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The Journal of Neuroscience, September 15, 2000, 20(18):6811-6819
The Inhibitory Effect of Interleukin-1 on Long-Term
Potentiation Is Coupled with Increased Activity of
Stress-Activated Protein Kinases
E.
Vereker,
E.
O'Donnell, and
M. A.
Lynch
Department of Physiology, Trinity College, Dublin 2, Ireland
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ABSTRACT |
Long-term potentiation (LTP) in perforant path-granule cell
synapses is decreased in aged rats, stressed rats, and rats injected intracerebroventricularly with the proinflammatory cytokine
interleukin-1 (IL-1). One factor that is common to these
experimental conditions is an increase in the concentration of IL-1
in the dentate gyrus, suggesting a causal relationship between the
compromise in LTP and increased IL-1 concentration. In this study,
we have investigated the downstream consequences of an increase in
IL-1 concentration and report that the reduced LTP in rats injected
intracerebroventricularly with IL-1 was accompanied by a decrease in
KCl-stimulated glutamate release in synaptosomes prepared from dentate
gyrus, although unstimulated glutamate release was increased. These
changes were paralleled by increased activity of the stress-activated
kinases, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated
protein kinase. Intracerebroventricular injection of IL-1
increased reactive oxygen species production in hippocampal tissue,
whereas IL-1 and H2O2 increased activities
of both JNK and p38 in vitro. Dietary manipulation with
antioxidant vitamins E and C blocked the increase in reactive oxygen
species production, the stimulation of JNK and p38 activity, the
attenuation of glutamate release, and the IL-1-induced inhibitory of
LTP. We propose that IL-1 stimulates activity of stress-activated
kinases, which in turn may inhibit glutamate release and result in
compromised LTP and that these actions are a consequence of increased
production of reactive oxygen species.
Key words:
LTP; dentate gyrus; IL-1; stress-activated kinases; glutamate release; reactive oxygen species
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INTRODUCTION |
Consistent with the high expression
of IL-1 receptors in the hippocampus (Lechan et al., 1990 ; Ban et al.,
1991; Parnet et al., 1994) are several observed effects of exogenous
IL-1 in this brain area. For example, IL-1 exerts an inhibitory
effect on (1) long-term potentiation (LTP) in CA1 (Bellinger et al.,
1993), CA3 (Katsuki et al., 1990), and dentate gyrus (Cunningham et
al., 1996; Murray and Lynch, 1998a,b), (2) release of acetylcholine (Rada et al., 1991) and glutamate (Murray et al., 1997) in hippocampal synaptosomes, (3) calcium influx in hippocampal synaptosomes (Murray et
al., 1997), and (4) Ca2+ channel currents
in hippocampal neurons (Plata-Salaman and ffrench-Mullen, 1994).
The mechanism by which IL-1 inhibits LTP remains to be established.
Because maintenance of LTP has been associated with increased glutamate
release (Bliss and Collingridge, 1993; Canevari et al., 1994; McGahon
and Lynch, 1996; McGahon et al., 1997), one factor that may contribute
to inhibition of LTP is the inhibitory effect of IL-1 on glutamate
release. However, it has been recently reported that the
IL-1-induced attenuation of LTP in dentate gyrus in vitro
is blocked by SB203580 (Coogan et al., 1997), an inhibitor of p38 that
is one member of the family of mitogen-activated protein (MAP) kinases.
The MAP kinase family has been identified as a major player in cellular
signaling and markedly influences such diverse processes as cell
proliferation, cell differentiation, and cell death. Consistent with
the evidence that nerve growth factor and other growth factors
stimulate extracellular signal-regulated protein kinase (ERK), is the
generally held view that activation of this particular pathway results
in neurite outgrowth, cell proliferation, or differentiation (Seger and
Krebs, 1995; Xia et al., 1995; Creedon et al., 1996). In contrast,
c-Jun N-terminal kinase (JNK) and p38 are activated by environmental
stress, including oxidative stress (Raingeaud et al., 1995;
Uciechowski et al., 1996; Junger et al., 1997), and activation
leads to growth arrest or even cell death (Park et al., 1996; Maroney
et al., 1998). JNK and p38 are stimulated by IL-1 (Derijard et al.,
1994; Raingeaud et al., 1995; Rizzo and Carlo-Stella, 1996; Uciechowski
et al., 1996; Lu et al., 1997), which is consistent with the
observation that IL-1 has been implicated in cell death (Rothwell,
1999). In general, the evidence that indicates that IL-1 activates
JNK and p38 and that activation of these pathways induces cell damage or cell death has been obtained in various circulating and cultured cells, whereas evidence for similar changes in neuronal tissue is lacking.
In this study we have investigated the downstream consequences of an
increase in IL-1 in hippocampal tissue and report that this cytokine
increases activity of both JNK and p38. We also provide evidence that
IL-1-induced activation of JNK and p38 leads to a decrease in
glutamate release and might be responsible for the attenuation in both
the early and later components of LTP observed in rats which received
an intracerebroventricular injection of IL-1.
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MATERIALS AND METHODS |
Animals. Groups of male Wistar rats (300-350 gm)
were used in these experiments. Animals were housed in groups of two to
four under a 12 hr light/dark schedule. Ambient temperature was
controlled between 22 and 23°C. Food and water were available
ad libitum. In some experiments food and water intake was
measured daily for 1 week, and at the end of this period rats were
randomly subdivided into two groups. One group received normal
laboratory chow with added vitamin E (250 mg of
DL- -tocopheryl acetate per rat per day,
dissolved in corn oil; Beeline Healthcare, Dublin, Ireland). The
laboratory chow contained 3.5% crude oil and 55 mg/kg vitamin E; thus
average daily intake of vitamin E from this diet was 2.75 mg/rat.
Ascorbic acid (250 mg/rat per day) was added to the water given to
these rats. The second group received normal laboratory chow with corn
oil added to ensure isocaloric intake with the first group. Rats were
offered 100% of their average daily food and average water intakes so
that the full daily allowances of vitamins would be ingested. Diet was
prepared freshly each day. Food and water intake did not vary between
groups, and there was no significant difference in daily food and water
intake before and after dietary modifications were made. Rats were fed
on the respective control or supplemented diet for 5 d and were
under veterinary supervision for the duration of this experiment.
Induction of LTP in perforant path-granule cell synapses in
vivo. LTP was induced as described previously (McGahon and Lynch, 1996). Rats were anesthetized by intraperitoneal injection of urethane
(1.5 gm/kg), placed in a head holder in a stereotaxic frame, and
injected intracerebroventricularly with either IL-1 (5 µl; 3.5 ng/ml; human recombinant; 5 × 10 7 U/mg;
The Biological Response Modifiers Program, National Cancer Institute,
Bethesda, MD) or saline (5 µl). [We measured deep body temperature immediately before injection and at 15 min intervals after
injection for 90 min. The temperature increased slightly from 35.18°C
(±1.29, SEM, n = 5) to 36.05°C (± 2.08) in
saline-injected rats and 35.08°C (±0.32) to 35.22°C (±0.61) in
IL-1-treated rats during the course of the treatments.] A window of
skull was removed to allow placement of recording and stimulating
electrodes in the molecular layer of the dentate gyrus (2.5 mm lateral
and 3.9 mm posterior to bregma) and perforant path, respectively
(angular bundle, 4.4 mm lateral to lambda). The depth of the electrodes was adjusted to obtain maximal responses in the cell body region. Stable baseline recordings were recorded for ~15 min, and
electrophysiological recording commenced 30 min after
intracerebroventricular injection; this was ~60 min after
administration of urethane. Test shocks at the rate of 1/30 sec were
delivered for 10 min before and 40 min after tetanic stimulation (three
trains of stimuli; 250 Hz for 200 msec; intertrain interval 30 sec). In
a separate series of experiments, a group of four rats received tetanic
stimulation, and another group of four received the same total number
of stimuli, but no high-frequency train of stimuli, i.e., one stimulus
every 12 sec. At the end of the electrophysiological recording
period, rats were killed by decapitation, the hippocampus was removed, and the tetanized and untetanized dentate gyri, as well as the hippocampus proper, were dissected on ice and cross-chopped into slices
(350 × 350 µm) using a McIlwain tissue chopper. The time taken
to prepare slices from the time of death was 2.5-3.5 min. All samples
were frozen separately in 1 ml of Krebs' solution (composition of
Krebs' in mM: NaCl 136, KCl 2.54, KH2PO4 1.18, MgSO4.7H2O 1.18, NaHCO3 16, glucose 10, and
CaCl2 1.13) containing 10% dimethylsulfoxide
according to the method of Haan and Bowen (1981). For analysis, thawed
slices of untetanized and tetanized dentate gyrus were rinsed three
times in fresh ice-cold Krebs' solution and homogenized in 1 ml of
ice-cold sucrose (0.32 M) for
preparation of P2 (McGahon and Lynch, 1996),
which was used for analysis of glutamate release and activity of p38
and JNK. Slices of hippocampus were rinsed and homogenized in either
200 µl of fresh Krebs' solution for analysis of vitamins E and C and superoxide dismutase activity or 40 mM Tris-HCl,
pH 7.4, for analysis of reactive oxygen species production.
Release of glutamate. The impure synaptosomal preparation
P2 was resuspended in oxygenated Krebs' solution
containing 2 mM CaCl2 (McGahon and
Lynch, 1996), and glutamate release was assessed as described
previously (McGahon et al., 1999). Briefly, synaptosomal tissue was
aliquoted onto Millipore (Bedford, MA) filters (0.45 µm), rinsed
under vacuum, and the filtrate was discarded. Synaptosomes were then
incubated in 250 µl of oxygenated Krebs' solution at 37°C for 3 min, in the presence or absence of 40 mM KCl, and filtrate was collected and stored for analysis as described (Ordronneau et al.,
1991). Triplicate samples (50 µl) or glutamate standards (50 µl; 25 nM to 1 µM prepared in 100 mM
Na2HPO4 buffer, pH 8.0) were added to glutaraldehyde-coated 96-well plates, incubated for 60 min at 37°C, and washed with 100 mM
NaH2PO4 buffer.
Ethanolamine (250 µl; 0.1 M in 100 mM
Na2HPO4 buffer) was used to
bind unreacted aldehydes and donkey serum (200 µl; 3% in PBS-T) was
added to block nonspecific binding. Samples were incubated overnight at 4°C in the presence of antiglutamate antibody (raised in rabbit; 100 µl; 1:5000 in PBS-T; Sigma, Poole, UK), washed and reacted with
secondary antibody [anti-rabbit horseradish peroxidase (HRP)-linked secondary antibody; 100 µl; 1:10,000 in PBS-T; Amersham, UK] for 60 min at room temperature. 3,3',5,5'-Tetramethylbenzidine liquid substrate was added as chromogen, and incubation continued for exactly
60 min at room temperature, at which time the reaction was stopped by
H2SO4 (4 M; 30 µl). Optical densities were determined at 450 nm using a multiwell
plate reader, and values were calculated with reference to the standard
curve, corrected for protein (Bradford, 1976) and expressed as
micromoles of glutamate per milligram of protein.
Analysis of the activity of the MAP kinases. The activities
of JNK and p38 were analyzed in P2 preparations
obtained from frozen hippocampal slices obtained from saline-pretreated
and IL-1-pretreated rats, some of which were fed on control and
experimental diets. Activity of the kinases was also assessed by
preincubating samples for 20 min in the absence and presence of IL-1
(10 pg/ml) and in the absence and presence of
H2O2 (5 mM);
these experiments were performed in P2 obtained
from freshly prepared hippocampus. In all experiments, samples were
analyzed for protein, diluted to equalize for protein concentration,
and these samples of synaptosomal protein (10 µl, 1 mg/ml) were added
to 10 µl of sample buffer (Tris-HCl, 0.5 mM, pH 6.8;
glycerol 10%; SDS, 10%; -mercaptoethanol, 5%; bromophenol blue,
0.05% w/v), boiled for 5 min, and loaded onto gels (10% SDS for p38
and 12% for JNK). Proteins were separated by application of 30 mA of
constant current for 25-30 min, transferred onto nitrocellulose strips
(225 mA for 75 min), and immunoblotted with the appropriate antibody.
Proteins were immunoblotted with antibodies that specifically target
phosphorylated JNK [Santa Cruz Biotechnology, Santa Cruz, CA; 1:500 in
PBS-Tween (0.1% Tween 20) containing 2% nonfat dried milk]
or phosphorylated p38 [Santa Cruz Biotechnology; 1:500 in PBS-Tween
(0.1% Tween 20) containing 2% nonfat dried milk] by incubating for 2 hr at room temperature. Nitrocellulose strips were washed and incubated
for 2 hr at room temperature with secondary antibody
[peroxidase-linked anti-mouse IgG; 1:1000 dilution (Sigma) in the case
of JNK and peroxidase-linked anti-mouse IgM; 1:1,000 dilution
(Amersham) in the case of p38]. Visualization was achieved by ECL
detection (Amersham); immunoblots were exposed to film overnight and
processed using a Fuji x-ray processor. Quantification of protein bands
was achieved by densitometric analysis using two software packages,
Grab It (Grab It Annotating Grabber, version 2.04.7, Synotics;
UVP Ltd) and Gelworks (Gelworks ID, version 2.51; UVP Ltd) for
photography and densitometry, respectively. Gelworks provides a single
value (in arbitrary units) representing the density of each blot, and
the values presented here are means of data generated from at least
four separate experiments. The antibodies used in these experiments
were specific as judged by the fact that only one band was observed
after ECL detection.
Analysis of reactive oxygen species formation. Formation of
reactive oxygen species was assessed by the method of Lebel and Bondy
(1990), which relies on the measurement of 2'7'-dichlorofluorescein (DCF), the oxidized, fluorescent product of 2'7'-dichlorofluorescin diacetate (DCFH-DA). Assessments were made in synaptosomes prepared from hippocampus of saline-injected and IL-1-injected rats and also
in synaptosomes prepared from freshly dissected hippocampus (in which
the effects of incubating in the presence/absence of IL-1 and
glutamate were assessed). Synaptosomes were incubated at 37°C for 15 min in the presence of DCFH-DA (10 µl; 5 µM, from a
stock of 500 µM in methanol). To terminate the reaction,
the dye-loaded suspensions were centrifuged at 13,000 × g for 8 min at 4°C, and the pellets were resuspended in 2 ml of ice-cold 40 mM Tris buffer, pH 7.4, and
monitored for fluorescence at 37°C with the excitation wavelength at
488 nm and the emission wavelength at 525 nm. In some experiments
IL-1 (1 ng/ml) or glutamate (50 µM or 250 µM) was included in the incubation to medium to
assess its effect of reactive oxygen species production. Results were expressed as micromoles of DCF formed per milligram of protein from a
DCF standard curve (0.05-1 µM).
Analysis of superoxide dismutase activity. Superoxide
dismutase activity was determined according to the method described by
Spitz and Oberley (1989). Aliquots (800 µl) of incubation buffer [50
mM potassium buffer, pH 7.8, containing 1.8 mM
xanthine, 2.24 mM nitroblue tetrazolium (NBT), 40 U of
catalase, 7 µl/ml xanthine oxidase, and 1.33 mM
diethylenetriaminepentacetic acid] were added to 1.5 ml microfuge
tubes containing samples of supernatant prepared from hippocampal
tissue (100 µl) at different dilutions (1:2, 1:5, 1:10, 1:20, 1:50,
and 1:100) and analyzed by UV spectroscopy at 560 nm. Slices were
homogenized, and enzyme activity was assessed as the rate of reduction
of NBT, which was inhibited with increasing concentrations of protein.
One unit of activity was defined as the amount of protein necessary to
decrease the rate of the reduction of NBT by 50%.
Analysis of vitamin C. Vitamin C concentrations were
determined as previously described (Omaye et al., 1979). Briefly,
duplicate aliquots of supernatant prepared from hippocampus (100 µl)
were added to a 2,4-dinitrophenylhydrazine/thiourea/copper (DTC)
solution (in mM: 50 thiourea, 2 copper sulfate, and 150 dinitrophenylhydrazine in 9 N
H2SO4; 20 µl)
and incubated for 3 hr at 37°C. Ice-cold H2SO4 (65%; 150 µl) was
added to stop the reaction, and samples were vortex-mixed and incubated
at room temperature for 30 min before aliquots (100 µl) were
transferred to 96-well plates for assessment by UV spectroscopy at 545 nm. Results were expressed as micromoles per gram of tissue. Ascorbic
acid standards were prepared in 5% trichloroacetic acid.
Analysis of vitamin E. Vitamin E was analyzed according to
the method of Vatassery (1994). Briefly, aliquots of homogenate prepared from hippocampus (150 µl) were incubated in the presence of
ethanol containing 0.025% butylhydroxytoluene (150 µl), 25% ascorbic acid (70 µl), and 10% potassium hydroxide (135 µl) for 30 min at 60°C. Hexane (540 µl) containing 0.025% butylhydroxytoluene was added, samples were vortex-mixed for 1 min, and they were centrifuged at 1500 rpm for 6 min. The hexane phase was removed and
evaporated to dryness under nitrogen; the recovery of vitamin E using
this procedure was between 70 and 80%. For HPLC analysis, dried
samples were resuspended in methanol (150 µl) containing 0.025%
butylhydroxytoluene, and 30 µl volumes were injected onto an Intersil
C18 column. Separation of -tocopherol was achieved using a mobile
phase of 75% acetonitrile: 25% methanol at a flow rate of 1.2 ml/min,
and samples were detected by UV spectroscopy at 292 nm. Vitamin E
concentration was estimated by the external standard method and
expressed as nanomoles per gram of tissue.
Statistical analysis. A one-way ANOVA was performed to
determine whether there were significant differences between
conditions. When this analysis indicated significance (at the 0.05 level), a post hoc Student-Newman-Keuls test analysis was
used to determine which conditions were significantly different from
each other. The Student's t test was used to establish
statistical significance in some cases; for example, when analyses were
performed on aliquots of the same tissue incubated in the presence or
absence of IL-1. The use of the Student's t test for
paired values was also appropriate when analyses were performed on
tissue prepared from untetanized and tetanized tissue from the same rat.
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RESULTS |
Intracerebroventricular injection of IL-1 inhibited LTP in
perforant path-granule cell synapses. The mean percentage increases in
EPSP slope in the 2 min immediately after tetanic stimulation (compared
with the mean value in the 5 min immediately before tetanic
stimulation) were 158.6 ± 6.2 and 120.3 ± 3.1 in the
saline-pretreated and IL-1-pretreated groups, respectively
(n = 6 in each case). The mean percentage increases in
EPSP slope in the last 5 min of the experiment were 139.3 ± 1.6 and 106.2 ± 1.3 in the saline-pretreated and
IL-1-pretreated groups, respectively (Fig.
1A).
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Figure 1.
Intracerebroventricular injection of IL-1
inhibited LTP and the associated increase in glutamate release.
A, Tetanic stimulation induced an immediate increase in
EPSP slope in both saline-injected and IL-1-injected rats, although
this was attenuated after IL-1 injection. Mean EPSP slope decreased
in IL-1-treated rats so that the value was close to baseline at the
end of the 40 min recording period. Sample recordings in the 5 min
immediately before tetanic stimulation and in the last 5 min of the
experiment are superimposed for saline-injected
(left-hand records) and IL-1-injected
(right-hand record) rats. SEM values are included for
every 10th response. B, Endogenous glutamate release was
significantly increased in synaptosomes prepared from untetanized
dentate gyrus (Untet) of saline-injected rats by
addition of 40 mM KCl to incubation medium
(*p < 0.05; ANOVA), but this was enhanced to a
greater degree in synaptosomes prepared from tetanized dentate gyrus
(Tet; **p < 0.01; ANOVA). Injection
of IL-1 increased unstimulated release in synaptosomes prepared from
both untetanized and tetanized dentate gyrus (+p < 0.05; ANOVA; compared with the values obtained from saline-injected
rats), but addition of 40 mM KCl to the incubation failed
to enhance glutamate release in these preparations. The data are means
(± SEM) of six individual experiments.
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Analysis of endogenous glutamate release in synaptosomes prepared from
tetanized and untetanized tissue obtained from these rats (six rats per
group) revealed significant effects of IL-1 injection. Figure
1B shows that addition of 40 mM
KCl to synaptosomes prepared from untetanized dentate gyrus obtained
from saline-treated rats, significantly increased glutamate release
(p < 0.05; ANOVA), but a further enhancement of
release was observed in synaptosomes prepared from tetanized tissue
(p < 0.01; ANOVA). In contrast, KCl failed to
stimulate glutamate release in synaptosomes prepared from both
untetanized and tetanized tissue obtained from IL-1-pretreated rats
(Fig. 1B). In this experiment, we observed that
unstimulated glutamate release was significantly greater in tissue
prepared from IL-1-pretreated rats compared with saline-treated
animals (p < 0.05; ANOVA). However, although an
increase in unstimulated glutamate release was also observed in a
separate experiment (see Fig. 7A), the increase did not
reach statistical significance on this second occasion.
Activities of JNK and p38 were assessed in aliquots of synaptosomal
tissue prepared from the hippocampus of the same group of rats. Figure
2 demonstrates that tetanic stimulation
did not affect JNK (A) or p38 (B)
activity in tissue prepared from saline-pretreated rats. Both the
sample immunoblot and the mean data obtained from densitometric
analysis indicate that the activities of both kinases were enhanced in
tissue prepared from IL-1-pretreated rats (*p < 0.05;  p < 0.01; ANOVA). In the case of p38
activity, the increase was similar in untetanized and tetanized tissue,
but in the case of JNK, the increase was more marked in untetanized,
compared with tetanized, tissue (*p < 0.05; ANOVA). To
confirm that the changes observed in glutamate release and activities
of JNK and p38 were, in fact, LTP-associated, we compared these
measures in ipsilateral and contralateral dentate gyri prepared from
rats that received tetanic stimulation (as described above) or that
received the same total number of stimuli to the perforant path but
without the high-frequency train of stimuli. Figure
3A shows that stimulation at a
rate of one shock per 12 sec (low-frequency stimulation) for 50 min did
not significantly affect EPSP slope. Figure 3B indicates
that addition of KCl stimulated glutamate release to a similar extent
in synaptosomes prepared from dentate gyrus of rats that received
low-frequency stimulation (both sides) and from the untetanized tissue
of rats that received tetanic stimulation (p < 0.05 in all cases; n = 4; ANOVA); however, release was
enhanced in synaptosomes prepared from tetanized dentate gyrus
(p < 0.01; ANOVA). Figure 3, C and
D, indicates that activation of JNK and p38 were similar in
all preparations.
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Figure 2.
IL-1 increased activities of JNK and p38 in
synaptosomes prepared from dentate gyrus. A, JNK
activity was significantly increased in synaptosomes prepared from
untetanized and tetanized (*p < 0.05;
+p < 0.01; ANOVA) dentate gyrus of
IL-1-injected rats compared with either untetanized or tetanized
tissue prepared from saline-injected rats. JNK activity was reduced in
tetanized, compared with untetanized, tissue after IL-1 injection
but was similar in the two preparations obtained from saline-injected
rats. B, Activity of p38 tissue was significantly
increased in synaptosomes prepared from untetanized and tetanized
dentate gyrus of IL-1-injected rats compared with either untetanized
and tetanized tissue obtained from saline-injected rats
(*p < 0.05; ANOVA). Tetanic stimulation did not
affect enzyme activity in tissue prepared from saline- or
IL-1-treated rats. The data are means of six (± SEM) individual
experiments. Sample immunoblots in A and
B demonstrate kinase activities in untetanized and
tetanized tissue prepared from saline-treated (lanes 1
and 2) and IL-1-treated (lanes 3 and
4) rats.
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Figure 3.
Glutamate release and activation of JNK and p38
were not affected by low-frequency stimulation. A, Mean
EPSP slope was unchanged by stimulation at a rate of one shock per 12 sec for a 50 min recording period, whereas tetanic stimulation
increased mean EPSP slope. B, Addition of KCl
significantly increased glutamate release in synaptosomes prepared from
dentate gyrus of rats that received low-frequency stimulation (both
sides; p < 0.05; ANOVA) and from the untetanized
(p < 0.05; ANOVA) and tetanized
(p < 0.01; ANOVA) tissue of rats that
received tetanic stimulation. C, D, Activation of JNK
and p38 were similar in all preparations. Values are means (± SEM) of
four separate experiments for JNK and three for p38.
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Previous studies have suggested that IL-1 might induce an increase
in reactive oxygen species production, and because activities of JNK
and p38 have been shown to be increased by both reactive oxygen species
and IL-1 in some cell types, we investigated these changes in
hippocampal tissue. Figure
4A shows that
incubation of hippocampal synaptosomes in the presence of IL-1 (1 ng/ml) in vitro significantly increased reactive oxygen
species production (p < 0.05; Student's
t test for paired values). Because IL-1 may increase
unstimulated glutamate release, we assessed the effect of glutamate (50 and 250 µM) on reactive oxygen species
production in vitro and found that it was without effect
(data not shown). Figure 4B-E shows sample
immunoblots and the mean data derived from densitometric analysis in
seven separate experiments in which the effects of IL-1 (10 pg/ml)
and H2O2 (5 mM) were assessed on activity of JNK and four
separate experiments in which effects on p38 activity were assessed.
Analysis of the mean data indicated that IL-1 significantly
increased activities of both JNK and p38 (p < 0.05 in each case; Student's t test for paired values; Fig.
4B,C). Although in the case of p38, SEM values in
control and IL-1-treated tissue overlapped, the difference between
the mean values was significant because IL-1 increased p38
phosphorylation in all experiments.
H2O2, like IL-1,
significantly increased activities of both kinases
(p < 0.05; Student's t test for
paired values; Fig. 4D,E).
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Figure 4.
Activities of JNK and p38 were increased by
IL-1 and reactive oxygen species. A, IL-1
significantly increased reactive oxygen species (ROS)
production in hippocampal synaptosomes prepared from untreated rats
(*p < 0.05; Student's t test for
paired samples; n = 6). IL-1 (10 pg/ml)
significantly increased activities of both JNK
(B) and p38 (C), as shown
in the sample immunoblots (compare lane 2 with lane
1) and in the mean data that was derived from densitometric
analysis of seven separate immunoblots for JNK and four for p38
(p < 0.05 in each case; Student's
t test for paired samples). H2O2
(5 mM) also significantly increased activities of JNK
(D) and p38 (E), as shown
in the sample immunoblots (compare lane 2 with lane
1) and in the mean data (± SEM) that was derived from
densitometric analysis of six separate immunoblots
(p < 0.05 in each case; Student's
t test for paired samples).
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These data suggested that at least some of the effects of IL-1 might
arise from its stimulatory effect on reactive oxygen species
production; if this is the case, it might be predicted that the effect
of IL-1 will be inhibited by antioxidants. We therefore assessed the
effect of intracerebroventricular injection of IL-1 on LTP in rats
fed on control diet and on a diet enriched in antioxidant vitamins E
and C. Figure 5 demonstrates that the IL-1-induced impairment in LTP was absent in rats which were fed on
the vitamin-enriched diet. In these experiments, the mean percentage
increases in EPSP slope in the 2 min immediately after tetanic
stimulation (compared with the mean value in the 5 min immediately
before to tetanic stimulation) were 143.2 ± 5.6 and 127.1 ± 2.0 in the saline-pretreated and IL-1-pretreated groups fed on the
control diet and 141.0 ± 3.7 and 172.7 ± 9.7 in the saline-pretreated and IL-1-pretreated groups fed on the
vitamin-enriched diet. The corresponding mean percentage increases in
EPSP slope in the last 5 min of the experiment were 120.1 ± 1.2 and 107.5 ± 1.6 and 119.3 ± 3.5 and 125.8 ± 2.3 in
the saline- and IL-1-pretreated groups fed on control and
vitamin-enriched diets, respectively (Fig. 5); the difference between
the values in the two groups fed on the vitamin-enriched diet did not
reach statistical significance.
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Figure 5.
The IL-1-induced impairment in LTP was reversed
by dietary manipulation with antioxidant vitamins E and C. LTP was
inhibited in IL-1-injected rats fed on the control diet, but
supplementation with a diet enriched in vitamins E and C (see Materials
and Methods for details) reversed this effect. Dietary
manipulation did not affect LTP in saline-treated rats. The data are
derived from six observations in each treatment group, and SEM values
are included for every 10th response.
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To assess the changes that accompanied dietary manipulation, we
analyzed the activity of superoxide dismutase, the formation of
reactive oxygen species, and the concentrations of vitamins E and C in
hippocampal tissue prepared from saline- and IL-1-injected rats that
were fed on control and vitamin-enriched diets. Figure 6 shows that IL-1 significantly
increased activity of superoxide dismutase in tissue prepared from rats
fed on both control and experimental diets (p < 0.05; Student's t test for paired samples; Fig.
6A). We observed that intracerebroventricular
injection of IL-1 resulted in a significant increase in reactive
oxygen species production in hippocampal synaptosomes prepared from
rats fed on the control diet (p < 0.05;
Student's t test for independent means) but that dietary
manipulation reversed this effect (Fig. 6B). There
was a significant increase in vitamin C concentration in hippocampus of
rats fed on the experimental, compared with the control, diet
(p < 0.05; Student's t test for
independent means; Fig. 6C), but vitamin E concentration was
unaffected by dietary manipulation (Fig. 6D); IL-1
pretreatment did not alter the concentration of either vitamin.
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Figure 6.
Dietary manipulation reversed the IL-1-induced
increase in reactive oxygen species formation. Intracerebroventricular
injection of IL-1 significantly increased activity of superoxide
dismutase (SOD; p < 0.05;
Student's t test for paired means); dietary
manipulation did not affect activity of the enzyme
(A). Reactive oxygen species formation
(ROS) was significantly increased in hippocampal
synaptosomes prepared from IL-1-injected rats compared with
synaptosomes prepared from saline-injected rats (p 0.05;
Student's t test for paired means). Dietary
manipulation reversed this effect (B). The
concentrations of vitamin C (C) and vitamin E
(D) were similar in hippocampal tissue prepared
from saline-injected and IL-1-injected rats, but dietary
manipulation significantly increased vitamin C concentration in tissue
prepared from both groups of rats (p < 0.05; Student's t test for paired means). Vitamin E
concentration was unaffected by diet. The values are means (± SEM) of
six observations in each case.
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|
Glutamate release and the activities of JNK and p38 were assessed in
synaptosomes prepared from dentate gyrus of saline- and IL-1-treated
rats that were fed on the control and vitamin-enriched diet. Figure
7A demonstrates that addition
of 40 mM KCl significantly increased glutamate
release in tissue prepared from saline-injected rats fed on the control
and experimental diets (p < 0.05; ANOVA). The
KCl-induced enhancement of release was inhibited in tissue prepared
from IL-1-injected rats that were fed on the control diet, but this
inhibition was reversed in rats that received the experimental diet,
such that KCl-stimulated release was significantly greater than
unstimulated release (p < 0.05; ANOVA).
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[in a new window]
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Figure 7.
Dietary manipulation reversed some of the effects
of IL-1. A, Glutamate release was significantly
increased by addition of 40 mM KCl to synaptosomes of
dentate gyrus prepared from saline-injected rats fed on both the
control and experimental diets (*p < 0.05;
Student's t test for paired values). This effect was
blocked in synaptosomes prepared from dentate gyrus of IL-1-injected
rats that were fed on the control diet, but the attenuation was
reversed in synaptosomes prepared from IL-1-injected rats that were
fed on the experimental diet (*p < 0.05;
Student's t test for paired values). Activities of JNK
(B) and p38 (C) were
assessed in aliquots of hippocampal synaptosomes prepared from the same
rats. Dietary manipulation did not significantly alter activity of
either enzyme in samples prepared from saline-injected rats. However,
activities of both JNK and p38 were significantly increased in
synaptosomes of IL-1-injected rats (compare lanes 3 and
4 with lanes 1 and 2), as shown by the
sample immunoblots and mean data derived from densitometric analysis;
(*p < 0.05; Student's t test for
paired values). The IL-1-induced changes in activities of both
enzymes were blocked by dietary manipulation (lanes 2 and
4). The values are means (± SEM) of six observations in all
experiments.
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|
Analysis of the effect of these treatments on activity of JNK revealed
a significant increase in enzyme activity in IL-1-treated rats that
were fed on the control diet compared with enzyme activity in
saline-treated rats in either dietary group or IL-1 treated rats fed
on the experimental diet (p < 0.05; Student's
t test; Fig. 7B). In parallel with these effects
on JNK activity, we observed that p38 activity was similar in tissue
prepared from saline-pretreated rats fed on either diet, whereas enzyme
activity was significantly increased in IL-1-pretreated rats fed on
the control diet (p < 0.05; Student's
t test for paired values; Fig. 7C). Assessment of
p38 activity was made in each of the four conditions (saline-pretreated rats and IL-1-pretreated rats fed on control and experimental diets)
on six separate samples and, in each case, enzyme activity was enhanced
in tissue prepared from IL-1-pretreated rats fed on control diet
compared with saline-pretreated rats. Thus, dietary manipulation
reversed the effects of IL-1 injection. Sample immunoblots indicate
these trends in activities of JNK (Fig. 7B) and p38 (Fig. 7C).
| |
DISCUSSION |
We set out to investigate the downstream consequences of an
increase in IL-1 in hippocampus, with the objective of increasing our understanding of the mechanisms that might contribute to impairment of LTP in dentate gyrus. The data indicate that among the cellular consequences of increased IL-1 concentration that accompany the impairment in LTP is an increase in reactive oxygen species production with the consequent increased activity of JNK and p38. On the basis of
the evidence presented we propose that the IL-1-induced increase in
reactive oxygen species production increases activation of JNK and p38
which, in turn, inhibits LTP. IL-1-induced inhibition of LTP may
also result from the observed inhibition of glutamate release. This
working hypothesis is presented in schematic form in Figure
8.
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Figure 8.
Scheme suggesting cascade of events leading to the
IL-1-induced impairment in LTP. Intracerebroventricular injection of
IL-1 leads to an increase in reactive oxygen species production that
increases activity of JNK and p38. We propose that glutamate release is
compromised by activation of IL-1 receptors, one consequence of which
is activation of these kinases, and that this inhibition of glutamate
release significantly contributes to the IL-1-induced impairment in
LTP.
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|
Consistent with this hypothesis, we report that the inhibitory effect
of IL-1 on LTP in perforant path-granule cell synapses was
accompanied by increased activity of both JNK and p38. The IL-1-induced attenuation of LTP confirms our previous observations (Murray and Lynch, 1998a) and also confirms the results of
in vitro experiments that demonstrated that
IL-1 inhibited LTP in dentate gyrus (Cunningham et al., 1996), CA1
(Bellinger et al., 1993), and CA3 (Katsuki et al., 1990). Coupled with
the IL-1-induced inhibition of LTP, we observed an IL-1-induced
inhibition of KCl-induced glutamate release. Thus, whereas an increase
in KCl-stimulated release was observed in synaptosomes prepared from
tetanized tissue obtained from saline-treated rats, KCl-stimulated
release was markedly decreased in synaptosomes prepared from both
untetanized and tetanized tissue obtained from IL-1-treated rats.
These data support the hypothesis that LTP in dentate gyrus is tightly
coupled with an increase in glutamate release at perforant path-granule cell synapses (Canevari et al., 1994; McGahon and Lynch, 1996; McGahon
et al., 1999). We observed that IL-1 increased unstimulated release
of glutamate, however this change did not always reach statistical significance.
We observed that the inhibitory effect of IL-1 on LTP was coupled
with a stimulatory effect on the activities of JNK and p38. Thus,
whereas activity of both kinases was unaffected by tetanic stimulation,
both were markedly increased in synaptosomes prepared from hippocampus
obtained from rats that were injected with IL-1. One interpretation
of this finding is that IL-1 activates these kinases and that this
action may result in inhibition of LTP; this is consistent with the
reported inhibitory effect of the p38 inhibitor SB203580 on
IL-1-induced attenuation of LTP (Coogan et al., 1997). To address
this question directly, we analyzed the effect of IL-1 on activity
of JNK and p38 in vitro and found that activities of both
kinases were increased by incubation in the presence of the cytokine. A
number of groups using different cell types have reported such an
action. For example, IL-1 has been reported to increase activity of
JNK in human glomerular mesangial (Uciechowski et al., 1996) and HeLa
(Raingeaud et al., 1995) cells, whereas IL-1-induced activation of
p38 has been reported in Chinese hamster CCl39 (Guay et al., 1997) and
HeLa (Raingeaud et al., 1995) cells.
It has been suggested that certain effects of IL-1 might be mediated
through an increase in reactive oxygen species production (Sumoski et
al., 1989; Raingeaud et al., 1995; Murray and Lynch, 1998b), and in
this study we provide further evidence to support this view by
demonstrating that (1) IL-1 increases reactive oxygen species
formation in hippocampal tissue and (2) hydrogen peroxide, which leads
to formation of the hydroxyl radical (Qin et al., 1999), mimics the
effect of IL-1 by stimulating JNK and p38 in vitro. These
findings are consistent with the observation that UV radiation (Zhang
et al., 1997) and osmotic stress (Qin et al., 1999), which also induce
formation of reactive oxygen species, stimulate activities of both JNK
and p38 (Raingeaud et al., 1995) in HeLa cells. These results support
our working hypothesis; if IL-1 concentration in hippocampus is
increased, reactive oxygen species formation is increased,
stress-activated kinases are activated, and expression of LTP is
blocked. Although the data, in particular the in vitro
analyses, are consistent with the idea that these effects may be
sequential, this remains to be unequivocally established.
To challenge this hypothesis, it is reasonable to propose that if
IL-1 acts by stimulating reactive oxygen species production, then
subsequent actions of IL-1 will be inhibited by antioxidants. We
attempted to address this question by feeding groups of rats with the
antioxidant vitamins E and C before IL-1 injection. The data show
that the IL-1-induced inhibition of LTP was blocked by dietary
manipulation, leading us to the conclusion that the IL-1 effect is
mediated through reactive oxygen species production. This is supported
by the work of Pellmar et al. (1991), who reported that hydrogen
peroxide inhibits LTP in guinea pig CA1 in vitro. The data
presented here suggest that the increase in reactive oxygen species
production in hippocampus of IL-1-treated rats is a consequence of
increased superoxide dismutase activity, which is consistent with
previous reports of an IL-1-induced upregulation of Mn-superoxide
dismutase gene expression (Antras-Ferry et al., 1997), mRNA (Borg et
al., 1992), and enzyme activities in various cell preparations (Borg et
al., 1992). Analysis of hippocampal tissue prepared from rats fed on
control and vitamin-enriched diets revealed that reactive oxygen
species production was increased in tissue prepared from
IL-1-treated rats that were given the control diet, but that this
IL-1-induced change was blocked in vitamin-treated rats. No change
in tissue concentration of vitamin E was observed after dietary
manipulation, but this is not surprising because it has been shown that
long-term treatment with this lipid-soluble vitamin is necessary for
its incorporation into the membrane (Halliwell 1992; Murray and Lynch,
1998b). These findings are consistent with previous observations from
this laboratory in which we found that IL-1 concentration and
reactive oxygen species production were increased in hippocampal tissue
prepared from aged rats, which demonstrated an impaired ability to
sustain LTP (McGahon et al., 1997; Murray and Lynch, 1998a,b). They are
also consistent with the observation that dietary manipulation with
vitamins E and C for 3 months restored ability of aged rats to sustain
LTP (Murray and Lynch, 1998b). Predictably, dietary manipulation did not effect IL-1-induced stimulation of superoxide dismutase, therefore we propose that the enhanced tissue concentration of vitamin
C that was observed after dietary manipulation was responsible for
reversing the IL-1-induced increase in reactive oxygen species production.
To obtain further evidence in support of the hypothesis that
antioxidant treatment reverses the effects of IL-1 on
hippocampal function, we analyzed glutamate release and activity of JNK
and p38 in synaptosomes prepared from saline-treated and
IL-1-treated rats fed on the control and vitamin-enriched diets. The
data showed that the inhibitory effect of IL-1 on release was
blocked by dietary manipulation. Coupled with this change, we observed
that dietary manipulation reversed the IL-1-induced increases in
activities of JNK and p38. These results suggest that the increase in
tissue vitamin C induced by dietary manipulation prevents the
stimulatory effect of IL-1 and its subsequent inhibitory effect on
glutamate release. If the argument that the inhibitory effect of
IL-1 on LTP is a consequence of activation of JNK and/or p38, then
it must be predicted that LTP will be inhibited, and activities of JNK
and/or p38 will be increased when endogenous IL-1 concentration in
hippocampus is increased, for example in hippocampal tissue prepared
from aged rats (Murray and Lynch, 1998a,b). We have recently observed
that JNK activity and p38 activity are increased in hippocampal tissue
prepared from aged rats (O'Donnell et al., 2000), in which IL-1
concentration and reactive oxygen species production are increased
(Lynch, 1998).
Increased activation of both JNK and p38 have been associated with cell
death (Yang et al., 1997; Luo et al., 1998), and evidence suggests that
IL-1 plays a role in cell death induced by ischemia (Rothwell,
1999). It might be speculated that, under the current experimental
conditions, IL-1 stimulates JNK and/or p38 and that cell damage
might result from this action. This proposal concurs with our recent
finding that parenteral administration of lipopolysaccharide increased IL-1 concentration and cell degeneration in entorhinal cortex and that these changes were inhibited by intracerebroventricular injection of a caspase-1 inhibitor indicating a key role for IL-1 (Campbell et al., 2000).
We propose that the inhibitory effect of IL-1 on LTP in perforant
path-granule cell synapses is a consequence of an increase in reactive
oxygen species formation, and the evidence suggests that the primary
effect of IL-1 is to stimulate activity of superoxide dismutase. Our
evidence suggests that increased activation of JNK and p38 represent
critical downstream events of the increase in reactive oxygen species,
leading to the inhibitory effect of IL-1.
| |
FOOTNOTES |
Received April 13, 2000; revised June 22, 2000; accepted July 6, 2000.
This work was supported by the Health Research Board (Ireland).
Correspondence should be addressed to Marina A. Lynch at the above
address. E-mail: lynchma{at}tcd.ie.
| |
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A. Kelly, A. Lynch, E. Vereker, Y. Nolan, P. Queenan, E. Whittaker, L. A. J. O'Neill, and M. A. Lynch
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TOP
ABSTRACT
INTRODUCTION
