 h after
hypoxemia, splenic macrophage IL-6 release was significantly depressed
in vehicle-pretreated male mice compared with vehicle-pretreated sham
animals (P < 0.05; Fig. 2B). However, in
male mice pretreated with 17
-estradiol, splenic macrophage IL-6
release was maintained at sham levels after hypoxemia. Similar to the
production of IL-6, splenic macrophage IL-10 release was significantly
depressed after hypoxemia in vehicle-pretreated mice (P < 0.05; Fig. 3A).
Pretreatment with 17
-estradiol prevented the depression of splenic
macrophage IL-10 production in male mice subjected to hypoxemia. In
splenic macrophages harvested from mice pretreated with vehicle,
PGE2 production was maintained at sham levels after
hypoxemia (Fig. 3B). PGE2 production by splenic macrophages from 17
-estradiol-pretreated male mice was significantly reduced after hypoxemia compared with 17
-estradiol-pretreated sham
animals (P < 0.05).
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DISCUSSION |
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Previous studies have shown that the inflammatory response to
severe hypoxemia exhibits a gender-specific pattern (18). In those studies, hypoxemia led to significantly increased plasma concentrations of proinflammatory cytokines in males, but not in
females. Furthermore, splenic macrophage cytokine productive capacity
was significantly depressed in males, but not in females, after
hypoxemia. Additionally, a shift toward an immunosuppressive Th-2
cytokine profile was found in males after hypoxemia, whereas no such
shift was observed in females under those conditions. These results
indicate that, unlike males, females in the proestrous state do not
manifest immunosuppression after severe hypoxemia. Because circulating
levels of female sex hormones are increased in the proestrous state of
the estrous cycle (29), we hypothesized that these
hormones are involved in maintaining immunocompetence in females after
hypoxemia. The aim of the present study, therefore, was to determine
whether pretreatment of male mice with 17-estradiol has any salutary
effects on splenocyte and splenic macrophage immune functions after
severe hypoxemia.
The results presented here indicate that, at 2 h after sham
hypoxemia or hypoxemia, plasma concentrations of 17-estradiol were
significantly increased in male mice pretreated with 17
-estradiol compared with vehicle-pretreated male mice. Furthermore, the plasma concentrations of 17
-estradiol measured in pretreated males were similar to those described in the literature in proestrous females, suggesting physiological relevance of the treatment regimen used (29).
Hypoxemia resulted in markedly depressed splenocyte proliferation as
well as splenocyte IL-2 and IL-3 release capacity in vehicle-pretreated
male mice. These results are comparable to the results of our previous
studies (18). However, in male mice that were pretreated
with 17-estradiol before the induction of hypoxemia, the
splenocyte functional parameters were unaltered compared with those in
mice subjected to sham hypoxemia. After hypoxemia, the pattern of
splenocyte and splenic macrophage function observed in
17
-estradiol-pretreated males closely resembled that in proestrous
females under such conditions (18). Additional support for
the notion that 17
-estradiol has salutary effects on depressed
splenocyte immune functions comes from studies that have shown
restoration of the depressed splenocyte immune responses in males
treated with 17
-estradiol after trauma-hemorrhage (16). Furthermore, trauma-hemorrhage led to immune depression in
ovariectomized females with decreased plasma levels of estrogens;
however, treatment with 17
-estradiol during fluid resuscitation
normalized splenocyte immune functional parameters (16).
In those studies, in vitro addition of 17
-estradiol to splenocyte
cultures from animals subjected to trauma also resulted in stimulation
of splenocyte proliferation and cytokine production, supporting the
notion that estradiol administration before hypoxemia had direct
effects on splenocytes. However, it is possible that the beneficial
effects of 17
-estradiol pretreatment on splenocyte immune functions
are not solely direct actions of this hormone on splenocytes but are also mediated via indirect mechanisms, such as macrophage-splenocyte interactions. In this regard, 17
-estradiol administration altered splenic macrophage functions after severe hypoxemia. Although splenic
macrophage IL-1
, IL-6, and IL-10 release was depressed in
vehicle-pretreated male mice after hypoxemia, no differences in the
release of these cytokines were observed between
17
-estradiol-pretreated male mice subjected to hypoxemia or sham
hypoxemia. These results, therefore, suggest that 17
-estradiol
prevented the depression of splenic macrophage cytokine productive
capacity after hypoxemia. Our results further indicate that splenic
macrophage PGE2 production was maintained in
vehicle-pretreated male mice after hypoxemia, while in
17
-estradiol-pretreated male mice the production of PGE2
was significantly lower under those conditions. These results are in
line with the results from previous studies which indicate that, in
proestrous females with increased circulating estrogens, splenic
macrophage PGE2 production was significantly lower after hypoxemia than in sham animals (18). Furthermore, studies
have shown that, after hypoxemia, plasma concentrations of
PGE2 were significantly increased in male animals
(32).
Studies have shown that hypoxemia led to significantly increased plasma
concentrations of IL-6 in males, whereas in females no differences in
plasma IL-6 levels were observed between animals subjected to hypoxemia
and those subjected to normoxemia (10, 18). Our
observation that plasma concentrations of IL-6 were significantly
increased in vehicle-pretreated male mice 2 h after hypoxemia is
in accordance with those studies. Regarding the depression of splenic
macrophage IL-6 productive capacity observed in vehicle-pretreated males after hypoxemia, it appears likely that cell populations other
than splenic macrophages are responsible for the increased systemic
concentrations of IL-6. Previously, studies have also shown that the
elevation of circulating proinflammatory cytokines was associated with
a marked activation of Kupffer cells to release those cytokines in
vitro (10). Although Kupffer cell cytokine production was
not determined in the present study, it appears likely that the
increased IL-6 plasma levels after the hypoxic insult result from
activation of these macrophage populations. The finding that IL-6 was
not increased in 17-estradiol-pretreated males 2 h after
hypoxemia further suggests that 17
-estradiol prevented the increased
release of this cytokine by Kupffer cells. Nonetheless, studies also
support other tissues (i.e., gut) as an important source of IL-6 after
injury (8, 23). In this regard, Nelson et al.
(21) showed that inhibition of gut-derived IL-6 with
pentoxifylline improved survival after sepsis. Thus the beneficial
effects of 17
-estradiol after hypoxia may also be related to
attenuation of the cytokine (IL-6) response of the gut.
Although our findings suggest several possibilities by which
17-estradiol might contribute to maintain immune functions after hypoxemia, the target level of immunoendocrine interactions remains unclear. Because estrogen receptors have been identified in macrophages (3, 13) as well as splenic T lymphocytes
(28), it appears likely that these cells may be prone to
functional modulation by exogenous estrogens administered before
hypoxemia. Although estrogen's interactions with lymphocytes (4,
27) and macrophages (6, 7, 26) have been reported
in various experimental settings, the exact effects of estrogens on
immune cells under hypoxic conditions remain to be determined. It is
possible that the beneficial modulatory effects of 17
-estradiol
pretreatment on immune functions after hypoxemia might, in
part, be the indirect result of the hormone's effects on other organ
systems. In this regard, Razandi et al. (25) showed that
17
-estradiol via membrane-bound estrogen receptor rapidly activates
p38 mitogen-activated protein kinase in endothelial cells, thereby
preserving endothelial cell structure and function and preventing
apoptosis under hypoxic conditions. Griffin et al.
(12) demonstrated that although female cardiac fibroblasts
are resistant to hypoxia-induced inhibition of DNA synthesis, male
fibroblasts are susceptible, and estrogen partially reversed the
proliferative response in male cells via estrogen receptor-dependent
mechanisms. Furthermore, it is possible that other effects of
17
-estradiol, such as vasodilatation due to changes in ion channel
function (11, 14) or increased endothelial nitric oxide
production (5, 19), also indirectly contribute to the
beneficial effects on immune functions by improving the microcirculation during hypoxemic conditions. Recent studies have demonstrated that proestrous females (with elevated estrogen levels) subjected to trauma-hemorrhage (a condition associated with regional tissue hypoxia) do not display an increased mortality after subsequent sepsis, whereas the mortality rate in males was markedly increased (9). These findings suggest that 17
-estradiol may play
a critical role in the improved outcome in proestrous females under
such conditions. Thus it can be speculated that the
17
-estradiol-induced improvement in immune functions after hypoxia
would likely translate into reduced mortality after a subsequent septic insult.
In summary, the data presented here demonstrate that, in
vehicle-pretreated males, splenocyte immune functional parameters and
splenic macrophage proinflammatory cytokine production were significantly depressed after severe hypoxemia. Pretreatment with 17-estradiol over 3 days before hypoxemia prevented this depression of splenocyte and splenic macrophage immune functions. At 2 h after hypoxemia, plasma IL-6 levels were significantly increased in
vehicle-pretreated males, and 17
-estradiol pretreatment
significantly attenuated the increase in circulating IL-6. These
findings indicate that pretreatment with 17
-estradiol prevented the
adverse effects of hypoxemia on splenocyte and splenic macrophage
immune functions as well as increased plasma IL-6 levels and suggest
that the low levels of 17
-estradiol in male animals contribute to
the depressed immune responses after hypoxemia. Because 17
-estradiol
pretreatment attenuated immune responses after hypoxemia,
administration of this sex hormone before major surgery might be a
useful approach for preventing the depression in cell-mediated immune
responses in patients at risk of hypoxemia.
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ACKNOWLEDGEMENTS |
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This study was supported by National Institute of General Medical Sciences Grant R01 GM-37127 (I. H. Chaudry) and Deutsche Forschungsgemeinschaft Fellowship Kn 475/1-1 (M. W. Knöferl).
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FOOTNOTES |
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Present address of M. W. Knöferl: Dept. of Trauma-Surgery, University of Ulm, Steinhövelstr. 9, 89075 Ulm, Germany.
Address for reprint requests and other correspondence: I. H. Chaudry, Center for Surgical Research, University of Alabama at Birmingham, G094 Volker Hall, 1670 University Blvd., Birmingham, AL 35294-0019 (E-mail: Irshad.Chaudry{at}ccc.uab.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published December 12, 2001;10.1152/ajpcell.00454.2001
Received 24 September 2001; accepted in final form 9 December 2001.
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