Vol. 278, Issue 5, R1275-R1281, May 2000
Evidence that platelet-derived growth factor may be a novel
endogenous pyrogen in the central nervous system
Irene R.
Pelá1,
Márcia E. S.
Ferreira1,
Miriam C. C.
Melo1,
Carlos A. A.
Silva1,
Márcio M.
Coelho2, and
C.
Fernando
Valenzuela3
1 Laboratory of Pharmacology, School of
Pharmaceutical Sciences of Ribeirão Preto, University of
São Paulo, Ribeirão Preto, São Paulo;
2 Laboratory of Pharmacology, School of Pharmacy,
Federal University of Minas Gerais, Belo Horizonte, Minas Gerais,
Brazil; and 3 Department of Neurosciences,
University of New Mexico Health Sciences Center, Albuquerque, New
Mexico 87131
 |
ABSTRACT |
Platelet-derived growth factor (PDGF) exerts neurotrophic and
neuromodulatory actions in the mammalian central nervous system (CNS).
Like the cytokines, PDGF primarily signals through tyrosine phosphorylation-dependent pathways that activate multiple intracellular molecules including Janus family kinases. We previously showed that
microinjection of PDGF-BB into the lateral ventricle induced a febrile
response in rats that was reduced by pretreatment with Win 41662, a
potent inhibitor of PDGF receptors (Pelá IR, Ferreira MES, Melo
MCC, Silva CAA, and Valenzuela CF. Ann NY Acad Sci 856: 289-293, 1998). In this study, we further characterized the role of PDGF-BB in the febrile response in rats. Microinjection of PDGF-BB
into the third ventricle produced a dose-dependent increase in colonic
temperature that peaked 3-4 h postinjection. Win 41662 attenuated
fever induced by intraperitoneal injection of bacterial lipopolysaccharide, suggesting that endogenous PDGF participates in the
febrile response to this exogenous pyrogen. Importantly, febrile
responses induced by tumor necrosis factor-
, interleukin-1
, and
interleukin-6 were unchanged by Win 41662. Both indomethacin and
dexamethasone blocked the PDGF-BB-induced increase in colonic temperature, and, therefore, we postulate that PDGF-BB may act via
prostaglandin- and/or inducible enzyme-dependent pathways. Thus our
findings suggest that PDGF-BB is an endogenous CNS mediator of the
febrile response in rats.
fever; hypothalamus; growth factor; lipopolysaccharide
| |
INTRODUCTION |
FEVER IS A HOST-DEFENSE MECHANISM that takes place in
response to a variety of pathogenic stimuli such as infection, injury, inflammation, and neoplasia. The generation of the febrile response involves a complex communication process between the immune system and
the central nervous system (CNS). It has been proposed that the immune
system relays signals that influence thermoregulatory processes in the
CNS via the interaction of cytokines with peripheral nerves,
circumventricular organs, and/or perivascular and meningial microglial
cells (6). Among the cytokines involved in this process
are interleukin (IL)-1, IL-1, IL-6, IL-8, tumor necrosis factor- (TNF-), and interferon -
(INF-) (13, 19). These cytokines activate membrane receptors that signal through tyrosine kinases of the Janus kinase (JAK) family that are constitutively associated with their intracellular domains and become phosphorylated after receptor activation (10). These activated JAKs phosphorylate intracellular tyrosine residues in these receptors, which then act as
docking sites for signal transducers and activators of transcription
(STATs) and other intracellular signaling proteins. These proteins are
thought to initiate intracellular signaling pathways responsible for
the production of mediators of fever such as PGs (19).
Platelet-derived growth factor (PDGF) is a multifunctional protein that
exerts particularly important actions in the CNS (27). There are three
isoforms of PDGF, denoted PDGF-AA, PDGF-AB, and PDGF-BB, which are
homo- or heterodimers of related A and B polypeptide chains (5). Like
the cytokines, PDGF primarily relays information via tyrosine
kinase-dependent pathways. It acts by binding to PDGF receptors
(PDGFRs) with intrinsic tyrosine kinase activity that dimerize on
ligand activation and become autophosphorylated on tyrosine residues.
These residues act as binding sites for a group of proteins that
contain Src homology 2 domains such as phospholipase C-, Src kinase,
ras-GAP, and many others (5). Like cytokine receptors, PDGFRs also
activate multiple JAK family kinases and STAT proteins (29).
PDGF and PDGFRs are widely expressed in both neurons and glial cells
throughout the CNS (27). PDGF-A and PDGF-B chains, as well as PDGFR
and PDGFR, are expressed in cells of CNS regions that are important
for control of body temperature, such as the hypothalamus, thalamus,
cortex, hippocampus, and brain stem (15, 20, 24, 29, 31). However, the
functions of PDGF in these and other regions of the adult mammalian CNS
are only partially understood. In the hippocampus, PDGF was shown to
produce a long-lasting modulatory effect on the function of
GABAa and N-methyl-D-aspartate receptors, which are two of the most important inhibitory and excitatory ligand-gated ion channels in this region and many other regions of the CNS, respectively (26, 28). Intracerebroventricular infusion of PDGF was reported to modulate specific components of the
feeding response in mice (18, 21). Moreover, PDGF levels are elevated
in several CNS diseases associated with fever, such as trauma, stroke,
meningitis, cerebral abscesses, glial and meningeal cysts, and
neoplasia (11, 14). Thus PDGF appears to be important for the function
of the CNS, not only under physiological conditions, but also during
pathophysiological states.
We recently reported (17) that microinjections of PDGF-BB (10-50
ng) into the lateral ventricle produced a febrile response in rats. We
also showed (17) that this febrile response was blocked by pretreatment
with Win 41662, a potent blocker of the intrinsic tyrosine kinase
activity of PDGFR. In this study, we present a more detailed
characterization of the PDGF-BB-induced febrile responses in rats. We
evaluated the effect of microinjections of three different
concentrations of PDGF-BB into the third ventricle. We determined the
effect of Win 41662 on bacterial lipopolysaccharide (LPS)- and
cytokine-induced changes in body temperature. We also studied the
effects of indomethacin and dexamethasone on the PDGF-BB-induced febrile response.
| |
MATERIALS AND METHODS |
Male Wistar rats (170-200 g) were used. All animals were housed in
individual cages at an ambient temperature of 23-25°C with standard laboratory diet and tap water ad libitum. Lighting was on a
12:12-h light-dark cycle, beginning at 6 AM. One week before the
experiments, rats were anesthetized with pentobarbitone (45 mg/kg ip)
and stereotaxically implanted with a stainless steel guide cannula (0.8 mm OD × 15 mm length). The cannula was implanted into the right
lateral ventricle [coordinates in relation to the bregma: area
postrema 0.8 mm, (L) 1.5 mm, and (V) 4 mm] or into the third ventricle
(coordinates in relation to the bregma: area postrema 
0.8 mm, L
1.5 mm, and V 12.5) according to Paxinos and Watson (16).
Each guide cannula was fixed to the skull by an acrylic dental cement
attached to two self-trapping stainless steel screws inserted into the
frontal bones of the animals. At the end of each experiment, the
position of the cannula was confirmed histologically.
Colonic temperature was measured with a telethermometer (Yellow Spring
Instruments) in animals that were conscious and gently restrained only
at the moment of the measurement. Plastic-coated thermocouples were
inserted 5 cm beyond the anal sphincter. All animals were trained to
accept handling and colonic temperature measurements the day before the
experiments. All temperature measurements were performed at 30-min
intervals. Baseline temperature measurements were obtained 2 h before
drug application. Basal colonic temperature was the average of four
measurements made before any treatment. Effects of drugs on temperature
were measured for 6-7 h. All experiments were performed at the
thermoneutral zone for rats (28 ± 1°C).
All drugs were dissolved in pyrogen-free saline (0.9% NaCl) and
microinjected in a 2 µl vol over a 30-s period, using a stainless steel needle (70 mm OD). Recombinant human (rh) PDGF-BB and Win 41662 were a gift from Amgen (Boulder, CO) and Sanofi Laboratories (Toulouse,
France), respectively. PDGF-BB and BSA (0.01% ) solutions were
determined to be endotoxin-free by means of the limulus amoebocyte lysate (LAL) (QCL-1000 quantitative chromogenic LAL, BioWittaker) (8). PDGF-BB samples were sonicated and placed in plastic
containers to minimize loss of material. These samples contained final
BSA concentrations of 0.001%. Control experiments demonstrated that these concentrations of BSA did not change body temperature. BSA, LPS
(Escherichia coli, 0111:B4), rhTNF-, rhIL-1, and rhIL-6 were from Sigma Chemical (St. Louis, MO). Indomethacin, supplied as a
base by Merck Sharp and Dohme, was dissolved in pyrogen-free 0.2 M
Tris · HCl buffer, pH 8.2, immediately before
intraperitoneal injection. Dexamethasone (Decadronal; Prodrome) was
dissolved in pyrogen-free saline immediately before subcutaneous injection.
All values are means ± SE. Statistical differences were determined by
one-way ANOVA followed by Duncan's post hoc test or by two way ANOVA
using statistical software from SPSS (Chicago, IL). P 
0.05 was considered statistically significant. Area under the curve over the
6-h monitoring period (i.e., fever index; expressed in°C · h) and linear regression analysis were
performed with Fig.P software (Biosoft, Cambridge, UK). For linear
regression analysis, we used the equation y = 1.63x + 0.92 (for intracerebroventricular injection) and y = 1.57x + 1.14 (for injection into the third ventricle), where
y is the fever index and x is the log of the PDGF-BB dose.
| |
RESULTS |
Microinjection of PDGF-BB into the third ventricle induced a
dose-dependent increase in colonic temperature (Fig.
1A). Injection of 10 and 100 ng of
PDGF-BB induced a statistically significant increase in colonic
temperature that peaked 3-4 h after injection (P < 0.0001, one-way ANOVA). The peak changes in colonic temperature induced
by 1, 10, and 100 ng of PDGF-BB were 0.3 ± 0.09, 0.6 ± 0.2, and 1.0 ± 0.2°C, respectively. The increase in colonic temperature remained stable until the end of the experiment (6 h after injection). The fever indexes (area under the curve over the 6-h monitoring period)
were 1.1 ± 0.3, 2.7 ± 0.7, and 4.3 ± 0.8°C · h in animals injected with 1, 10, and 100 ng of PDGF-BB, respectively (Fig. 1B). The effect of PDGF-BB
injection on the fever index was linear (r = 0.99) with respect
to the PDGF-BB doses used.
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Fig. 1.
A: time course of increase in colonic temperature induced by
microinjection of platelet-derived growth factor-BB (PDGF-BB) into
third ventricle.  , Saline (SAL) (n = 4);  , 1 ng PDGF-BB
(n = 5);  , 10 ng PDGF-BB (n = 5); and X,
100 ng PDGF-BB (n = 5). B: correlation (y = 1.57x + 1.14; r = 0.99) between PDGF-BB dose and fever
index (area under the curve measured over 6-h monitoring period and
expressed in °C · h). Basal colonic temperatures
were 37.3 ± 0.1, 37.0 ± 0.1, 37.0 ± 0.1, and 37.0 ± 0.1°C for the groups treated with saline and 1, 10, and 100 ng of
PDGF-BB, respectively. * Significantly different from saline-treated
group. + Significantly different from 1 ng PDGF-BB.
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Microinjection of PDGF-BB into the lateral ventricle also induced a
statistically significant increase (P < 0.05, one-way ANOVA)
in colonic temperature (data not shown). This increase in colonic
temperature peaked 3-4 h after injection. The peak changes in
colonic temperature induced by 1, 10, and 100 ng of PDGF-BB were 0.2 ± 0.1, 0.7 ± 0.1, and 1.0 ± 0.1°C, respectively. The increase
in colonic temperature remained stable until the end of the experiment
(6 h after injection). Fever indexes were 0.8 ± 0.4, 2.8 ± 0.3, and
4.1 ± 0.5°C · h in animals injected with 1, 10, and 100 ng of PDGF-BB, respectively. The effect of PDGF-BB injection on
the fever index was also linear (r = 0.99) with respect to the
PDGF-BB doses used. These findings are in agreement with our previously
published results (17).
We next investigated the effect of Win 41662, a potent inhibitor of the
intrinsic tyrosine kinase activity of PDGFRs (22), on LPS-induced
fever. Win 41662 was reported to competitively inhibit PDGFR tyrosine
kinase activity in vitro with a Michaelis inhibitor constant of 15 ± 5 nM and to inhibit PDGF-BB-induced Ca2+ mobilization and
proliferation in intact human vascular smooth muscle cells with an
IC50 of 0.43 and 2.3 µM, respectively.
Previously, we showed (17) that treatment with Win 41662 significantly
reduced the increase of colonic temperature induced by microinjection of PDGF-BB into the lateral ventricle. In the present study, we show
that this antagonist also inhibits LPS-induced fever. LPS (10 µg/kg
ip) induced an increase in colonic temperature of 0.7 ± 0.1°C 3 h
postinjection (Fig. 2). In animals
pretreated with Win 41662 (4 µM into the lateral ventricle, 15 min
before injection), LPS only induced a change of 0.3 ± 0.1°C 3 h
postinjection. Statistical analysis revealed that Win 41662 significantly decreased the LPS-induced change in colonic temperature
(two-way ANOVA, P < 0.0001). It should be noted that
intracerebroventricular injection of Win 41662 alone did not induce a
significant effect on basal colonic temperature (Fig. 2).
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Fig. 2.
Effect of previous treatment (15 min) with Win 41662 (4 µM)
microinjected into lateral ventricle on febrile response induced by
lipopolysaccharide (LPS) (10 µg/kg ip). , Saline/saline (n = 4); , Win 41662 /saline (n = 5); , saline/LPS
(n = 5); X, Win 41662/LPS (n = 5). Basal colonic temperatures were 36.9 ± 0.1, 37.0 ± 0.1, 36.9 ± 0.1, and 37.1 ± 0.1°C for groups treated with
saline/saline, Win 41662 /saline, saline/LPS, and Win 41662 /LPS,
respectively. * Significantly different from saline/saline.
# Significantly different from saline/LPS.
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Next, we investigated the effect of intracerebrovenricular injection of
Win 41662 on the febrile response induced by a number of cytokines.
Intracerebroventricular injection of TNF- (50 ng), IL-1 (2.5 ng),
and IL-6 (50 ng) induced an increase in colonic temperature of 1.1 ± 0.3, 2.0 ± 0.1, and 1.0 ± 0.2°C, respectively, 3 to 4 h
postinjection. Pretreatment with Win 41662 (4 µM into the lateral ventricle, 15 min before injection of cytokines) did not
change the febrile response induced by these cytokines (Figs. 3, 4, and 5).
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Fig. 3.
Effect of previous treatment (15 min) with Win 41662 (4 µM)
microinjected into lateral ventricle on febrile response induced by
tumor necrosis factor- (TNF-) (50 ng icv). , Saline/saline
(n = 5); , Win 41662/saline (n = 4); ,
saline/TNF- (n = 6); X, Win 41662/TNF-
(n = 6). Basal colonic temperatures were 37.0 ± 0.1, 37.1 ± 0.1, 36.9 ± 0.1, and 37.0 ± 0.1°C for the groups treated with
saline/saline, Win 41662/saline, saline/TNF-, and Win 41662/TNF-,
respectively. * Significantly different from saline/saline.
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Fig. 4.
Effect of previous treatment (15 min) with Win 41662 (4 µM)
microinjected into lateral ventricle on febrile response induced by
interleukin-1 (IL-1) (2.5 ng icv). , Saline/saline (n = 4); , Win 41662/saline (n = 4); , saline/IL-1
(n = 7); X, Win 41662/IL-1 (n = 7).
Basal colonic temperatures were 37.0 ± 0.1, 37.0 ± 0.1, 36.9 ± 0.1, and 36.9 ± 0.1°C for groups treated with saline/saline, Win
41662/saline, saline/IL-1, and Win 41662/IL-1, respectively.
* Significantly different from saline/saline.
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Fig. 5.
Effect of previous treatment (15 min) with Win 41662 (4 µM)
microinjected into lateral ventricle on febrile response induced by
IL-6 (50 ng icv). , Saline/saline (n = 4); , Win
41662/saline (n = 5); , saline/ IL-6 (n = 7);
X, Win 41662/ IL-6 (n = 6). Basal colonic
temperatures were 37.0 ± 0.1, 37.1 ± 0.1, 37.1 ± 0.1, and 37.1 ± 0.1°C for groups treated with saline/saline, Win 41662/saline,
saline/IL-6, and Win 41662/IL-6, respectively. * Significantly
different from saline/saline.
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Finally, we investigated the effect of indomethacin and dexamethasone
on the increase in colonic temperature induced by microinjection of
PDGF-BB (10 ng) into the lateral ventricle. Indomethacin (2 mg/kg ip,
30 min before PDGF-BB injection) markedly reduced the PDGF-BB-induced
increase in colonic temperature (Fig.
6). Microinjection of PDGF-BB
induced an increase in colonic temperature of 1.2 ± 0.1°C 4 h
postinjection, whereas in the group pretreated with indomethacin it
only induced a change of 0.4 ± 0.1°C 4 h postinjection. Dexamethasone (1 mg/kg sc, 35 min before PDGF-BB injection) also blocked the PDGF-BB-induced increase in colonic temperature (Fig. 7). Microinjection of PDGF-BB induced an
increase in colonic temperature of 1.0 ± 0.2°C 4 h postinjection,
whereas in the group pretreated with dexamethasone it only induced a
change of 0.3 ± 0.1°C 3 h postinjection. Statistical analysis
revealed that both indomethacin and dexamethasone significantly reduced
the increase in colonic temperature induced by PDGF-BB (two-way ANOVA,
P < 0.001). It should be noted that injection of indomethacin
or dexamethasone alone did not significantly affect basal colonic
temperature (Figs. 6-7).
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Fig. 6.
Effect of previous treatment (30 min) with indomethacin (Indo) (2 mg/kg
ip) on increase in colonic temperature induced by PDGF-BB (10 ng)
microinjected into third ventricle. , Saline/saline (n = 4);
, Indo/saline (n = 4); , saline/PDGF-BB (n = 5);
X, Indo/PDGF-BB (n = 6). Basal colonic temperatures
were 36.9 ± 0.1, 37.0 ± 0.1, 36.9 ± 0.1, and 36.9 ± 0.1°C
for groups treated with saline/saline, Indo/saline, saline/PDGF-BB, and
Indo/PDGF-BB, respectively. * Significantly different from
saline/saline. # Significantly different from saline/PDGF-BB.
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Fig. 7.
Effect of previous treatment (35 min) with dexamethasone (Dex) (1 mg/kg
sc) on increase in colonic temperature induced by PDGF-BB (10 ng)
microinjected into third ventricle. , Saline/saline (n = 4);
, Dex/saline (n = 4); , saline/PDGF-BB (n = 4);
X, Dex/PDGF-BB (n = 5). Basal colonic temperatures
were 37.3 ± 0.1, 37.2 ± 0.1, 37.2 ± 0.1, and 37.1 ± 0.1°C
for groups treated with saline/saline, Dex/saline, saline/PDGF-BB, and
Dex/PDGF-BB, respectively. * Significantly different from
saline/saline. # Significantly different from saline/PDGF-BB.
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| |
DISCUSSION |
The results of the present study suggest that PDGF-BB is a novel
endogenous pyrogen in the rat CNS. PDGF-BB appears to fulfill some of
the criteria that a substance must meet to be considered an endogenous
mediator of fever (13). One criterion is that application of the
putative mediator of fever at the hypothetical site of action results
in a rise in body temperature and that the effect is dose dependent.
Present results show that this occurs after intracerebroventricular
injection of exogenous PDGF-BB. We observed dose-dependent changes in
body temperature after injection of PDGF-BB into the lateral or third
ventricle in amounts ranging from 10 to 100 ng per animal. Assuming
that the average cerebrospinal fluid (CSF) volume in an adult rat is
~250 µl (1), then the concentrations of PDGF-BB that are required
to achieve this effect appear to fall within physiologically relevant
limits. PDGF concentrations in whole blood were reported to be ~17
and 3 ng/ml in humans and baboons, respectively (2). Unfortunately,
normal values for PDGF-BB levels in the CSF for any animal species have
yet to be reported. In a recent study (14), however, it was shown that PDGF levels can reach values ranging from 10 to 200 ng/ml in the CSF of
patients with neoplastic and nonneoplastic brain lesions, including CNS
infections. Thus the PDGF-BB levels achieved during our experiments can
be probably found in the CSF at least during some pathophysiological
conditions of the CNS.
Another criterion for a substance to be considered an endogenous
pyrogen is that its effect be prevented by blockers of its pathway of
action (13). Indeed, we have shown (17) that Win 41662 blocks the
PDGF-BB- and LPS-induced febrile responses in rats. Win 41662 is a
novel biarylhydrazone that appears to be competitive with respect to
substrate (Mn2+-ATP) and is specific to PDGFRs in
comparison to other tyrosine kinase receptors (epidermal growth factor
receptor, p561ck, erbB2), cAMP-dependent protein kinase or protein
kinase C (22). Importantly, the same dose of Win 41662 that inhibited fever induced by PDGF-BB and LPS did not change the
response induced by TNF-, IL-1, and IL-6, which also activate
receptors that signal through tyrosine kinases (10). Although it cannot
be completely ruled out that the antipyretic effect of Win 41662 may be
due to nonspecific effects, these results suggest that it blocks the
PDGF-BB- and LPS-induced febrile responses by specifically preventing
activation of the PDGFR intrinsic tyrosine kinase activity. These
results can also be interpreted to indicate that the role of PDGF-BB in the febrile response induced by an exogenous pyrogen like LPS precedes
the involvement of the mentioned cytokines. However, it must be kept in
mind that PDGF-BB and the cytokines could also act concomitantly to
induce the elevation in rat body temperature. Evidence is beginning to
emerge indicating that PDGF-BB and cytokines can induce expression of
each other. PDGF-BB has been shown to induce IL-6 expression in
osteoblasts (7), whereas cytokines (TNF-, TGF-1, and IL-1)
have been shown to induce PDGF expression in human astrocytes (23).
Thus establishing the role of PDGF-BB in the sequence of events that
mediate a complex biological response such as the generation of
fever is a challenging question for future research.
Additional criteria for a substance to be considered an endogenous
mediator of fever involve the demonstration that the putative mediator
is produced during a naturally occurring fever and that there is a
relationship between its production and the magnitude of fever.
Although our study does not directly demonstrate that PDGF-BB meets
these criteria, our finding that Win 41662 blocks LPS-induced fever
suggests that this growth factor is produced in response to this
bacterially derived pyrogen. As mentioned before, PDGF-BB and PDGFRs
are endogenously expressed in neuronal and glial cells of CNS regions
closely involved in the generation of fever, such as the hypothalamus
(15, 20, 24, 29, 31, 32). Thus we postulate that endogenous PDGF-BB may
be released from neuronal and/or glial cells in response to
intraperitoneal injection of LPS and that PDGFRs become activated in
the process, contributing to the generation of fever. However,
definitive proof that PDGF-BB meets these criteria will require, for
example, determining CSF levels of this growth factor in response to
pyrogenic stimuli. It should also be noted that we previously reported
(17) that boiled PDGF-BB did not induce fever in rats. It is unclear
why boiling produced this effect since PDGF-BB is a thermostable
protein (for review, see Ref. 27). This effect of boiling may be due to
partial denaturation of a critical domain of PDGF-BB required for fever
induction or to PDGF-BB depletion due to binding to tube walls. This
uncertainty must be kept in mind when interpreting the results of the
present study.
Our finding that indomethacin markedly inhibited the PDGF-BB-induced
increase in colonic temperature suggest that cyclooxygenase (COX)-dependent pathways may be involved in this process. Inducible enzymes, such as phospholipase A2 (PLA2), COX2,
and inducible nitric oxide synthase, may also be involved, as previous
treatment of rats with dexamethasone significantly inhibited
PDGF-induced increases in colonic temperature. Little is known about
the effects of PDGF-BB on the activity of brain PLA2 and
other enzymes such as COX1 and COX2 or about its effects on the
synthesis and release of arachidonic acid and PGs. However, it is well
established that this growth factor can activate arachidonic acid- and
PG-related biochemical pathways in nonneuronal cells. PDGF-BB was shown
to induce arachidonic acid and PGE2 synthesis and release
and to transcriptionally regulate gene expression of COX2 in NIH 3T3 fibroblasts (4, 12, 30). PDGF-BB was also shown to stimulate the rapid
release of arachidonic acid and PGE2 in human arterial smooth muscle cells by a mechanism involving Ca2+ and
mitogen-activated protein kinase-dependent activation of cytosolic
PLA2 (9). Moreover, activation of cytosolic
PLA2 by PDGF-BB was shown to be essential for
COX2-dependent PGE2 synthesis in mouse osteoblasts cultured
with IL-1 (3). Thus it is possible that PDGF-BB induces fever via
similar mechanisms in certain neuronal or glial cell populations.
Perspectives
This study presents evidence that PDGF-BB may be a novel mediator of
the febrile response in the CNS of rats. The precise mechanism of
action of PDGF-BB and the CNS region(s) involved in this process,
including the hypothalamus, are presently under investigation. The
hypothalamus is recognized as one of the most important regions for the
control, not only of body temperature, but also of food intake and
autonomic outflow (19). Interestingly, intracerebroventricular
injection of PDGF was shown to modulate feeding responses in rats (18,
21) and PDGF-BB levels were shown to increase in the rat CSF after
feeding (21). Therefore, PDGF-BB could be an important mediator of
hypothalamic regulatory functions of body temperature and food intake.
Important tasks for future research on the role of PDGF-BB in
hypothalamic function include the determination of which specific
hypothalamic regions express PDGFs and PDGFRs and the details of the
intracellular signaling cascades activated and/or modulated by this
growth factor in this CNS region. These studies should also be extended
to parts of the brain that may be involved in thermoregulation, such as the hippocampus, cortex, and thalamus.
| |
ACKNOWLEDGEMENTS |
We thank Amgen-Boulder and Sanofi Laboratories for providing
PDGF-BB and Win 41662, respectively. We thank Dr. Hugo C. Faria Castro
(FioCruz, Rio de Janeiro, Brazil) for kindly testing our solutions by
LAL assay. We also thank Dr. Andrius Kazlauskas for constant advice and
support and Rita A. Cardoso for critically reading the manuscript.
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FOOTNOTES |
This study was supported by the National Council for Research
(CNPq-Brazil, Project 300751/96-6).
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: I. R. Pelá, c/o C. Fernando Valenzuela, Dept. of Neurosciences, Univ.
of New Mexico Health Sciences Center, Albuquerque, NM 87131 (E-mail:
fvalenzuela{at}salud.unm.edu).
Received 3 December 1998; accepted in final form 3 December 1999.
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