| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Department of Life and Health Sciences, Hyogo University of Teacher Education, Hyogo 673-1494; 2 Department of Intelligence Science and Technology, Graduate School of Informatics, Kyoto University, Kyoto 606-8501; 4 Department of Physiology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan; and 3 Molecular Neurobiology Laboratory, SRI International, Menlo Park, California 94025
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHOD
RESULTS
DISCUSSION
REFERENCES
|
|---|
Attenuation of fever occurs in pregnant animals. This study examined a hypothesis that brain production of PGE2, the final mediator of fever, is suppressed in pregnant animals. Near-term pregnant rats and age-matched nonpregnant female rats were injected with lipopolysaccharide (100 µg/kg) intraperitoneally. Four hours later, colonic temperature was measured, their cerebrospinal fluid (CSF) was sampled for PGE2 assay, and their brains were processed for immunohistochemistry of cyclooxygenase-2, an enzyme involved in PGE2 biosynthesis. In the pregnant rats, lipopolysaccharide injection resulted in significantly smaller elevations in both colonic temperature and CSF-PGE2 level than in nonpregnant rats. In the pregnant rats, lipopolysaccharide-induced cyclooxygenase-2 expression was blunted in terms of the number of positive cells. There was a significant correlation between PGE2 level in CSF and the number of cyclooxygenase-2-positive endothelial cells. These results suggest that suppressed PGE2 production in the brain is one cause for the attenuated fever response at near-term pregnancy and that this suppressed PGE2 production is due to the suppressed induction of cyclooxygenase-2 in brain endothelial cells.
prostaglandin; endothelial cell; lipopolysaccharide; cytokine
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHOD
RESULTS
DISCUSSION
REFERENCES
|
|---|
PREGNANCY IS ACCOMPANIED by alterations in various physiological responses. In 1978, Kasting et al. (21) reported that the febrile response to LPS was suppressed in near-term pregnant ewes. Later on, a similar observation was made in guinea pigs (42) and in rats (27). For example, in pregnant rats that were given Escherichia coli LPS, fever was attenuated in a peri-term period between 48 h before and 24 h after parturition, whereas nonpregnant rats developed fever of nearly 2°C with the same dose of LPS (27). Especially in the 24-h period before the expected time of parturition, no rats developed fever; instead, the majority of them became hypothermic in response to LPS (27). As a possible mechanism of this, an attenuated febrile response to centrally injected PGE was demonstrated (8, 11, 28, 39). PGE2, the dominant form of endogenous E-series prostaglandins, is produced in the brain in response to pyrogens and seems to be the crucial neuronal mediator of fever in the brain (31). Thus, in near-term pregnancy, either PGE2 sensitivity of the hypothalamic neurons or a certain step in the efferent neuronal pathway from the hypothalamic neurons to effecter organs, such as brown adipose tissue and blood vessels, may be downregulated.
On the other hand, it is also possible that pyrogen-induced PGE2 biosynthesis in the brain, which is apparently a crucial step for fever genesis, is suppressed during pregnancy. However, none of the studies to date have addressed whether LPS-induced PGE2 biosynthesis in the brain is attenuated or unaltered in near-term pregnancy. Recent studies in male rats have indicated that during fever, PGE2 biosynthesis in the brain is enhanced through the induction of cyclooxygenase-2 (COX-2), an isoform of cyclooxygenase (6, 7, 29). COX-2 was discovered in 1991 (24, 40) as an inducible type of cyclooxygenase, which converts arachidonic acid to PGH2, a precursor of prostaglandins. COX-2 was strongly induced in the brain endothelial cells by various types of pyrogens including LPS and pyrogenic cytokines (2, 4-6, 12, 25, 35). COX-2-specific inhibitors almost completely suppressed both LPS-induced fever (7, 15) and the increase in PGE2 in the cerebrospinal fluid (CSF) (41). Furthermore, COX-2 induction was well correlated with fever in terms of timing and magnitude (7).
These facts led us to hypothesize that the attenuated febrile response in the pregnant animals might be due to suppressed biosynthesis of PGE2 as a consequence of suppressed COX-2 induction in the brain. In the present study, we therefore investigated whether the PGE2 response and COX-2 induction in the brain are altered in near-term pregnant rats injected with LPS intraperitoneally.
| |
MATERIALS AND METHOD |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHOD
RESULTS
DISCUSSION
REFERENCES
|
|---|
Materials. Pregnant Wistar rats (expected parturition at gestational day 22) and age-matched nonpregnant female Wistar rats were purchased from Japan SLC (Shizuoka, Japan). They were housed in individual cages at 25°C in a room with a light-dark cycle (lights on from 0700 to 1900) and fed standard laboratory chow ad libitum. Chemicals used in the present study and their sources were as follow: LPS (Escherichia coli O26:B6) from Sigma; PGE2 enzyme immunoassay (EIA) kit and rabbit anti-murine COX-2 polyclonal antibody from Cayman Chemical; sheep polyclonal antibody against rat von Willebrand factor from Affinity Biologicals; normal goat serum, avidin/biotin blocking kit, and biotin-labeled anti-rabbit IgG from Vector Labs; Cy3-streptoavidin from Amersham Life Science; Cy3-anti rabbit IgG and FITC-anti sheep IgG from Jackson Lab; and TOTO-3 for nuclear DNA staining from Molecular Probes.
Experimental procedures. Experiments were conducted on the pregnant rats at gestational day 21 and on age-matched nonpregnant female rats. The mean body weight of the nonpregnant rats and near-term pregnant ones was 173 ± 4 g (means ± SE; n = 16) and 238 ± 3 g (n = 11), respectively. Just before the intraperitoneal injection of LPS or saline, their colonic temperature (Tco) was measured with a copper-constantan thermocouple. During the measurement, the base of their tail was held lightly and the thermocouple, which had been prewarmed and lubricated with warm water (37°C), was inserted into the anus to a depth of 5 cm. The thermocouple was kept there for 10 to 15 s, the time required for the digital thermometer to stabilize. The rats were accustomed to this protocol before the experiment and did not show any signs of stress such as vocalization and vigorous movement. Intraperitoneal injection of LPS (100 µg/kg in 400 µl saline) or saline alone (400 µl) was made between 10:00 and 11:00 AM. Care was taken so that the injection needle penetrated only the abdominal wall but not the uterus. This was achieved by slowly inserting the needle with blunted tip, which produced some resistance against the abdominal wall and became resistance-free when it penetrated the abdominal wall. After the injection, the animals were returned to their home cages and allowed to move freely.
Four hours after the intraperitoneal injection of LPS or saline, Tco of the rats was measured again in the same manner as described above. This time point was selected based on our previous result that LPS-induced fever and COX-2 expression were at their maximum between 4 and 5 h after the LPS injection. After Tco was measured, animals were deeply anesthetized with pentobarbital sodium (50 mg/kg ip) and their heads were fixed in a stereotaxic apparatus. The skin of the dorsal neck was cut at the midline, and muscle layers covering the occipital bone were retracted on both sides so that the connective tissue over the cisterna magna would become visible under a stereomicroscope. Cerebrospinal fluid (CSF) was sampled from the cisterna magna by insertion of a 27-gauge stainless steel needle connected to a microsyringe via PE tubing (PE-20, Clay Adams). The CSF samples, between 60 and 100 µl in volume, were expelled into 1.5-ml plastic tubes, quickly frozen in liquid nitrogen, and stored at
80°C until processed for
PGE2 assay. Care was taken not to include blood in the CSF
sample. When CSF samples were colored with blood, they were excluded
from the PGE2 assay. Therefore, the numbers of animals in
Tco measurement and those in PGE2 assay were
not identical. After CSF sampling, the rats were released from the
stereotaxic apparatus and perfused via the left ventricle of the heart
with 100 ml of ice-cold 20 mM phosphate-buffered saline (pH 7.4). The
brains were quickly removed, frozen in dry-ice powder, and stored at
80°C until being processed for immunohistochemistry. The above
experiment was performed in accordance with the ethical guidelines of
Osaka Bioscience Institute and American Physiological Society
(1).
PGE2 enzyme immunoassay. PGE2 in the CSF was extracted with ethyl acetate before the measurement of it by an EIA. The CSF samples (60-90 µl), after addition of 1 ml of H2O (adjusted to pH 3 with HCl) and 1 ml of ethyl acetate, were vigorously mixed and centrifuged for 5 min. The supernatant (i.e., ethyl acetate phase), which contained the extracted PGE2, was transferred to another tube. This extraction procedure was repeated three times for each CSF sample. Then the ethyl acetate was evaporated by vacuum centrifugation, during which the PGE2 was retained at the bottom of the tube. EIA buffer was then added to the tube to dissolve the PGE2, and the EIA was conducted according to the manufacturer's instructions. In a separate experiment using [3H]PGE2, the recovery rate of PGE2 in this extraction protocol was ~95%, so the values presented in this study were adjusted 5% upward.
COX-2 immunohistochemistry.
Brain sections of 14-µm thickness were made in a cryostat at 15°C
and thaw-mounted on 3-aminopropyl-triethoxysilane-coated glass slides.
All of the following protocols were carried out at room temperature
unless otherwise mentioned. After the sections had been air-dried for
30 min, they were fixed with 2% paraformaldehyde in 0.1 M PBS (pH 7.4)
for 10 min. After a rinse with PBS, the sections were treated with 3%
normal goat serum (NGS) and 0.25% Triton X-100 in PBS. Endogenous
biotin activity was blocked with an avidin-biotin blocking kit
according to the manufacturer's instructions. The sections were then
incubated with rabbit anti-murine COX-2 polyclonal antibody (2,000 times dilution in PBS containing 3% NGS and 0.25% Triton X-100) for
60 h at 4°C and subsequently with biotinylated goat anti-rabbit
IgG (200 times dilution) for 1 h. After a rinse, the sections were
incubated with ABC solution (Vectorstain) for 1 h. COX-2-like
immunoreactivity was visualized with DAB and
H2O2. We previously confirmed by Western blot
analysis that the antibody against COX-2 specifically recognized a
protein band ~70 kDa, which corresponded well to the molecular mass
of COX-2 protein (29). The tissue staining with the
anti-COX-2 polyclonal antibody was eliminated when the antibody was
preabsorbed with the antigen peptide (a synthetic 30-mer peptide
identical to the COOH-terminal amino acid sequence of COX-2) or with
purified ovine COX-2 (29). Since the brains had not been
perfusion-fixed with paraformaldehyde but all brain sections were
postfixed on glass slides under the same condition, there was no
possibility of varied COX-2 staining due to varied fixation
state. In addition, three brain sections from pregnant rats and those
from nonpregnant rats were mounted on the same glass slide, and all the
glass slides were processed at the same time with the same treatment
period. This control allowed us to compare the degree of COX-2 staining between the pregnant and nonpregnant rats. To identify the type of
COX-2-positive cells, brain sections were first incubated with rabbit
anti-COX-2 antibody, which was visualized with Cy3-anti-rabbit IgG.
Then the sections were further incubated with sheep anti-von Willebrand
factor, an endothelial marker, which was visualized with
FITC-anti-sheep IgG.
Analysis. Data were expressed as means ± SE. Statistical significance of the difference among multiple groups was examined by the analysis of variance followed by post hoc multiple comparison. The Mann-Whitney U-test was used for comparison between two groups. A P < 0.05 level of significance was set for all statistical analyses. For counting the numbers of COX-2-positive cells in the rostral part of the preoptic area and subarachnoidal space ventral to it, microscopic images were captured with a high-resolution video camera (Olympus) mounted on a microscope (Olympus) and displayed on a high-resolution color monitor. Counting of COX-2-positive cells was made on the display. For each rat, five serial sections were examined and the mean value was obtained.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHOD
RESULTS
DISCUSSION
REFERENCES
|
|---|
Suppressed fever response in near-term pregnant rats.
Table 1 summarizes Tco of
nonpregnant rats and near-term pregnant rats before and 4 h after
injection of LPS or saline. There was no significant difference in
Tco before injection. Four hours after the injection,
Tco of LPS-injected nonpregnant rats was significantly
higher than that of other groups. Figure
1 shows the group means of
Tco changes in nonpregnant and near-term pregnant rats
4 h after the intraperitoneal injection of saline or LPS. In
nonpregnant rats, the mean increase in Tco 4 h after
the injection was 1.69 ± 0.14°C, whereas that after saline
injection was 0.27 ± 0.12°C; and this difference was
statistically significant (P < 0.001). In near-term
pregnant rats, however, the mean increase in Tco after the
LPS injection (0.12 ± 0.14°C) was not significantly different
from that after the saline injection (0.18 ± 0.16°C), and was
significantly smaller than that in the LPS-injected nonpregnant rats
(P < 0.001). Thus the suppression of fever in
near-term pregnant rats was confirmed under the present experimental
conditions.
|
|
PGE2 level in the CSF.
Concentrations of PGE2 in the CSF were measured in
nonpregnant rats and near-term pregnant ones 4 h after the
intraperitoneal injection of saline or LPS (Fig.
2). In both groups of rats, the LPS
injection resulted in a significantly higher PGE2 in the
CSF than did the saline injection [1,196 ± 262 vs. 38 ± 8 pg/ml in the nonpregnant rats (P < 0.01) and 283 ± 67 vs. 24 ± 2 pg/ml in the pregnant rats (P < 0.01), respectively]. However, the PGE2 level in the CSF
of LPS-injected pregnant rats was less than one-third of that of the
LPS-injected nonpregnant ones (P < 0.01). These results imply that LPS-induced PGE2 production was
suppressed in the near-term pregnant rats.
|
Induction of COX-2 by LPS.
We previously showed that PGE2 production in the brain of
LPS-challenged rats was brought through de novo synthesis of COX-2 (7). To examine whether induction of COX-2 is altered
during pregnancy, we carried out immunohistochemical staining for COX-2 in the rat brain. Intraperitoneal injection of LPS but not of saline
induced expression of COX-2 in brain blood vessels by 4 h (Fig. 3,
b and c). The
induction of COX-2 occurred in blood vessels of the entire brain and
was more prominent in veins than in arteries or capillaries. These
COX-2-positive structures were oval- or round-shaped and located in the
most luminal side of the vessels (Fig. 3d). In line with our
previous study in male rats (29), the COX-2-positive
structure corresponded to the nuclear envelope of the endothelial cells
as revealed by triple staining for COX-2, von Willebrand factor, and
nuclear DNA (photos not shown). Figure 3, e-n, shows
LPS-induced COX-2-positive cells of five nonpregnant rats (Fig. 3,
e-i) and of five pregnant rats (Fig. 3, j-n) in
the subarachnoidal space (the ventral part of the central sulcus as
indicated by #1 in Fig. 3a). All of the five nonpregnant
showed a number of intensely stained COX-2-positive structures along
the blood vessel wall. In contrast, COX-2 staining in the pregnant rats
was generally weak in terms of the number of COX-2-positive cells
and the intensity of COX-2 immunostaining (Fig. 3,
j-n).
|
|
|
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHOD
RESULTS
DISCUSSION
REFERENCES
|
|---|
Studies on several animal species demonstrated that fever is
attenuated during near-term pregnancy. This attenuation of fever can be
caused by any suppression in the following steps for fever genesis:
1) production of endogenous pyrogen in response to exogenous pyrogen, 2) enhancement of PGE2 biosynthesis in
the brain by the action of endogenous pyrogen, 3) activation
of PGE2 receptor in the thermoregulatory center, and
4) activation of the efferent neuronal pathway that
increases heat production and decreases heat loss (22,
36). The present study for the first time demonstrated that
LPS-induced PGE2 elevation in the CSF was blunted in the near-term pregnant rats, implicating that the suppression in
steps 2 and/or 1 could be the reasons for the
attenuated fever. Since IL-1
-evoked fever is also attenuated at
near-term pregnancy (38), at least the suppression in
step 2 seems to occur. This idea is further supported by a
recent study demonstrating that IL-1-induced elevation of
PGE2 in the organum vasculosum laminae terminalis is
impaired during pregnancy (13).
The present study further showed that induction of COX-2, an enzyme involved in PG production, was also suppressed in brain endothelial cells at near-term pregnancy, the number of COX-2-positive endothelial cells being approximately one-half of that in the nonpregnant rats. In addition, although not quantitatively analyzed, the intensity of COX-2-immunoreactive signals in individual cells was less in the pregnant rats. Thus the net reduction in LPS-induced COX-2 activity in the pregnant rats seemed to be larger than that estimated from the reduction in the number of COX-2-positive cells. This reduction of COX-2 activity is likely responsible for lower PGE2 levels in the CSF of the pregnant rats and, hence, caused the blunted fever response to LPS.
Although PGE2 may be produced not only by COX-2 but also by COX-1, accumulating evidence indicates that COX-2 in brain endothelial cells is primarily involved in brain PGE2 production during fever. First, a COX-2-selective inhibitor completely suppressed the LPS-induced fever (7) and elevation of PGE2 in the CSF (41). Second, mice lacking the COX-2 gene did not develop fever in response to LPS but those lacking the COX-1 gene did develop fever (25). Finally, COX-2 was induced by various pyrogenic stimuli mainly in brain endothelial cells (3-5, 29).
In addition to the reduced induction of COX-2, there may also be other
factors that could suppress PGE2 elevation in the CSF. There are two other enzyme activities that are essential to
PGE2 biosynthesis (30). One is phospholipase
A2 (PLA2), which cleaves arachidonic acid from
the membrane phospholipids and supplies arachidonic acid to COX as the
substrate. The other is PGE synthase (PGES), which converts
PGH2, the product of COX, to PGE2. Suppression in either of these enzymes should also result in the reduced
PGE2 generation. If this occurs in combination with
suppressed COX-2 induction, the overall attenuation of PGE2
production should be even more prominent. There are a number of
PLA2 subtypes and, unfortunately, it is not yet known if
just one or more of them cooperate with COX-2 in brain endothelial
cells during fever and whether their activity in brain endothelial
cells is reduced at near-term pregnancy. As for PGES, one subtype was
recently cloned from humans and molecularly identified
(19), although there seem to be more unidentified
subtypes. Interestingly, the identified PGES is similar to COX-2 in the
point that it is induced by IL-1 (19) and LPS
(41). Thus it is possible that inductions of COX-2 and
PGES are regulated in a parallel manner and that both inductions are
attenuated at near-term pregnancy.
While we proposed here that production of PGE2 is suppressed at near-term pregnancy, other groups demonstrated that the body temperature response to PGE is suppressed in pregnant rats and that this could be the mechanism for the attenuated fever response. For example, intracerebroventricular injection of PGE1 into near-term pregnant rats evoked fever but with smaller amplitude compared with that into nonpregnant rats (28, 39). Furthermore, in a thermocline environment where they could use behavioral thermoregulatory responses, rats at near-term pregnancy still show an attenuated febrile response to intracerebroventricular injection of PGE1 (11). Arginine vasopressin is supposed to mediate the attenuated response to PGE1 (10), but another study using PGE2 showed an opposite result (8). Thus the mechanism of reduced PGE sensitivity is still equivocal. In addition, at a late stage of pregnancy, cold-induced thermogenesis (18) and stress-induced thermogenesis (14) are also suppressed. Thus, at near-term pregnancy, the effecter system for heat gain is generally suppressed in both autonomically and behaviorally. Considering these facts together, the attenuated fever response at near-term pregnancy seems to be brought about by the suppressions in both production of PGE2 and thermogenic response to it. This may also explain the present finding that although the pregnant rats showed a slight elevation of PGE2 in the CSF, their Tco did not elevate at all.
Is there any adaptive value to the suppressed fever response during pregnancy? It is well known that an elevated body temperature in the mother is harmful to the fetus and prevention of it has an adaptive value. Maternal hyperthermia causes fetal death and fetal brain defects (9, 26, 37), although such toxic effect of hyperthermia is more critical in the earlier gestational stage rather than in the near-term stage.
Another reason might relate with the prevention of premature delivery.
Normal delivery is associated with elevations of PGE2 and
PGF2
in the amniotic fluid, which evoke uterine
contraction (17). These PGs are produced through the
action of COX-2, whose expression seems to be precisely controlled by
the hormonal state. However, when the pregnant animals become infected,
proinflammatory cytokines, COX-2, and PGs are produced, and, as a
result, premature delivery tends to occur (17). To prevent
this unwanted response, pregnant animals establish a state in which the
immune system responds to infection with only mild inflammation.
Urinary trypsin inhibitor and uromoduline are suspected to be a
molecule involved in the suppression of inflammatory responses during
pregnancy (16, 20, 23, 33). It would be interesting to
examine if this molecule is involved in the suppressed COX-2 response
in the present experimental model. If this were the case, suppressed fever itself might not have an adaptive value but rather be a byproduct
of the mechanism that prevents premature delivery.
However, it should be noted again that fever suppression in rats is most evident in the 24-h period before the expected time of parturition, at which time prevention of premature delivery is not necessary. Thus prevention of fever specifically at near term might have another physiological meaning. Recent retrospective cohort analysis on human subjects in the United States indicated that intrapartum fever is a risk factor for neonatal and infant death (34). Although this indicates the correlation between near-term fever and fetal death but not their causal relationship, attenuation of fever might be beneficial to the baby at near term. It is possible that antipyresis during the final stage of gestation may benefit the fetus by preventing excessive oxygen demand.
As discussed above, fever puts deep impact on pregnancy in multiple points, i.e., organogenesis, maintenance of pregnancy, and parturition, and there might be multiple endogenous antipyretic/anti-inflammatory mechanisms in operation during pregnancy. The present study for the first time demonstrated that, at near-term pregnancy, an attenuated production of both COX-2 and PGE2 in the brain is one possible mechanism of antipyresis and pinpointed the next question of how COX-2 inductions are suppressed at this stage. While this paper was under review, Mouihate et al. (32) demonstrated that both basal and LPS-induced COX-2 expression are reduced in rat hypothalamus at near term. They analyzed COX-2 protein by Western blot, while we did it by immunohistochemistry. These two studies are complementary since the former certified the molecular weight of COX-2-like immunoreactivity and the latter depicted its cellular distribution.
| |
ACKNOWLEDGEMENTS |
|---|
This work was partly supported by grant-in-aid for Scientific Research (C) to K. Imai-Matsumura and (B) to K. Matsumura from Japan Society for the Promotion of Science, and Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government.
| |
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: K. Matsumura, Dept. of Intelligence Science and Technology, Graduate School of Informatics, Kyoto Univ., Kyoto 606-8501, Japan (E-mail: matsu{at}i.kyoto-u.ac.jp).
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 August 29, 2002;10.1152/ajpregu.00396.2002
Received 7 July 2002; accepted in final form 24 August 2002.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHOD
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
American Physiological Society.
Guiding principles for research involving animals and human beings.
Am J Physiol Regul Integr Comp Physiol
283:
R281-R283,
2002
2.
Breder, CD,
and
Saper CB.
Expression of inducible cyclooxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolysaccharide.
Brain Res
713:
64-69,
1996[ISI][Medline].
3.
Cao, C,
Matsumura K,
Ozaki M,
and
Watanabe Y.
Lipopolysaccharide injected into the cerebral ventricle evokes fever through induction of cyclooxygenase-2 in brain endothelial cells.
J Neurosci
19:
716-725,
1999
4.
Cao, C,
Matsumura K,
Yamagata K,
and
Watanabe Y.
Cyclooxygenase-2 is induced in brain blood vessels during fever evoked by peripheral or central administration of tumor necrosis factor.
Brain Res Mol Brain Res
56:
45-56,
1998[Medline].
5.
Cao, C,
Matsumura K,
Yamagata K,
and
Watanabe Y.
Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1: a possible site of prostaglandin synthesis responsible for fever.
Brain Res
733:
263-272,
1996[ISI][Medline].
6.
Cao, C,
Matsumura K,
Yamagata K,
and
Watanabe Y.
Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain; its possible role in the febrile response.
Brain Res
697:
187-196,
1995[ISI][Medline].
7.
Cao, C,
Matsumura K,
Yamagata K,
and
Watanabe Y.
Involvement of cyclooxygenase-2 in LPS-induced fever and regulation of its mRNA in the rat brain by LPS.
Am J Physiol Regul Integr Comp Physiol
272:
R1712-R1725,
1997
8.
Chen, X,
Hirasawa M,
Takahashi Y,
Landgraf R,
and
Pittman QJ.
Suppression of PGE2 fever at near term: reduced thermogenesis but not enhanced vasopressin antipyresis.
Am J Physiol Regul Integr Comp Physiol
277:
R354-R361,
1999
9.
Edwards, MJ.
The experimental production of clubfoot in guinea-pigs by maternal hyperthermia during gestation.
J Pathol
103:
49-53,
1971[ISI][Medline].
10.
Eliason, HL,
and
Fewell JE.
AVP mediates the attenuated febrile response to administration of PGE1 in rats near term of pregnancy.
Am J Physiol Regul Integr Comp Physiol
275:
R691-R696,
1998
11.
Eliason, HL,
and
Fewell JE.
Influence of pregnancy on the febrile response to ICV administration of PGE1 in rats studied in a thermocline.
J Appl Physiol
82:
1453-1458,
1997
12.
Elmquist, JK,
Breder CD,
Sherin JE,
Scammell TE,
Hickey WF,
Dewitt D,
and
Saper CB.
Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages.
J Comp Neurol
381:
119-129,
1997[ISI][Medline].
13.
Fewell, JE,
and
Eliason HL.
Pregnancy impairs central prostaglandin release and the febrile response to intravenous IL-1 in rats.
FASEB J
15:
A1105,
2001.
14.
Fewell, JE,
and
Tang PA.
Pregnancy alters body-core temperature response to a simulated open field in rats.
J Appl Physiol
82:
1406-1410,
1997
15.
Futaki, N,
Yoshikawa K,
Hamasaka Y,
Arai I,
Higuchi S,
Iizuka H,
and
Otomo S.
NS-389, a novel nonsteroidal anti-inflammatory drug with potent analgesic and antipyretic effects, which causes minimal stomach lesions.
Gen Pharmacol
24:
105-110,
1993[ISI][Medline].
16.
Futamura, Y,
Kajikawa S,
Kaga N,
and
Shibutani Y.
Protection against preterm delivery in mice by urinary trypsin inhibitor.
Obstet Gynecol
93:
100-108,
1999
17.
Gravett, MG,
Witkin SS,
Haluska GJ,
Edwards JL,
Cook MJ,
and
Novy MJ.
An experimental model for intraamniotic infection and preterm labor in rhesus monkeys.
Am J Obstet Gynecol
171:
1660-1667,
1994[ISI][Medline].
18.
Imai-Matsumura, K,
Matsumura K,
Morimoto A,
and
Nakayama T.
Suppression of cold-induced thermogenesis in full-term pregnant rats.
J Physiol
425:
271-281,
1990
19.
Jakobsson, PJ,
Thoren S,
Morgenstern R,
and
Samuelsson B.
Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target.
Proc Natl Acad Sci USA
96:
7220-7225,
1999
20.
Kajikawa, S,
Kaga N,
Futamura Y,
and
Shibutani Y.
Tocolytic effect of magnesium sulfate and/or urinary trypsin inhibitor against lipopolysaccharide-induced preterm delivery in mice.
Acta Obstet Gynecol Scand
77:
598-602,
1998[ISI][Medline].
21.
Kasting, NW,
Veale WL,
and
Cooper KE.
Suppression of fever at term of pregnancy.
Nature
271:
245-246,
1978[Medline].
22.
Kluger, MJ.
Fever: role of pyrogens and cryogens.
Physiol Rev
71:
93-127,
1991[Abstract].
23.
Kobayashi, H,
Suzuki K,
Sugino D,
and
Terao T.
Urinary trypsin inhibitor levels in amniotic fluid of normal human pregnancy: decreased levels observed at parturition.
Am J Obstet Gynecol
180:
141-147,
1999[ISI][Medline].
24.
Kujubu, DA,
Fletcher BS,
Varnum BC,
Lim RW,
and
Herschman HR.
TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue.
J Biol Chem
266:
12866-12872,
1991
25.
Li, S,
Wand Y,
Matsumura K,
Ballou LR,
Morham SG,
and
Blatteis CM.
The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2 (/), but not in cyclooxygenase-1 (/) mice.
Brain Res
825:
86-94,
1999[ISI][Medline].
26.
Macfarlane, VW,
Pennycuik PR,
and
Thrift E.
Resorption and loss of foetuses in rats living at 35°C.
J Physiol
135:
451-459,
1957
27.
Martin, SM,
Malkinson TJ,
Veale WL,
and
Pittman QJ.
Fever in pregnant, parturient, and lactating rats.
Am J Physiol Regul Integr Comp Physiol
268:
R919-R923,
1995
28.
Martin, SM,
Malkinson TJ,
Veale WL,
and
Pittman QJ.
Prostaglandin fever in rats throughout the estrous cycle late pregnancy and post parturition.
J Neuroendocrinol
8:
145-151,
1996[ISI][Medline].
29.
Matsumura, K,
Cao C,
Ozaki M,
Morii H,
Nakadate K,
and
Watanabe Y.
Brain endothelial cells express cyclooxygenase-2 during lipopolysaccharide-induced fever: light and electron microscopic immunocytochemical studies.
J Neurosci
18:
6279-6289,
1998
30.
Matsumura, K,
Cao C,
Watanabe Y,
and
Watanabe Y.
Prostaglandin system in the brain: sites of biosynthesis and sites of action under normal and hyperthermic conditions.
Prog Brain Res
115:
275-295,
1998[ISI][Medline].
31.
Milton, AS.
Prostaglandins in fever and the mode of action of antipyretic drugs.
In: Pyretics and Antipyretics, edited by Milton AS.. Berlin: Springer-Verlag, 1982, p. 259-267.
32.
Mouihate, A,
Clerget-Froidevaux MS,
Nakamura K,
Negishi M,
Wallace JL,
and
Pittman QJ.
Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus.
Am J Physiol Regul Integr Comp Physiol
283:
R800-R805,
2002
33.
Muchmore, A,
and
Decker J.
Uromoduline. An immunosuppressive 85-kilodalton glycoprotein isolated from human pregnancy urine is a high affinity ligand for recombinant interleukin 1 alpha.
J Biol Chem
26:
13404-13407,
1986.
34.
Petrova, A,
Demissie K,
Rhoads GG,
Smulian JC,
Marcella S,
and
Ananth CV.
Association of maternal fever during labor with neonatal and infant morbidity and mortality.
Obstet Gynecol
98:
20-27,
2001
35.
Quan, N,
Whiteside M,
and
Herkenham M.
Cyclooxygenase 2 mRNA expression in rat brain after peripheral injection of lipopolysaccharide.
Brain Res
802:
189-197,
1998[ISI][Medline].
36.
Rothwell, NJ.
Neuroimmune interactions: the role of cytokines.
Br J Pharmacol
121:
841-847,
1997[ISI].
37.
Shah, MK.
Reciprocal egg transplantation to study the embryo-uterine relationship in heat induced failure of pregnancy in rabbits.
Nature
177:
1134-135,
1956[Medline].
38.
Simrose, RL,
and
Fewell JE.
Body temperature response to IL-1 in pregnant rats.
Am J Physiol Regul Integr Comp Physiol
269:
R1179-R1182,
1995
39.
Stobie-Hayes, KM,
and
Fewell JE.
Influence of pregnancy on the febrile response to intracerebroventricular administration of PGE1 in rats.
J Appl Physiol
81:
1312-1315,
1996
40.
Xie, WL,
Chipman JG,
Robertson DL,
Erikson RL,
and
Simmons DL.
Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing.
Proc Natl Acad Sci USA
88:
2692-2696,
1991
41.
Yamagata, K,
Matsumura K,
Inoue W,
Shiraki T,
Suzuki K,
Yasuda S,
Sugiura H,
Cao C,
Watanabe Y,
and
Kobayashi S.
Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever.
J Neurosci
21:
2669-2677,
2001
42.
Zeisberger, E,
Merker G,
and
Blahser S.
Fever response in the guinea pig before and after parturition.
Brain Res
212:
379-392,
1981[ISI][Medline].
This article has been cited by other articles:
|
|
 |
|
  S. J. Spencer, A. Mouihate, M. A. Galic, and Q. J. Pittman Central and peripheral neuroimmune responses: hyporesponsiveness during pregnancy J. Physiol., January 15, 2008; 586(2): 399 - 406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Aguilar-Valles, S. Poole, Y. Mistry, S. Williams, and G. N. Luheshi Attenuated fever in rats during late pregnancy is linked to suppressed interleukin-6 production after localized inflammation with turpentine J. Physiol., August 15, 2007; 583(1): 391 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. Begg, S. Kent, M. J. McKinley, and M. L. Mathai Suppression of endotoxin-induced fever in near-term pregnant rats is mediated by brain nitric oxide Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2007; 292(6): R2174 - R2178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ashdown, S. Poole, P. Boksa, and G. N. Luheshi Interleukin-1 receptor antagonist as a modulator of gender differences in the febrile response to lipopolysaccharide in rats Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1667 - R1674. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Moore and J. E. Fewell Mifepristone (RU38486) influences the core temperature response of term pregnant rats to intraperitoneal lipopolysaccharide Exp Physiol, July 1, 2006; 91(4): 741 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mouihate, S. Ellis, E.-M. Harre, and Q. J. Pittman Fever suppression in near-term pregnant rats is dissociated from LPS-activated signaling pathways Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2005; 289(5): R1265 - R1272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Scholz Prostaglandins Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2003; 285(3): R512 - R514. [Full Text] [PDF]
|
|
|
|
|
|
A. A. Romanovsky and S. R. Petersen The spleen: another mystery about its function Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2003; 284(6): R1378 - R1379. [Full Text] [PDF]
|
|
|
|
|
|
H. Scholz Fever Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2003; 284(4): R913 - R915. [Full Text] [PDF]
|
|
|
|
|
|
A. I. Ivanov, A. A. Romanovsky, K. Matsumura, A. Mouihate, M. S. Clerget-Froidevaux, J. L. Wallace, and Q. J. Pittman Near-term suppression of fever: inhibited synthesis or accelerated catabolism of prostaglandin E2? Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2003; 284(3): R860 - R865. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
, Values from 4 LPS-injected nonpregnant rats;
, values from 4 LPS-injected pregnant rats. Correlation
is significant (P < 0.01).