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increases norepinephrine level in rat frontal cortex:
involvement of prostanoids, NO, and glutamate
Departments of 1 Psychiatry and 2 Physiology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The effects of local administration of
interleukin-1
(IL-1) were studied by using an intracerebral
microdialysis technique in rats. A local injection of IL-1 (3 and 10 ng) induced an elevation of norepinephrine (NE) concentration in the
medial prefrontal cortex (mPFC). IL-1-receptor antagonist (800 ng)
completely blocked the IL-1-induced NE increase. Diclofenac, a
cyclooxygenase inhibitor (500 µM), and
N
-nitro-L-arginine,
a nitric oxide (NO) synthase inhibitor (100 µM), applied through the
dialysis probe, did not affect the initial rise in NE levels observed
20 min after injection of IL-1 but completely suppressed the late
phase of IL-1-induced NE increase at 40 min and thereafter. In
contrast, local perfusion of 6-cyno-7-nitroquinoxaline-2,3-dione, a
non-N-methyl-D-aspartic
acid (NMDA) glutamate-receptor antagonist (50 µM), but not
DL-2-amino-5-phosphonovaleric
acid, an NMDA-receptor antagonist (100 µM), blocked both phases of
IL-1-induced NE increase. Furthermore, a microinjection of IL-1
elevated the extracellular concentration of glutamate in the mPFC.
These findings suggest that the IL-1-induced rise in NE levels in
the mPFC is caused by activation of the glutamatergic system and the
glutamate-induced increases in prostanoids and NO.
interleukin-1; microdialysis; prefrontal cortex; nitric oxide
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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THE NORADRENERGIC SYSTEM in the brain has been shown to be involved in stress-induced responses (3). During stressful events, such as immobilization and brain ischemia, norepinephrine (NE) is released in the cerebral cortex, hypothalamus, and striatum (17, 19, 28). The medial prefrontal cortex (mPFC) has long been considered to be one of the critical brain sites for the manifestation of emotional behaviors (23). The mPFC receives dense noradrenergic innervation by the dorsal noradrenergic bundle originating from the locus ceruleus, which is known to mediate anxiety, vigilance, and affective behaviors (3). Our previous study using an intracerebral microdialysis technique (17) revealed that the NE release from the nerve terminals in the mPFC of rats increased during immobilization stress or after administration of an anxiogenic compound. Furthermore, the immobilization stress-induced release of NE in the mPFC was attenuated by an anxiolytic drug (17).
Interleukin-1 (IL-1), which is released from peripheral immune
cells, is now known to be synthesized in the brain (4). IL-1 binding
sites and IL-1 mRNAs are widely distributed in the rat brain,
including the cerebral cortex (4, 9). There is evidence that the
brain-derived IL-1 may also be involved in the immobilization
stress-induced responses (28). The induction of IL-1 mRNA in the
brain occurs after immobilization stress as well as various insults in
the brain, such as cerebral ischemia and injury (15, 31, 33).
It was recently reported that local application of IL-1 augments the
release of NE, dopamine, and serotonin in the anterior hypothalamus in
the rat (27). The IL-1-induced release of NE was found to be
independent of arachidonate metabolism (27), although PGs are generally
known to mediate many of the biological functions of IL-1 (24). As
to the other possible substances to regulate the release of NE from the
nerve terminals, nitric oxide (NO) and glutamate have been suggested (14, 19, 30). Recent in vitro and in vivo studies (19, 30) have
revealed the presence of glutamate receptors on noradrenergic nerve
terminals, suggesting the possibility that glutamate may regulate NE
release. Furthermore, it was shown that there is a close relationship
between the glutamatergic system and IL-1 in neural injuries (6,
34).
The purpose of the present study was to determine
1) whether local injection of
IL-1 affects NE release in the mPFC and, if so,
2) whether the IL-1-induced NE
release involves arachidonate metabolism, NO system, and glutamate
receptors. All the studies were performed using a microdialysis
technique in conscious rats.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Subjects. Adult male Wistar rats (250-350 g) were purchased from Kyudo (Tosu, Japan). They were individually housed at 23 ± 1°C with artificial light illumination from 0700 to 1900. Food and water were provided ad libitum.
Surgery.
One week before the experiments, rats were anesthetized with
pentobarbital sodium (50 mg/kg ip), and a stainless steel guide cannula
(21-gauge), 9.0 mm long, was stereotaxically implanted just above the
left mPFC for penetration of a microdialysis probe. The stereotaxic
coordinates of the guide cannula implantation were as follows: AP, +3.3
mm from bregma; L, +0.4 mm from midline; H, 
0.8 mm from the
cortical surface (20a). The cannula was anchored to the skull with
screws and acrylic dental cement. An obturator of stainless steel wire
was installed into the guide cannula and held in place by a screw cap.
During a postsurgical recovery period of 7 days, the rats were placed
and handled in an opaque acrylic cage (25 cm long, 30 cm wide, and 30 cm deep) for ~5 min daily to habituate them to handling.
Microdialysis probe. The microdialysis probe consisted of hollow dialysis membrane (acetate cellulose membrane; 50-kDa cutoff, 220 µm OD), two silica tubes (75 µm OD), and a microinjection silica tube (75 µm OD). Two silica tubes (inlet and outlet) were inserted into the dialysis fiber, which had been sealed at one end with epoxy resin. The exposed length of dialysis membrane was 4.0 mm. The microinjection tube was placed parallel to the dialysis membrane. It was half the length of the membrane. The three silica tubes were fastened together with epoxy resin, and each was connected with stainless steel tubing at the top of the probe.
Drugs.
Recombinant human IL-1 and IL-1-receptor antagonist (IL-1RA) were
the generous gifts of Drs. Y. Masui and Y. Hirai, Institute of Cellular
Technology, Otsuka Pharmaceutical, Tokushima, Japan. The IL-1 had a
specific activity of 2 × 107
half-maximal U/mg of protein. Diclofenac sodium and
6-cyno-7-nitroquinoxaline-2,3-dione (CNQX) were purchased from Wako
(Japan). L-Arginine
(L-Arg), and N-nitro-L-arginine
(L-NNA) were obtained from Sigma (St. Louis, MO).
DL-2-Amino-5-phosphonovaleric
acid (AP-5) was obtained from Genosys Biotechnologies (UK).
and IL-1RA were dissolved in physiological saline. Diclofenac,
L-Arg,
L-NNA, and AP-5 were dissolved in the perfusion solution. A 10 mM CNQX stock solution was prepared by dissolving CNQX
in 0.1 N NaOH. Before use, the stock solution was diluted to 50 µM
with perfusion solution; the pH of the resulting solution was 7.4.
General procedures.
On the evening before the experiment, the obturator of the implanted
guide cannula was removed, and the microdialysis probe was inserted
into the guide shaft. The tip of the probe extended 4.0 mm beyond the
tip of the guide shaft to reach the mPFC. The animals were allowed to
move freely in the above-mentioned experimental cage, to which the
animals become fully acclimatized. On the morning (0800) of the
experiment, a microinfusion pump with a gastight syringe was used to
begin perfusion of artificial cerebrospinal fluid (147 mM NaCl, 4 mM
KCl, and 2.2 mM CaCl2, pH 7.4)
through the microdialysis probe at a rate of 1.0 µl/min.
For the measurement of NE, perfusate from the mPFC (20 µl) was
injected into the HPLC every 20 min by an automatic injector. In the
experiments of glutamate analysis, the dialysate samples were collected
every 20 min into the polyethylene tubes containing 20 µl of 0.1 M
phosphate buffer (pH 6.0) with 30% methanol. Sampling was continued
for 500 min while the microtubes were maintained at 4°C. Samples
were frozen (20°C) until analysis, which was performed 1 day
after collection. The extracellular concentrations of NE and glutamate
were stabilized within 200 min of the start of the perfusion, and the
experiments were then started.
Treatment procedures.
In experiment 1, IL-1 (3 and 10 ng), heat-inactivated IL-1 (10 ng, 80°C for 30 min), or
physiological saline was microinjected directly into the mPFC through
the microinjection tube in a volume of 0.1 µl at a rate of 0.1 µl/min. The concentration of NE in samples, collected every 20 min,
was analyzed for further 400 min. In experiment
2, IL-1RA (400 ng) or physiological saline was
microinjected twice, 80 and 4 min before microinjection of IL-1 (3 ng) or saline, and the effect of IL-1RA on the IL-1-induced increase
in NE concentration was examined. In experiments
3-5, diclofenac (500 µM), L-NNA (100 µM) with or without L-Arg (300 µM), CNQX (50 µM), AP-5 (100 µM), or their vehicles were applied into the mPFC continuously for 240 min through the membrane of a
microdialysis probe. Eighty minutes after the start of perfusion of
these blocking agents, IL-1 (10 ng) or physiological saline was
microinjected, and the concentration of NE was analyzed for further 400 min. The perfusion of blocking agents stopped 160 min after
microinjection of IL-1 or saline. In experiment
6, after the glutamate levels had stabilized for at
least 100 min, IL-1 (10 ng) was microinjected into the mPFC, and the
concentration of glutamate was examined for 400 min.
Analyses of NE in dialysate. The dialysate was analyzed for NE by using reverse-phase HPLC with electrochemical detection (ECD; Eicom, Kyoto, Japan). The composition of the mobile phase was 0.1 M phosphate buffer (pH 6.0), 4% methanol, 450 mg/l sodium 1-octanesulfate, and 50 mg/l EDTA. The mobile phase was delivered by a pump at a flow rate of 1.0 ml/min onto the chromatographic column (4.6 × 150 mm, Eicompak CA-5ODS, Eicom). The column temperature was kept at 28°C. The graphite electrode (WE-3G, Eicom) was maintained at +0.50 V (vs. an Ag/AgCl reference electrode). The detection limit for NE was ~500 fg at a 3:1 signal-to-noise ratio. The in vitro recovery of NE (i.e., ratio of concentration in perfusate to concentration outside dialysis membrane) was 20.3 ± 0.7% (n = 7).
The identification of the NE peak in the chromatogram was established, since it was done in our previous study (17). The addition of the authentic standard of NE at 10 pg into the perfusate elicited an increase in the electrochemical signal by ~500% of the basal amplitude, which appeared at 10.8 min. We have also determined that the NE recovered in the mPFC dialysate is derived from nerve terminals on the basis of an increase of peak on the chromatogram after applications of methamphetamine, desipramine, and high-K+ solution and its decrease after administration of Ca2+-free solution, tetrodotoxin, and
-methyl-p-tyrosine (17). Furthermore, it was found that electrical stimulation and electrolytic lesion of the dorsal noradrenergic bundle, which contains noradrenergic fibers of locus ceruleus neurons, increased and abolished NE release in
the mPFC, respectively (17).
Analysis of glutamate in dialysates. A 20-µl sample of each fraction collected as described above was mixed and reacted with 20 µl of derivatizing reagent (o-phthalaldehyde) for 1 min at 10°C, and 20 µl of the derivatized sample were injected onto the HPLC with an ECD and analyzed for glutamate. The composition of the mobile phase was 0.1 M phosphate buffer (pH 6.0) with 30% methanol. The mobile phase was delivered by a pump at a flow rate of 1.0 ml/min onto a chromatography column (4.6 × 150 mm, Eicompak MA-5ODS). The column temperature was maintained at 30°C. The graphite electrode (WE-3G, Eicom) was maintained at +0.60 V (vs. an Ag/AgCl reference electrode).
Expression of data and statistical analyses. Changes in the concentration of NE and glutamate in brain dialysates were expressed as a percentage of the basal release, measured before drug administration. All data are presented as means ± SE. Statistical analyses were performed using two-way ANOVA. When a significant overall F score was obtained, comparisons of the individual corresponding time points in the drug-injected groups and the saline-control group were carried out by Student's t-test or one-way ANOVA followed by Dunnett's test. P < 0.05 was regarded as significant.
Histology. At the end of the experiments, the rats were deeply anesthetized and transcardially perfused with 10% neutral formaldehyde solution. Serial coronal sections (100 µm thick) of the mPFC were prepared using a freezing microtome and stained with neutral red to verify the tip position of the microdialysis probe histologically.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Experiment 1. IL-1-induced increase in NE
concentration in mPFC.
The basal extracellular level of NE in the mPFC was estimated to be
2.08 ± 0.12 pg/20 µl of perfusate
(n = 107). No correction was made for
total recovery because the diffusion from the brain and that in vitro
are likely to be different.
at 3 and 10 ng in a volume of 0.1 µl
produced a dose-dependent increase in NE levels in the mPFC (Fig.
1). Injection of 3 ng of IL-1 elicited
an increase in the NE concentration that was apparent 20 min after the
injection. The NE concentration stabilized at this level (~150% of
preinjection level) until the end of the experiment (400 min). After
local injection of 10 ng of IL-1, the NE concentration increased,
reached an initial peak 20-40 min, and stayed stable for ~80 min
(1st phase). It then began to rise again at 100 min and reached a
maximum of ~200% of the baseline ~200 min after injection. This
second phase lasted for ~200 min until the termination of the
experiments. It is unlikely that the effects of IL-1 were caused by
contamination of endotoxin, because a microinjection of heat-treated
(80°C for 30 min) IL-1 (10 ng) did not alter the NE
concentration from that of the saline-treated group (Fig. 1).
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Experiment 2. Effects of IL-1-receptor antagonist on
IL-1-induced increase in NE concentration.
To ascertain whether the effect of IL-1 on the NE release occurred
via IL-1 receptors in the mPFC, we tested the effects of local
injection of IL-1RA on the IL-1-induced increase in NE level in the
mPFC. As shown in Fig.
2A, 400 ng
of IL-1RA injected locally, both 80 and 4 min before injection of 3 ng
of IL-1, completely abolished the IL-1-induced increase in NE
concentration. However, IL-1RA given locally twice (400 ng each)
followed by saline injection had no effect on the NE concentration
(Fig. 2B). The increase in NE after
IL-1 (3 ng) injection preceded by two injections of saline exhibited
a biphasic response (Fig. 2A), whereas the NE response after injection of IL-1 (3 ng) without any
pretreatment showed a monophasic characteristics (Fig. 1). It is not
clear why the same dose (3 ng) of IL-1 produced different NE
responses. It might be due to different experimental protocols, i.e.,
injection of IL-1 with and without preinjection of saline. Preinjection of saline twice 80 and 4 min before IL-1 injection might affect the time course of NE responses to IL-1 differently.
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Experiment 3. Effects of diclofenac on IL-1-induced
increase in NE concentration.
We subsequently investigated whether diclofenac, a cyclooxygenase (COX)
inhibitor, blocked the IL-1 (10 ng)-induced increase in NE
concentration. Diclofenac (500 µM) was applied locally through the
microdialysis membrane for 240 min, starting 80 min before the IL-1
injection. Although a local infusion of diclofenac did not affect the
initial rise in the NE concentrations observed 20 min after injection
of IL-1, it completely abolished the later rise in NE concentration
between 100 and 200 min. The IL-1-induced increase in NE
concentrations was restored after cessation of infusion of diclofenac
(Fig.
3A). The
administration of diclofenac followed by injection of saline did not
alter the NE concentration in the mPFC (Fig.
3B). These findings suggest that the
second phase of NE increase is dependent on the local production of
PGs.
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Experiment 4. Effects of L-NNA with or without
L-Arg on IL-1-induced
increase in NE concentration.
Because IL-1 reportedly elicits NO production in many tissues (24),
we investigated whether NO mediates the IL-1-induced changes of NE
levels in the mPFC. L-NNA (100 µM), a NO
synthase (NOS) inhibitor, was administered through the microdialysis
membrane continuously for 240 min, from 80 min before and 160 min after IL-1 injection. Local infusion of L-NNA
abolished the later IL-1 (10 ng)-induced rise in NE concentration
without affecting the initial rise (Fig.
4A).
This inhibitory effect of L-NNA on the IL-1-induced NE increase was restored by concurrent infusion of
L-Arg at 300 µM. The infusion
of L-NNA at this concentration followed by
microinjection of saline did not affect the NE concentration at the
basal condition (Fig. 4B).
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Experiment 5. Effects of glutamate-receptor antagonists on
IL-1-induced increase in NE concentration.
To investigate the involvement of glutamate on the IL-1-induced
increase in prefrontal cortex dialysate NE, the effects of local
infusion of CNQX (a non-NMDA-receptor antagonist) and AP-5 (a
NMDA-receptor antagonist) were studied. Local perfusion of CNQX at 50 µM through the microdialysis membrane suppressed both the initial and
the late phases of IL-1 (10 ng)-induced NE increase in the mPFC
(Fig.
5A),
whereas the infusion of CNQX by itself did not affect the concentration
of NE (Fig. 5B). In contrast, the
perfusion of AP-5 at 100 µM had no effect on the second phase of the
IL-1-induced increase in NE concentration, although it inhibited the
first phase response (Fig.
6A).
These findings suggest that the IL-1-induced increase in NE
concentration was mediated by glutamate receptors, specifically
non-NMDA receptors.
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Experiment 6. IL-1-induced increase in extracellular
glutamate levels.
Having observed the involvement of glutamate receptors, we measured the
extracellular concentration of glutamate in the mPFC after local
injection of IL-1. The average concentration of glutamate in the
mPFC under the control conditions was estimated to be 34.5 ± 3.9 pmol/20 µl (n = 12). As shown in
Fig. 7, a local injection of 10 ng of
IL-1 caused an increase in the glutamate concentration (151.3 ± 8.0% of basal, n = 6), which started
20 min after injection. The concentration of glutamate continued to
increase, reached a maximum (188.0 ± 31.7%,
n = 6) at 160 min and began
to decline 280 min after the injection.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The present study demonstrated that a local injection of IL-1 at 3 and 10 ng elicited a dose-dependent increase in the extracellular concentration of NE in the mPFC. In both cases, the increase in the NE
level was apparent 20 min after injection and was maintained for the
entire period of the observation (400 min). A similar long-lasting
increase in the NE level as assessed by microdialysis was demonstrated
in the rat anterior hypothalamus after the local injection of similar
doses of IL-1 (1 and 10 ng) (27, 28). Local injection of comparable
doses of IL-1 (50 and 100 ng) was shown to stimulate the release of
dopamine and dihydroxyphenylacetic acid in the hypothalamus by a
push-pull perfusion study (16).
Inhibition of IL-1-induced NE increase by an
IL-1RA.
IL-1RA, which had been originally found in the urine of patients of
monocytic leukemia as an IL-1 inhibitor, was cloned and was shown to
competitively block the binding of IL-1 and IL-1 to their
receptor (2). Recombinant human IL-1RA has also been demonstrated to
inhibit all the IL-1-induced responses of central and peripheral
origins so far examined (2). The present work showed that IL-1RA, which
by itself had no effect on NE concentration, abolished the ability of
IL-1 (3 ng) to increase NE level. This indicates that the
IL-1-induced increase of NE concentration is mediated by IL-1
receptors in the mPFC.
production locally after 24-48
h (31). However, such endogenously released IL-1, if any, is
unlikely to be involved in the increased NE levels in the mPFC in the
present study, because the experiment was completed within 24 h and
IL-1RA injected locally did not decrease the basal concentration of NE.
Involvement of glutamate receptors in NE increase in mPFC.
The present study demonstrated that CNQX (a non-NMDA-receptor
antagonist), but not AP-5 (a NMDA-receptor antagonist),
completely blocked the IL-1-induced NE release and that a local
injection of IL-1 increased the extracellular concentration of
glutamate. Furthermore, the initial rise in NE concentration observed
20 min after injection of IL-1 was not affected by diclofenac or L-NNA. These findings suggest that an activation of the
glutamatergic system is an essential step for IL-1 to increase the
NE levels in the mPFC. It is well known that glutamate stimulates NE
release through NMDA and non-NMDA receptors in rat brain cortical and hippocampal slices (30).
increases the extracellular concentrations of glutamate.
One possible site of action of IL-1 is the nerve terminals or soma
of glutamatergic neurons in the mPFC. It has been known that the
mediodorsal thalamus and basolateral amygdaloid nucleus send axons to
the mPFC (11, 22) and contain neurons which express type I
IL-1-receptor mRNA (32). It has been demonstrated that stimulation of
mediodorsal thalamus neurons induces an excitation of prefrontal cortex
neurons through
DL--amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (22). Another possibility is that IL-1 may act on
glial cells to increase the extracellular concentration of glutamate.
This may be achieved by inhibiting the uptake of glutamate by
astrocytes demonstrated in the rat hippocampus in vitro after IL-1
administration (34). The third possibility is that the increased
concentration of glutamate is mediated by IL-1-induced increases in
arachidonic acid and its metabolites, which are known to facilitate the
release of glutamate from nerve endings (10, 21) and to inhibit
glutamate uptake by glial cells (5).
Involvement of prostanoids and NO systems in NE increase in mPFC.
Various lines of evidence have established that the central and
peripheral actions of IL-1 and its inducer, endotoxin, are mediated
by the local synthesis of PGs and/or NO (6, 12, 24, 25). NO and
PGD2 are known to stimulate NE
release from brain tissues in vitro (14) and NE turnover in vivo (29). In the present study, local infusion of diclofenac (a COX inhibitor) or
L-NNA (a NOS inhibitor) did not affect the initial rise in NE in the mPFC 20 min after IL-1 injection (1st phase), but they inhibited the NE rise 40 min and thereafter (2nd phase). The present finding that CNQX in the absence of diclofenac and L-NNA
inhibited both the first and second phases of IL-1-induced increase
of NE may suggest a link between the glutamatergic system and PGs-NO system. In support of this, glutamatergic synaptic excitation has been
demonstrated to induce COX-2 in the rat cerebral cortex (1) and NOS in
the rat cerebellar cortex (20). On the other hand, NO has been shown
not only to increase glutamate release from nerve terminals as a
retrograde messenger (18) but also to enhance COX activity to increase
the production of PGs (26). Furthermore,
PGE2 and
PGF2
can activate glutamate
release (10). These findings suggest very complex interactions among these signal molecules.
-induced NE release. Local IL-1 produces an increase in the
concentration of glutamate by its action on glutamatergic neurons and
possibly glial cells having IL-1 receptors (22, 32, 34). The increased extracellular glutamate stimulates the release of NE through non-NMDA receptors (19, 30), thus generating the initial phase of the NE
increase. Glutamate also stimulates COX and NOS enzymes, which induce
PGs and NO, respectively (1, 20). PGs and NO stimulate NE release (12,
14, 29). Furthermore, NO stimulates the induction of COX (26), and
glutamate release is facilitated by increased PGs and NO (10, 18), thus
creating a positive feedback between the glutamatergic system and the
PGs-NO system. These signal molecules synergistically enhance the
release of NE in the mPFC, forming the second phase of NE increase,
which lasts as long as the observation period (400 min).
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Perspectives
Although the precise functional role of NE in the mPFC released after application of IL-1 is unknown at present, NE in the mPFC might
contribute to the manifestation of affective behaviors, such as
anxiety- and fearlike behaviors, during stress (3, 17, 23).
IL-1 is known to promote neurodegeneration during various types of
brain insults, probably by the releasing arachidonic acid metabolites
and/or NO (6, 24, 25). This neurotoxic action of IL-1 at
higher concentrations (µM range) was found in the rat
cortical neurons in culture, but IL-1 at concentrations in the
nanomolar range exhibited a neuroprotective effect probably by
releasing endogenous nerve growth factor (25). The concentrations of
IL-1 that are capable of increasing the NE concentration observed in
the present study are in the micromolar range, corresponding to a
neurotoxic concentration of IL-1 (25). It is interesting to ask
whether IL-1-induced NE is also involved in the neurodegeneration. It has been shown that NE reacts with NO to form 6-nitronorepinephrine, which may elicit a neurotoxic response (8). However, it has been
suggested that the monoamines and their metabolites provide an
antioxidant defense in the brain (13). Furthermore, bilateral lesions
of the locus ceruleus projections to the forebrain aggravated ischemic
damage of hippocampal and cortical neurons, suggesting a
neuroprotective action of the noradrenergic locus ceruleus system (7).
Further studies are required to elucidate whether the IL-1-induced
NE is beneficial or detrimental to neuronal survival.
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ACKNOWLEDGEMENTS |
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We are grateful to Dr. K. Akazawa, Dept. of Medical Informatics,
Faculty of Medicine, Kyushu University, for his kind advice on
statistical analysis of data. We also thank to Dr. Y. Masui and Dr. Y. Hirai, Institute of Cellular Technology, Otsuka Pharmaceutical, for the
gifts of IL-1 and IL-1RA.
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FOOTNOTES |
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This work is supported in part by Grants-in-Aid for Scientific Research 09557006, 08877017, and 10307001 (to T. Hori).
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: H. Kamikawa, Dept. of Physiology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan.
Received 12 January 1998; accepted in final form 21 May 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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