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Following are the abstracts of the articles discussed in the subsequent letter:
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ABSTRACT |
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Imai-Matsumura, Kyoko, Kiyoshi Matsumura, Akira Terao, and
Yasuyoshi Watanabe. Attenuated fever in pregnant rats is associated with blunted syntheses
of brain cyclooxygenase-2 and PGE2. Am J Physiol
Regul Integr Comp Physiol 283: R1346-R1353, 2002.
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.
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ABSTRACT |
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Mouihate, A., M.-S. Clerget-Froidevaux, K. Nakamura, M. Negishi, J. L. Wallace, and Q. J. Pittman. 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.The
fever response is blunted at near term. As the enzyme cyclooxygenase-2
(COX-2) plays a critical role in fever development, we measured its
expression in rat hypothalamus during pregnancy and lactation. Western
blot analysis revealed a 72-kDa COX-2-immunoreactive band in
non-immune-challenged, pregnant rats at day 15 of pregnancy.
In contrast, it was almost undetectable at near term and at lactation
day 5. COX-2 was significantly induced at the 15th day of
pregnancy and at the 5th lactating day after intraperitoneal
lipopolysaccharide (50 µg/kg). However, this COX-2 induction was
significantly reduced at near term compared with values before and
after term. The protein levels of the EP3 receptor in the hypothalamus,
one of the prostaglandin E2 (PGE2) receptors suggested to be a key receptor for fever induction, were unaffected throughout the pregnancy and lactation in both non-immune-challenged and lipopolysaccharide-treated rats. These data suggest that
suppression of fever at near term is associated with a significantly
reduced induction of COX-2 by lipopolysaccharide, resulting in a
reduced production of PGE2. Altered expression of the EP3
receptor does not seem to be involved in this fever refractoriness at
near term.
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LETTER |
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To the Editor: Recently, Mouihate et al. (12) and Imai-Matsumura et al. (6) proposed the intriguing hypothesis that decreased febrile responsiveness to LPS and cytokines at near term reflects the reduced expression of a PGE2-synthesizing enzyme cyclooxygenase (COX)-2. The importance of this hypothesis was promptly recognized (14). The hypothesis is based on the observations that LPS-induced expression of COX-2 protein (12) and increase in the number of COX-2-positive cells (6) in the hypothalamus were both attenuated (<2-fold) in pregnant rats. Although profound pharmacological or genetic blockade of COX-2 does suppress fever, the febrile response is probably insensitive to small changes in COX-2 expression. Indeed, in vitro studies (for review, see Ref. 16) question a rate-limiting role for COX within the PGE2-synthesizing cascade, whereas recent in vivo data (7, 8) demonstrate the lack of correlation between the tissue level of COX-2 (protein or mRNA) and either the concentration of PGE2 or the height of fever. Consistent with these data, Imai-Matsumura et al. (6) found that some LPS-treated pregnant rats showed the number of COX-2-positive cells well within the range observed in their nonpregnant counterparts but still exhibited a blunted PGE2 response (Fig. 6). This finding suggests involvement of a COX-2-independent mechanism. The existence of such a mechanism is strongly evidenced by the attenuated thermal response of pregnant rats to central administration of PGE2 (3, 11, 17).
The brain level of PGE2 reflects not only synthesis but also clearance of this mediator from the brain through the choroid plexus with subsequent inactivation by the lungs and liver. Transport and inactivation of PGE2 involve multiple proteins; the rate-limiting PGE2-inactivating enzyme is 15-hydroxy-PG dehydrogenase (15-PGDH) (5). Noteworthy, pharmacological inhibition of PGE2 efflux from the brain increases the pyrogenic activity of intrabrain PGE2 (1). LPS-induced transcriptional downregulation of four PGE2-transporting and -catabolizing proteins in the lungs and liver was found in our recent study (9); the gene suppressed most quickly (<30 min, latency) and most strongly (>25-fold) was 15-PGDH. Because the half-life of this enzyme is short, <50 min, transcriptional inhibition of 15-PGDH readily changes the protein level (2) and is likely to be of physiological significance for maintaining the febrile response (9).
Transport and catabolism of PGE2 are affected by pregnancy,
during which the uptake of PGF2
by the choroid plexus is accelerated (10). A similar acceleration of the
brain-to-blood efflux should be expected for PGE2, which is
carried by the same transporters (15). Even more
importantly, late pregnancy is accompanied by a strong transcriptional
upregulation and dramatic (50-fold) increase in the activity of 15-PGDH
in the lungs and other organs (13). That progesterone
induces 15-PGDH expression (18) may provide a triggering
mechanism for the upregulation of this enzyme.
We suggest that pregnancy-associated antipyresis reflects a facilitated efflux of PGE2 from the brain with facilitated catabolism in the lungs and liver. Such facilitation is the result of the expressional upregulation of PGE2 carriers and 15-PGDH. This hypothesis explains a wide range of phenomena observed in pregnant animals: the suppressed febrile response to peripheral LPS and cytokines (for review, see Refs. 6, 12), the blunted increase in brain PGE2 in response to peripheral LPS (6) and cytokines (4), and the decreased thermal response to central PGE2 (3, 11, 17). The facilitated transport and catabolism may play an adaptive role by protecting the body from the undesired systemic effects of PGs massively produced in the reproductive tract at near term.
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REFERENCES |
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Eliason, HL,
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Influence of pregnancy on the febrile response to ICV administration of PGE1 in rats studied in a thermocline.
J Appl Physiol
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Fewell, JE,
Eliason HL,
and
Auer RN.
Peri-OVLT E-series prostaglandins and core temperature do not increase after intravenous IL-1
in pregnant rats.
J Appl Physiol
93:
531-536,
2002
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Imai-Matsumura, K,
Matsumura K,
Terao A,
and
Watanabe Y.
Attenuated fever in pregnant rats is associated with blunted syntheses of brain cyclooxygenase-2 and PGE2.
Am J Physiol Regul Integr Comp Physiol
283:
R1346-R1353,
2002
7.
Inoue, W,
Matsumura K,
Yamagata K,
Takemiya T,
Shiraki T,
and
Kobayashi S.
Brain-specific endothelial induction of prostaglandin E2 synthesis enzymes and its temporal relation to fever.
Neurosci Res
44:
51-61,
2002[ISI][Medline].
8.
Ivanov, AI,
Pero RS,
Scheck AC,
and
Romanovsky AA.
Prostaglandin E2-synthesizing enzymes in fever: differential transcriptional regulation.
Am J Physiol Regul Integr Comp Physiol
283:
R1104-R1117,
2002
9.
Ivanov, AI,
Scheck AC,
and
Romanovsky AA.
Expression of genes controlling transport and catabolism of prostaglandin E2 in lipopolysaccharide fever.
Am J Physiol Regul Integr Comp Physiol
284:
R698-R706,
2003
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Krunic, N,
Adamson SL,
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Martin, SM,
Malkinson TJ,
Veale WL,
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Prostaglandin fever in rats throughout the estrous cycle late pregnancy and post parturition.
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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
13.
Okita, RT,
and
Okita JR.
Prostaglandin-metabolizing enzymes during pregnancy: characterization of NAD+-dependent prostaglandin dehydrogenase, carbonyl reductase, and cytochrome P450-dependent prostaglandin omega-hydroxylase.
Crit Rev Biochem Mol Biol
31:
101-126,
1996[ISI][Medline].
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Roth, J,
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What suppresses fever in pregnancy near term?
Am J Physiol Regul Integr Comp Physiol
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Tong, M,
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Induction of NAD+-linked 15-hydroxyprostaglandin dehydrogenase expression by androgens in human prostate cancer cells.
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|
Andrei I. Ivanov Department of Pathology and Laboratory Medicine Emory University Atlanta, Georgia 30322 | ||||||||||||
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Andrej A. Romanovsky Trauma Research St. Joseph's Hospital and Medical Center Phoenix, Arizona 85013 E-mail: aromano{at}chw.edu |
To the Editor: Attenuation of fever at near-term
pregnancy has been reported to occur in ewes (10), guinea pigs (21), and rats (12). Although more than 30 years have passed since the first
report of this phenomenon by Kasting et al. (10), the mechanism
underlying it is not yet fully understood. Recent papers from three
independent groups (3, 6, 16) have shed light on this issue by showing
an alteration in brain PGE2 biosythesis as a possible cause
of suppressed fever in near-term rats. Imai-Matsumura et al. (6) and
Fewell et al. (3) reported that near-term rats injected with either LPS
or interleukin-1 In response to the above idea, Ivanov and Romanovsky raised the
question as to whether the blunted COX-2 induction is really the cause
of the lowered PGE2 level. As the basis for this question, they cited two papers, one from their group (8) and one from our group
(7), and stated, "recent in vivo data demonstrate the lack of
correlation between the tissue level of COX-2 and either the
concentration of PGE2 or the height of fever." We are afraid that this sentence is oversimplified and may mislead the readers. In fact, the study by Inoue et al. (7) showed a good correlation between COX-2 protein and PGE2 level in a
limited time window. In that study, LPS was injected into male adult
rats intraperitoneally at a dose of 100 µg/kg. Their cerebrospinal fluid (CSF) and brain were sampled at seven time points, i.e., 0 min,
45 min, 1.5 h, 3 h, 5 h, 12 h, and 24 h after
the LPS injection. Up to 3 h after the injection, the amount of
induced COX-2 protein and CSF PGE2 level correlated well.
Thus the time point of 3 h taken by Mouihate et al. (16) was
reasonable. In addition, Imai-Matsumura et al. (6) showed a good
correlation between the PGE2 level and the number of
COX-2-positive cells at 4 h after LPS injection into female rats
(Fig. 6 in the paper). In respect to this correlation plot, Ivanov and
Romanovsky pointed out that one nonpregnant rat had a higher
PGE2 value with a smaller number of COX-2-positive cells
than two of the pregnant rats, suggesting that the amount of COX-2 is
not the major determinant of the PGE2 level. However, because the number of animals analyzed was small, it is hard to draw
any conclusion from one split point. Although it is possible that some
factor other than COX-2 influenced the PGE2 level around this time point, the correlation between COX-2 and PGE2 was
still good as a whole at 4 h after the LPS injection. Therefore,
we consider that blunted COX-2 induction in the brain at near term is
one of the major causes of the lowered PGE2 level in the CSF.
On the other hand, Inoue et al. (7) showed that, at 5 h after the
LPS injection, the PGE2 level decreased by 50% from the level at 3 h, whereas COX-2 protein level was comparable to that at 3 h. Thus, if we expand the time window up to 5 h,
"the lack of correlation" becomes apparent. We speculate that an
additional mechanism that lowers the PGE2 level was
activated around 5 h after LPS injection and later. Perhaps it
might be the so-called endogenous antipyretic mechanism, which may
involve antipyretic peptides, glucocorticoid,
PGE2-catabolizing enzymes, P-450 products of arachidonic
acid, or PGE2 transporter for the clearance. This is
another important issue for future study.
As an alternative hypothesis, Ivanov and Romanovsky proposed that
accelerated PGE2 catabolism at near term could be the cause of the lowered PGE2 level in the brain and, thereby, the
cause of suppressed fever. They recently demonstrated in male rats that intravenous injection of LPS downregulated PG-catabolizing enzymes and
PG-transporting proteins in the lung and liver, but not in the brain
(9). They speculated that reduced PGE2 catabolism in the
peripheral organs may cause an elevation in circulating PGE2 level, which, in turn, reduces the brain-blood
PGE2 gradient. This may contribute to keeping high levels
of PGE2 in the brain during fever. In relation to near-term
suppression of fever, they referred studies from other groups showing
that PG dehydrogenase (PGDH), a major PGE2-catabolizing
enzyme, is upregulated in the lung and reproductive organs at near term
in rabbits and rats (18). Upregulation of PGDH in these organs may
lower the PGE2 level in the circulation, increase the
brain-blood PGE2 gradient, and accelerate the clearance of
PGE2 from the brain. However, it should be noted that
circulating levels of PGs, including PGE2, increase
dramatically during pregnancy (17, 19), probably because enhanced PG
production in reproductive organs overwhelms PG catabolism by PGDH. If
PGE2 level increases in the arterial blood during
pregnancy, the brain-blood PGE2 gradient should be lower in
pregnant animals than in nonpregnant ones. Unfortunately, as far as I
know, there is no study that compared the arterial PGE2
level between pyrogen-treated pregnant and non-pregnant animals. Thus
the hypothesis by Ivanov and Romanovsky is intriguing but needs further
verification. Pregnancy is accompanied by alterations in various
physiological responses, including reduced febrile response to
PGE2 (2, 13) and suppressed thermogenesis in the cold (5).
Therefore, it would be reasonable to consider that multiple mechanisms
are involved in the near-term suppression of fever, and the suppressed
COX-2 induction at near term is one of the major mechanisms. Whatever
the truth may be, the argument by Ivanov and Romanovsky is of value
because it reminds us that PGE2 and fever should be
discussed on the basis of the production, reception, and clearance of
PGE2.
REPLY
showed lower PGE2 levels in their brain
extracellular fluid than nonpregnant female rats treated in the same
way. Imai-Matsumura et al. (6) and Mouihate et al. (16) further showed
LPS-induced cyclooxygenase-2 (COX-2) expression in the rat brain was
blunted at near-term pregnancy. Inasmuch as COX-2 is one of the
rate-limiting enzymes in PGE2 biosynthesis and is essential
to fever (1, 4, 11, 14, 15, 20), the above results suggest that blunted
induction of brain COX-2 lowers the extracellular PGE2
level, which, in turn, leads to suppression of fever in near-term rats.
| |
REFERENCES |
|---|
1.
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
2.
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.
3.
Fewell, JE,
Eliason HL,
and
Auer RN.
Peri-OVLT E-series prostaglandins and core temperature do not increase after intravenous IL-1 in pregnant rats.
J Appl Physiol
93:
531-536,
2002.
4.
Herschman, HR.
Prostaglandin synthase.
Biochim Biophys Acta
1299:
125-140,
1996[Medline].
5.
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
6.
Imai-Matsumura, K,
Matsumura K,
Terao A,
and
Watanabe Y.
Attenuated fever in pregnant rats is associated with blunted syntheses of brain cyclooxygenase-2 and PGE2.
Am J Physiol Regul Integr Comp Physiol
283:
R1346-R1353,
2002
7.
Inoue, W,
Matsumura K,
Yamagata K,
Takemiya T,
Shiraki T,
and
Kobayashi S.
Brain-specific endothelial induction of prostaglandin E2 synthesis enzymes and its temporal relation to fever.
Neurosci Res
44:
51-61,
2002[ISI][Medline].
8.
Ivanov, AI,
Pero RS,
Scheck AC,
and
Romanovsky AA.
Prostaglandin E2-synthesizing enzymes in fever: differential transcriptional regulation.
Am J Physiol Regul Integr Comp Physiol
283:
R1104-R1117,
2002
9.
Ivanov, AI,
Scheck AC,
and
Romanovsky AA.
Expression of genes controlling transport and catabolism of prostaglandin E2 in lipopolysaccharide fever.
Am J Physiol Regul Integr Comp Physiol
284:
R698-R706,
2002
10.
Kasting, NW,
Veale WL,
and
Cooper KE.
Suppression of fever at term of pregnancy.
Nature
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Li, S,
Wang Y,
Matsumura K,
Ballou LR,
Morham SG,
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Blatteis CM.
The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2 (
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Martin, SM,
Malkinson TJ,
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Martin, SM,
Malkinson TJ,
Veale WL,
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Pittman QJ.
Prostaglandin fever in rats throughout the estrous cycle late pregnancy and post parturition.
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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.
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Matsumura, K,
Cao C,
Watanabe Y,
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16.
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
17.
Mucha, I,
and
Losonczy G.
Prostaglandin E2 and gestational hypotension in rabbits.
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18.
Okita, RT,
and
Okita JR.
Prostaglandin-metabolizing enzymes during pregnancy: characterization of NAD(+)-dependent prostaglandin dehydrogenase, carbonyl reductase, and cytochrome P450-dependent prostaglandin omega-hydroxylase.
Crit Rev Biochem Mol Biol
31:
101-126,
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Venuto, RC,
and
Donker AJ.
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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
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21.
Zeisberger, E,
Merker G,
and
Blahser S.
Fever response in the guinea pig before and after parturition.
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|
Kiyoshi Matsumura Department of Intelligence Science and Technology Graduate School of Informatics Kyoto University Kyoto 606-8501, Japan E-mail: matsu{at}i.kyoto-u.ac.jp |
To the Editor: The suppression of fever at near term
appears to be a feature of most mammalian species studied to date (16), yet the mechanism responsible for this has eluded definition for over
20 years (19). Our recent demonstration (13) that both basal and
LPS-stimulated cyclooxygenase-2 (COX-2) levels were reduced at near
term provided a possible explanation for at least some of the reduced
response. As COX-2 is considered the rate-limiting enzyme for the
synthesis of PGE2, we postulated that a reduction in the
levels of COX-2, as demonstrated by semi-quantitative Western blot of
hypothalamic proteins, would result in reduced synthesis of
PGE2 and consequently a reduced fever. This finding has now been corroborated in two other publications. Fewell and colleagues (5)
carried out microdialysis of the preoptic area and analyzed PGE2 levels in the dialysates in response to intravenous
recombinant rat interleukin-1 Nonetheless, Ivanov and Romanovsky question both the correlation
between COX-2 levels and the magnitude of fever and our conclusion that
reduced PGE2 levels, due to reduced COX-2 activity, are, in
part, responsible for the reduced fever at term. They raise another
possibility, that of accelerated catabolism or efflux of
PGE2. Their comments are welcomed, as we also feel that
there may be more than one alteration in the cascade of events leading to fever that occur at term. However, some of their points reflect a
possible misunderstanding of our data and the published literature and
we will take this opportunity to clarify some of the issues they raised.
As they point out, the reduction in COX-2 levels we report is of
the order of 40%, and they question whether this is sufficient to
affect either the level of PGE2 or the magnitude of fever. Although this is a valid consideration, it would appear that the data
in the papers by Fewell et al. (5) and Imai-Matsumura et al. (6)
clearly indicate that PGE2 levels are indeed suppressed. Furthermore, Imai-Matsumura et al. (6) demonstrate an excellent correlation between PGE2 levels in the cerebrospinal fluid
and the numbers (and intensity of staining) of immunoreactive COX-2 cells after LPS. It is also noteworthy that COX-2 exists in the hypothalamus both in neurons under basal conditions (1) and in
endothelial and perivascular cells where it is induced by inflammatory stimuli (10, 12, 18, 20). Our extraction of the entire basal
hypothalamus and preoptic area undoubtedly included all of these cell
populations, and the true reduction of COX-2 in the cells responsible
for the PGE2 production important in the febrile process is
almost certainly much greater than that we were able to show.
Ivanov and Romanovsky also question a rate-limiting role of COX-2, as
they cite references purporting to demonstrate a lack of
correlation between the concentration of brain PGE2 and the magnitude of the fever. This appears to be a misinterpretation of the
data in these and other papers dealing with this issue. Matsumura et
al. (12) reported an excellent correlation between COX-2 levels and
the height and duration of fever (see their Fig. 7), a finding
complimented by a report that COX-2 inhibitors simultaneously suppressed both cerebrospinal PGE2 levels and fever (22).
Even the papers (7, 8) cited by Ivanov and Romanovsky both report an
excellent temporal relation between the expression of COX-2 in
endothelial cells, the elevation of PGE2 in cerebrospinal
fluid and the onset of fever at the time points when we collected our tissue (3 h after LPS). Where the relationship between these factors is
altered appears after the fever is entering a defervescence stage, when
endogenous antipyretics may become involved (3).
The alternate mechanism proposed by Ivanov and Romanovsky, that
of increased catabolism and transport of PGE2 from the
brain, could indeed contribute to the reduced fevers, given that
prostaglandins involved in fever appear to be inactivated via an efflux
from the hypothalamus (4, 21). Furthermore, such a mechanism would be
compatible with our observations of reduced central response to
PGE2 at near term (2, 11). However, the role in fever suppression of catabolism of PGE2 by the major catabolizing
enzyme 15-hydroxy-PG dehydrogenase (15-PGDH) is still an open question. This enzyme is induced by progesterone, a hormone whose levels and
activity vary dramatically during pregnancy. If this enzyme is indeed
important in controlling PGE2 levels (and by extension, fever magnitude), it is curious that at gestational day 15,
when there is little fever suppression, progesterone levels are at their highest in the rat, whereas at term, progesterone levels have
declined precipitously (15). In line with this observation, and in
contrast to what is suggested by Ivanov and Romanovsky, it has been
reported that 15-PDGH activity in a number of rat tissues decreases
significantly at parturition (14). Thus these facts cast some doubt on
an obligatory role for enhanced 15-PDGH activity in the suppression of
fever at term. However, as much of the data on the role(s) and
regulation of this and other catabolic enzymes during pregnancy have
been obtained in other species, in nonneuronal tissue, or from tissue
in vitro, this is an area requiring further study.
Also in need of further study is an examination of the expression,
throughout pregnancy, of other EP receptors and central nervous system
transmitters thought to be involved in thermogenesis (17). It will also
be important to determine the mechanism for the suppressed COX-2
induction, which may be due to alterations in levels of both
inflammatory and anti-inflammatory cytokines or hormonal action on
upstream regulators of COX-2. Our demonstration of suppressed COX-2
represents but the first step in our understanding of this fascinating response.
REPLY
. Whereas nonpregnant rats displayed
increases in PGE2 in concert with the elevation of body
temperature [as reported previously by Komaki et al. (9)], rats at
near term displayed neither a fever nor an elevation in
PGE2 levels. Similarly, a recent report by Imai-Matsumura
et al. (6) reported reduced fever, reduced cerebrospinal fluid
PGE2 levels, and significantly fewer COX-2-immunoreactive
endothelial cells in the preoptic area in response to LPS injection in
rats at term. Thus three independent groups have almost simultaneously
reported similar and complementary data and all have arrived at the
same conclusion, namely that there is a suppression of COX-2 activity
and concomitant PGE2 synthesis at term. It is important to
note that we and Imai-Matsumura and colleagues (6) both recognized that
other factors, downstream from PGE2 synthesis, could also
be involved in the suppression of fever. For this reason, we also
examined the levels of the PGE2 receptor, EP3
at term, but found that they did not change. In an editorial focus
accompanying our publication, Roth and Persson (19) also suggest that
there may be enhanced synthesis of endogenous antipyretics, another
avenue we have also pursued (2).
| |
FOOTNOTES |
|---|
10.1152/ajpregu.00618.2002
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|
A. Mouihate, 1 M. S. Clerget-Froidevaux, 1 J. L. Wallace, 2 Q. J. Pittman1 1 Neuroscience Research Group and 2 Mucosal Inflammation Research Group Department of Physiology and Biophysics Faculty of Medicine University of Calgary Alberta, T2N 4N1 Canada E-mail: pittman{at}ucalgary.ca |
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