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expression in the brain and activates HPA axis
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Possible
roles of the afferent vagus nerve in regulation of interleukin
(IL)-1
expression in the brain and hypothalamic-pituitary-adrenal (HPA) axis were examined in anesthetized rats. Levels of IL-1 mRNA
and protein in the brain were measured by comparative RT-PCR and ELISA.
Direct electrical stimulation of the central end of the vagus nerve was
performed continuously for 2 h. The afferent stimulation of the
vagus nerve induced increases in the expression of mRNA and protein
levels of IL-1 in the hypothalamus and the hippocampus. Furthermore,
expression of corticotropin-releasing factor mRNA was increased in the
hypothalamus 2 h after vagal stimulation. Plasma levels of ACTH
and corticosterone were also increased by this stimulation. The present
results indicate that activation of the afferent vagus nerves itself
can induce production of IL-1 in the brain and activate the HPA
axis. Therefore, the afferent vagus nerve may play an important role in
transmitting peripheral signals to the brain in the infection and inflammation.
corticotropin-releasing factor; adrenocorticotrophic hormone; corticosterone; lipopolysaccharide; neuroimmune interaction
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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INTERLEUKIN
(IL)-1 is a proinflammatory cytokine produced not only in the immune
system (e.g., lymphocytes and macrophage), but also in the brain
(neuronal and glial cells). Peripheral or central application of
IL-1 induces fever (22), inhibition of food intake
(28) and gastric acid secretion (19,
43), and activation of the sympathetic (29)
and hypothalamic-pituitary-adrenal (HPA) axis (4,
37). The effects induced by IL-1 mimic those produced
by bacterial endotoxin lipopolysaccharide (LPS) (22). The
expression of IL-1 in the brain is highly inducible by peripherally applied LPS (2, 25). IL-1 knockout mice
exhibited an impaired acute-phase inflammatory response and were
completely resistant to fever development and anorexia in response to
inflammation induced by turpentine (44). These
observations indicate that peripherally generated cytokines, such as
IL-1, mediate both the central and peripheral metabolic responses to
endotoxin. However, the fact that IL-1 is a 17.5-kDa hydrophilic
peptide that cannot cross the blood-brain barrier freely raises
questions as to how these immune signals can act on the central nervous
system (CNS). The precise mechanisms by which IL-1 signals the CNS
are unknown, but possibilities include 1) direct entry of
IL-1 into the brain across the blood-brain barrier by a saturable
transport mechanism (3), 2) interaction of
IL-1 with circumventricular organs [organum vasculosum of the
lamina terminalis (OVLT), area postrema, etc.], which lack the
blood-brain barrier (21), and 3) activation of
afferent neurons of the vagus nerve (42).
Increasing evidence has suggested that the vagus nerve is an important
neural pathway for communicating immune signals originating in the
periphery to the brain. IL-1 immunoreactivity was expressed in
dendritic cells and macrophages within connective tissues associated with the abdominal vagus after intraperitoneal injection of LPS (16), and systemic application of IL-1 increases
hepatic (32) and gastric (23) branch of the
vagus afferent nerve activity. Moreover, Ek et al. (11)
demonstrated that circulating IL-1 stimulates vagal sensory activity
via both prostaglandin-dependent and -independent mechanisms.
Peripheral administration of IL-1 and LPS produce c-Fos activation
in the nucleus of the solitary tract (NTS), which is the predominant
termination site of afferent vagus nerves (7,
13). Subdiaphragmatic vagotomy has been shown to inhibit
behavioral and neural effects of peripheral IL-1 or LPS including
social exploration (5, 6), anorexia
(8), fever response (17, 36,
40), stimulation of the HPA axis (15,
20), and IL-1 mRNA expression in the brain
(18, 24). Furthermore, the selective
transection of hepatic vagus nerve effectively inhibited a pyrogenic
response induced by LPS (41). In contrast, there is
inconsistent evidence showing that subdiaphragmatic vagotomy does not
block c-Fos and corticotropin-releasing factor (CRF) expression in the
brain (12) and suppression of food intake (34, 39) induced by the peripheral
application of LPS or IL-1.
In the present study, therefore, we examined possible roles of the
afferent vagus nerve in regulation of IL-1 expression in the brain
and HPA axis by means of direct electrical stimulation of central end
of the vagus nerves from the cervical vagal trunk.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Experimental animals. Adult male Sprague-Dawley rats weighing 350-400 g were maintained in a room at 22-24°C under a constant day-night rhythm and given food and water ad libitum. All animal experiments were carried out in accordance with National Institutes of Health Guide for Care and Use of Laboratory Animals and approved by the Animal Care and Use Committee at Hokkaido University.
Animals were anesthetized with urethan (1.2 g/kg ip), and the femoral artery was cannulated for collecting blood samples and measuring systemic blood pressure and heart rate. The arterial catheter was connected to a pressure transducer (model AP-641G, Nihon Kohden, Japan), and arterial blood pressure and heart rate were recorded. For the electrical stimulation of the afferent vagus nerve, the carotid arteries were exposed by a midline incision in the neck and the left vagus nerve was freed from the artery. The left vagus nerve was cut, and the central end of the nerve was placed on a platinum ring electrode and stimulated continuously throughout the experiment. The stimulus parameter consisted of square-wave pulses of 0.5-ms duration, at 10 Hz, 1 mA, delivered by means of an electric stimulator (model SEN-3301, Nihon Kohden, Japan). LPS from Escherichia coli endotoxin (055:B5, Sigma) was injected intraperitoneally at dose of 300 µg/kg dissolved in saline in an injection volume of 1 ml/kg. Animals were returned to their home cage and killed 2 h later.RT-PCR.
Total RNA was isolated using TRI-Reagent (Sigma). The
quantity of the RNA obtained was checked by measuring optical density at 260 and 280 nm. cDNA was synthesized from 2 µg of total RNA by
reverse transcription using 100 U of Superscript reverse transcriptase (GIBCO) and oligo(dt)12-18 primer in a 20-µl
reaction containing 1× Superscript buffer (GIBCO), 1 mM dNTP mix, 10 mM DTT, and 40 U of RNase inhibitor. After incubation for 1 h at
42°C, the reaction was terminated by a denaturing enzyme for 15 min
at 70°C. For PCR amplification, 1.2 µl of cDNA were added to 12 µl of a reaction mix containing 0.2 µM of each primer, 0.2 mM of
dNTP mix, 0.6 U of Taq polymerase, and 1× reaction buffer.
PCR was performed in a DNA Thermal Cycler (Perkin-Elmer 2400-R). The
primers employed are as follows: IL-1 (upstream) 5'-CCT TCT TTT CCT
TCA TCT TTG-3'; IL-1 (downstream) 5'-ACC GCT TTT CCA TCT TCT TCT-3';
CRF (upstream) 5'-GGA AAG GCA AAG AAA AGG A-3'; CRF (downstream) 5'-CGT
GGA GTT GGG GGA CAG C-3'; GAPDH (upstream) 5'-AAA CCC ATC ACC ATC TTC CAG-3'; GAPDH (downstream) 5'-AGG GGC CAT CCA CAG TCT TCT-3'. The
predicted PCR products of IL-1, CRF, and GAPDH were 375, 381, and
361 bp, respectively. The PCR products (10 µl) were resolved by
electrophoresis in an 8% polyacrylamide gel in 1× TBE (Tris-borate, EDTA) buffer. The gel was stained with ethidium bromide, and
band densities were obtained by densitometric measurements using an FLA-2000 image analyzer (Fujifilm).
, CRF, and GAPDH were determined to be 36, 36, and 17, respectively. The amount of each amplified product was integrated and
plotted graphically against the number of PCR cycles to determine whether the increase in intensity of the amplified product was linear
to the number of PCR cycles.
To compare the expression of IL-1 and CRF mRNAs in the different
experimental groups, the amount of IL-1 and CRF mRNA in each
structure studied was estimated as the ratio (IL-1 or CRF/GAPDH).
ELISA for IL-1.
Each tissue was added to 0.9-1.0 ml of 20 mM Tris · HCl (pH
7.4) buffer containing (in mM) 0.5 phenylmethylsulfonyl fluoride, 0.5 benzamidine, 1.0 1,4-dithiothreitol, and 1.0 EDTA. Total protein was
mechanically dissociated from tissue using an ultrasonic cell disrupter. Sonicated samples were centrifuged at 30,000 g at
4°C for 30 min. Supernatants were removed and stored at 
80°C
until an ELISA was performed. Bradford protein assays were also
performed to determine total protein concentrations in brain sonication samples. The ELISA for rat IL-1 was performed using a commercially available kit from Endogen (Woburn, MA). The detection limit was 16 pg/ml. This ELISA does not cross-react with rat IL-1
, rat tumor
necrosis factor-, mouse IL-1, human IL-1, human IL-1, human
pro-IL-1 (32 kDa), and human IL-1RA.
Measurement of plasma level of ACTH and corticosterone.
Arterial blood was collected in an EDTA tube via a cannula immediately
after the end of the vagus nerve stimulation. Blood samples were
centrifuged at 3,000 rpm at 4°C for 10 min, and aliquots were stored
at 80°C until further use. Plasma ACTH was determined using an
ACTH-RIA kit (Allegro, Nichols Institute Diagnostics, San Juan
Capistrano, CA). The assay sensitivity was 1 pg/ml. This RIA kit does
not cross-react with -MSH, -MSH, -LPH, and -endorphin. Plasma corticosterone was determined by RIA (30). The
assay sensitivity was 0.2 ng/ml.
Statistics. Results are expressed as the means ± SE. Statistical analysis was performed with Student's t-test.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Change in heart rate after electrical stimulation of the afferent
vagus nerve.
As shown in Fig. 1, continuous electrical
stimulation of the central side of the vagus nerve (10 Hz) markedly
reduced heart rate. This reduction in heart rate lasted during the
entire 2-h stimulation. This result clearly indicates a reduction in
heart rate by vago-vagal reflex and that the afferent vagus nerves were effectively stimulated under the experimental conditions at 10 Hz, 0.5 ms, 1 mA.
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Effects of the electrical stimulation of the afferent vagus nerve
on IL-1 mRNA and protein levels.
IL-1 mRNA does not abundantly exist in the brain, therefore, it may
be difficult to detect without amplification by RT-PCR. In line with
previous reports (18), we detected low basal levels of
IL-1 mRNA expression in the hypothalamus and the hippocampus of
sham-operated rats using comparative RT-PCR. In a preliminary experiment, electrical stimulation conditions of the vagus nerve were
examined at several frequencies of 5, 10, and 20 Hz, with the most
consistent increase in IL-1 mRNA in the hypothalamus observed at 10 Hz. Electrical stimulation of the afferent vagus nerve for 1 h (10 Hz, 0.5 ms, 1 mA) induced a slight increase in the expression of
IL-1 mRNA in the hypothalamus (data not shown). Two hours after the
stimulation, we observed significant increases in the expression of
IL-1 mRNA in the hypothalamus and the hippocampus (Fig.
2). We also noted a slight increase of
IL-1 mRNA in the cortex (data not shown). The expression of IL-1 mRNA in the hypothalamus after vagal stimulation was increased to 170% of that in the sham-operated group. This enhanced expression, however, was relatively less compared with that induced in the hypothalamus by LPS (300 µg/kg ip; Fig.
3). As measured by ELISA, IL-1 protein
was significantly increased 2 h after vagal stimulation in the
hippocampus, and a slight increase of this protein level was observed
in the hypothalamus (Table 1). To
determine whether or not the stimulation of the afferent vagus nerve
increases peripheral IL-1, we measured plasma levels of IL-1
protein. Plasma levels of IL-1 protein were not detected either in
sham-operated or in the vagal-stimulated rats (Table 1), indicating
that the increases in IL-1 protein in the brain originated from the
brain, and not from periphery.
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Effects of the electrical stimulation of the vagus nerve on the HPA
axis.
To elucidate the involvement of the vagus nerve in the HPA axis, we
measured the expression of CRF mRNA in the hypothalamus and plasma
levels of ACTH and corticosterone after vagal stimulation. By using
comparative RT-PCR, CRF mRNA in the hypothalamus was increased 2 h
after vagal stimulation (Fig. 4).
Furthermore, plasma levels of ACTH were markedly elevated 2 h
after vagal stimulation (Fig. 5). We also
observed increases in plasma levels of corticosterone 2 h after
vagal stimulation (Fig. 5).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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During peripheral inflammation, expression of IL-1 is induced
in the brain (2, 25) and IL-1 induces
symptoms of brain-mediated illness (22). It has been
suggested that the afferent vagus nerve transmits peripheral
inflammation signals to the brain. On the basis of subdiaphragmatic
vagotomy experiments, however, inconsistent observations have been
reported (12, 18, 24, 34, 36, 39). Recently, it has
been reported that type 1 IL-1 receptor was detected in situ over
neuronal cell bodies in the rat nodose ganglion (11). Such
a result indicates that circulating IL-1 might activate vagal
afferents, even at the level of nodose ganglion, and might explain the
ineffectiveness of subdiaphragmatic vagotomy to block c-FOS and CRF
expression in the brain (12) and suppression of food
intake (34, 39) induced by peripheral administration of LPS or IL-1. In the present study, we demonstrated that direct electrical stimulation of the afferent vagus nerve induced
an increase in the expression of IL-1 mRNA in the hypothalamus and
hippocampus. In addition, IL-1 protein was significantly increased
in the hippocampus after the stimulation. On the other hand, plasma
levels of IL-1 were not detected in sham-operated or
vagal-stimulated rats. These results indicate that the origin of the
IL-1 protein induced by the vagal stimulation may probably be the
brain, but not peripheral tissue. These data demonstrate direct
evidence that vagal afferent neurons play a critical role in
transmitting peripheral signals to the CNS.
The vagal stimulation-induced increase in IL-1 mRNA in the
brain was significant but rather less than that produced by
intraperitoneal LPS. Adrenal glucocorticoids are known to potently
suppress IL-1 transcription and mRNA stability (26). We
also observed that the stimulation of vagal afferent nerves induced
increases in plasma levels of corticosterone. Thus it was possible that
the production of IL-1 in the brain was suppressed by the increased level of corticosterone. Such an explanation is consistent with the
observation that the stress-induced rise in corticosterone masks a
robust and widespread increase in brain IL-1 (31). An
alternative interpretation is postulated suggesting that to attain an
efficacious expression of cytokine in the brain induced by peripheral
immune signals, cooperation with the vagal afferent nerves and other
pathways, such as direct interactions of cytokine with the brain,
nonvagal afferents, and/or humoral pathways are needed.
It has been reported that peripheral application of LPS and IL-1
activates the HPA axis (4, 35,
37). Ericsson et al. (13) demonstrated that
intravenous administration of IL-1 increases c-Fos and CRF mRNA in
the paraventricular nucleus of hypothalamus through the activation of
ascending catecholaminergic projections from the medulla oblongata.
Furthermore, several independent lines of evidence have indicated that
peripherally applied IL-1 activates afferent vagus nerves and
neurons in the NTS (7, 27, 32).
Subdiaphragmatic vagotomy has been shown to suppress increases in ACTH
secretion, but not corticosterone induced by intraperitoneally applied
LPS or IL-1 (15, 20). Because plasma
levels of corticosterone have been shown to be elevated by the direct
action of IL-1 at the level of adrenal glands (1), the
contribution of vagus nerve in LPS- or IL-1-induced corticosterone
response is difficult to estimate by means of vagotomy. Therefore, we
examined the effect of direct stimulation of the afferent vagus nerves
on HPA axis. In the present study, we demonstrated that vagal
stimulation induced an increase in the expression of CRF mRNA in the
hypothalamus and increases in plasma levels of both ACTH and
corticosterone. These results indicate that the afferent vagus nerves
may play a significant role in endotoxin- or cytokine-induced
activation of the HPA axis.
In conclusion, we examined direct electrical stimulation of the
afferent vagus nerves and demonstrated that activation of the vagal
afferent neurons alone induced the production of IL-1 in the brain
and activated the HPA axis. The vagus nerve may act as a
pathophysiological component for a rapid-signaling pathway in the
infection and inflammation.
Perspectives
It is interesting to note that the stimulation of afferent vagus nerves increased IL-1 transcript in the hippocampus. Recently, it
was reported that IL-1 gene expression is substantially increased in
the hippocampus during long-term potentiation (LTP), and blockage of
the IL-1 receptor resulted in a reversible impairment of LTP maintenance (38). It has been suggested that the vagus
nerve can modulate learning and memory. Subdiaphragmatic vagotomy
attenuates memory retention produced by peripherally applied
cholecystokinin octapeptide (14) or substance P
(33). Furthermore, electrical stimulation of the vagus
nerve enhances memory in rodents (9) and in human subjects
(10). The present results permit us to speculate that the
afferent vagus nerve may play a role in memory formation and/or
maintenance through enhancement of IL-1 transcript in the hippocampus.
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ACKNOWLEDGEMENTS |
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We thank Aki Kubohara for kindness in supporting this work.
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FOOTNOTES |
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This research was supported by grants-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture, Japan.
Address for reprint requests and other correspondence: Y. Okuma, Dept. of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido Univ., Sapporo 060-0812, Japan (E-mail: okumay{at}pharm.hokudai.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 8 July 1999; accepted in final form 9 February 2000.
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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