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1 Department of Psychology and 2 Department of Kinesiology and Applied Physiology, University of Colorado, Boulder, Colorado 80309
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The vagus nerve
appears to play a role in communicating cytokine
signals to the central nervous system, but the exact extent of its
involvement in cytokine-to-brain communication remains controversial.
Recently, subdiaphragmatic vagotomy was shown to increase bacterial
translocation across the gut barrier and thus may cause endotoxin
tolerance. The current experiment tested whether or not vagotomized
animals have similar systemic responses to endotoxin challenge as do
sham-operated animals. Subdiaphragmatically vagotomized and
sham-operated animals were injected intraperitoneally with one of three
doses (10, 50, 100 µg/kg) of lipopolysaccharide (LPS) or vehicle, and
blood samples were taken at 15, 30, 60, 90, and 120 min after the
injection. The intraperitoneal injection of LPS increased circulating
LPS levels at all time points examined. In addition, all three doses of
LPS significantly increased serum interleukin (IL)-1
, IL-6, and
corticosterone in both control and vagotomized rats. In conclusion,
vagotomy itself has no marked effect on circulating endotoxin levels or
the production of IL-1, IL-6, or corticosterone in blood after an
intraperitoneal injection of LPS.
interleukin-1; interleukin-6; vagus nerve; cytokine-to-brain
communication
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THERE HAS BEEN CONSIDERABLE recent interest in the
mechanisms involved in immune-to-brain communication. It is generally
thought that in response to an infection, cytokines are released and
are important mediators in signaling the central nervous system (CNS) to elicit "sickness behavior," which includes fever, increases in
sleep, depression in food-motivated behavior, exaggerated pain responses, and activation of the hypothalamic-pituitary-adrenal (HPA)
axis (19, 20, 32). Although there is considerable evidence for the
existence of a number of mechanisms by which blood-borne cytokines,
such as interleukin (IL)-1, can signal the CNS (2, 29, 33), more
recent studies have implicated a neural afferent pathway as well.
Indeed, systemic IL-1 increases electrical activity of vagal
afferents (8, 25), induces c-Fos in vagal primary afferent neurons (8,
14), and IL-1 binding and immunoreactivity have been localized to
abdominal vagal afferents and paraganglia (13, 15). Furthermore,
subdiaphragmatic vagotomy has blocked or attenuated a variety of the
brain-mediated responses to peripheral immune challenge (3, 6, 22).
It is generally assumed that vagotomy blocks brain activation by
interrupting afferent signaling. However, this assumption has recently
come into question (26, 30) due to data suggesting increased bacterial
translocation across the gut barrier in subdiaphragmatically vagotomized rats (7). Thus an alternative explanation for vagotomy blockade of brain activation and sickness behavior following the peripheral administration of agents such as lipopolysaccharide (LPS) is
that slowed gastrointestinal transit after vagotomy may cause increased
bacterial translocation across the gut and lead to endotoxin tolerance
(e.g., reduced cytokine production by immune cells in the periphery in
response to immune challenge) (30). In addition, it is plausible that
vagotomy may alter the tendency of intraperitoneally injected LPS
and/or cytokines to gain access to the general circulation. Thus the
aim of the current experiment was to examine the distribution of
endotoxin in the circulation after an intraperitoneal injection of LPS,
and the levels of IL-1, IL-6, and corticosterone in serum from
sham-operated and subdiaphragmatically vagotomized rats.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Adult male Sprague-Dawley rats (250 g at purchase; Harlan Sprague Dawley, Indianapolis, IN) were used in all studies. Animals (n = 64) were individually housed in hanging metal cages at 25 ± 1°C with a 12:12-h light-dark cycle (lights on at 0600). Standard rat chow and water were freely available unless otherwise noted. Care and use of the animals were in accordance with protocols approved by the University of Colorado Institutional Animal Care and Use Committee.
Surgery. Subdiaphragmatically vagotomized (Vag) rats or sham-operated (Sham) rats were prepared under Halothane anesthesia as previously described in detail (34). During the immediate postsurgical period (~2 days), both Sham and Vag rats were maintained on highly palatable food and received acetaminophen (0.5 mg/ml) in their drinking water. Rats who did not gain weight were killed (2 out of 32 Vag rats).
Vagotomy assessment. Approximately 3 wk after surgery, the completeness of vagotomy was assessed using the food intake analysis test as previously described (16, 17). This test is based on the satiety effect of cholecystokinin (CCK), which is known to be mediated by the vagus nerve (31). In brief, on separate days, each rat was injected intraperitoneally with saline or 4 µg/kg CCK (CCK-octapeptide; Sigma, St. Louis, MO) after 20 h of food deprivation; a minimum of 3 days was allowed between the saline and CCK injections. Food intake was measured after 1 h in both Sham and Vag rats.
Experimental protocol. Experiments began ~1 wk after the
completion of food intake analysis; thus ~5 wk after surgery. At the
time of experimental testing, all animals were gaining weight and
appeared healthy. In addition, all animals were food deprived overnight
but allowed access to water ad libitum in an attempt to normalize
interindividual variation in gastrointestinal status (8). Sham
(n = 32) and Vag (n = 30) rats received intraperitoneal injections of vehicle (sterile, pyrogen-free saline) or one of three
doses (10, 50, or 100 µg/kg) of LPS (Escherichia coli,
0111:B4; Sigma, St. Louis, MO) 2 h after light onset in an injection
volume of 1 ml/kg. Blood samples were taken from the tail vein at 15, 30, 60, and 90 min after the injection. The tail was cleaned with betadine prior to being nicked with a sterile #15 scalpel blade, and
all blood samples were collected in sterile 1.5-ml microcentrifuge tubes. Rats were killed by decapitation 2 h after the injection, and
trunk blood and peritoneal lavage fluid were collected. To collect
peritoneal lavage fluid, 2 ml of sterile phosphate-buffered saline was
added to the peritoneal cavity, after which the abdomen was gently
massaged. Peritoneal lavage fluid (~1 ml) was collected in sterile
1.5-ml microcentrifuge tubes, centrifuged to remove cells (10,000 rpm,
10 min, 4°C), and stored at 
20°C until assayed. Serum
was separated by centrifugation (3,000 rpm, 20 min, 4°C) and stored
at 20°C until time of assay. The liver was also dissected, snap-frozen in liquid nitrogen, and stored at 80°C until
processed as described previously (24). Briefly, ~100 mg of liver
tissue were sonicated in 1 ml of a sonication buffer containing 5%
fetal calf serum, and an enzyme inhibitor cocktail consisting of 100 mM
amino-N-caproic acid, 10 mM EDTA, 5 mM benzamidine-HCl, and 0.2 mM phenylmethylsulfonyl fluoride (all from Sigma, St. Louis, MO). Sonicated samples were centrifuged (10,000 rpm, 10 min, 4°C), and supernatants were removed and stored at 4°C
until assayed. In addition, Bradford protein assays were performed to
determine total protein concentrations (5).
Assays. Endotoxin levels were measured using a chromogenic
Limulus amebocyte lysate assay (BioWhittaker, Walkersville, MD) according to the manufacturer's instructions. Before testing, serum
was diluted 1:5 or 1:100, and peritoneal lavage fluid was diluted 1:5
or 1:1,000 with endotoxin-free water. IL-1 protein levels were
measured using a commercially available ELISA kit (R & D systems,
Minneapolis, MN). The validation and use of the kit has been previously
described in detail (24). IL-6 was measured using a commercially
available ELISA kit (BioSource International, Camarillo, CA)
according to the manufacturer's instructions with slight
modifications. For the IL-6 ELISA, samples were diluted 1:4 before
assay. Serum corticosterone was measured using a radioimmunoassay (ICN
Pharmaceuticals, Costa Mesa, CA) according to the instructions provided.
Data analysis. The effects of vagotomy and LPS on serum
IL-1, IL-6, endotoxin, and corticosterone were analyzed across time using a three-way repeated measures ANOVA. If ANOVA indicated a
significant surgery × drug × time interaction, a separate
two-way ANOVA was performed on individual times to see where the
significant differences occurred. IL-1 protein levels in the liver
and endotoxin levels in the peritoneal cavity were evaluated by two-way
ANOVA. When appropriate, post hoc analysis was done using the
Student-Newman-Keuls multiple comparison test. In all tests, an
-level of P < 0.05 was taken as an indication of
statistical significance. Three animals (1 Sham, 2 Vag) were excluded
from analysis because we were unable to detect any LPS from peritoneal
lavage fluid or serum in these animals, which received an
intraperitoneal injection of LPS. The absence of LPS from the
peritoneal cavity suggests that these rats may have received an
improper injection.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Food intake. In this experiment, food intake analysis was used to assess the completeness of vagotomy. CCK significantly inhibited food intake in Sham (P < 0.05), but not in Vag rats. Food intake was decreased by 47% in CCK-injected Sham rats compared with the saline injection (3.46 ± 0.15 vs. 6.52 ± 0.19 g, respectively). In contrast, CCK did not significantly decrease food intake in Vag rats compared with the saline injection (5.42 ± 0.23 vs. 5.42 ± 0.24 g, respectively).
Ten microgram per kilogram LPS. The intraperitoneal injection
of 10 µg/kg LPS increased circulating levels of LPS (Fig.
1A), resulting in a main effect of
drug [F(1,25) = 36.429, P < 0.0001], whereas there was no main effect of surgery or surgery × drug × time interaction. LPS levels were significantly increased at all time points examined in both Sham and Vag animals, and there were
no significant differences between the two groups. This dose of LPS
also resulted in main effects of drug on serum IL-1, serum IL-6, and
serum corticosterone [F(1,25) = 71.302, 49.123, and 47.157, respectively; P < 0.0001 for each comparison].
Significant increases in serum IL-1, serum IL-6, and serum
corticosterone were found at 60, 90, and 120 min after the injection
compared with the saline injection (Figs.
2, A and D, and
3A). There were no significant differences in the
magnitude of the increases between Sham and Vag rats.
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Fifty micrograms per kilogram LPS. The intraperitoneal
injection of 50 µg/kg LPS increased circulating levels of LPS (Fig. 1B), resulting in a main effect of drug [F(1,26) = 232.505, P < 0.0001], whereas there was no main
effect of surgery or surgery × drug × time interaction. LPS
levels were significantly increased at all time points examined in both
Sham and Vag animals, and there were no significant differences between
the two groups. This dose of LPS also resulted in main effects of drug
on serum IL-1, serum IL-6, and serum corticosterone
[F(1,26) = 115.309, 229.178, and 82.121, respectively;
P < 0.0001 for each comparison]. Again, significant
increases in serum IL-1, serum IL-6, and serum corticosterone were
found at 60, 90, and 120 min after the injection compared with the
saline injection (Figs. 2, B and E, and 3B). There were no significant differences in the magnitude of the increases
between Sham and Vag rats.
One hundred microgram per kilogram LPS. This dose of LPS
resulted in similar effects on circulating LPS levels and serum
cytokines and corticosterone, as did the two lower doses (Figs.
1C, 2, C and F, and 3C). That is, the
intraperitoneal injection of 100 µg/kg LPS increased circulating LPS
levels, serum IL-1, serum IL-6, and serum corticosterone compared
with the saline injection in both Sham and Vag animals. However, there
was a reduction in circulating levels of LPS in Vag rats compared with
Sham rats, resulting in a significant surgery × drug × time
interaction [F(4,104) = 6.935, P < 0.0001]. Significant differences were found at the 15-, 30-, 60-, and 120-min time points (P < 0.05). In addition, the
magnitude of the LPS-induced increases in serum IL-1 and IL-6 levels
in the Vag animals compared with the Sham animals was reduced,
resulting in significant surgery × drug × time interactions [F(4,104) = 6.62, P < 0.0001, and
F(4,104) = 6.685, P < 0.0001; for IL-1
and IL-6, respectively]. This difference was due to significantly
lower levels of IL-1 and IL-6 at the 90- and 120-min time points
(P < 0.05). This dose of LPS again elevated serum corticosterone, resulting in a significant drug effect
[F(1,26) = 106.604, P < 0.0001]. There
was no significant difference in the magnitude of the increase between
the LPS-injected Sham and Vag animals.
LPS in peritoneal lavage fluid and liver IL-1.
Intraperitoneal injections of LPS dose dependently increased LPS levels
in the peritoneal lavage fluid [F(3,51) = 91.195, P < 0.0001; Fig. 4A]. Furthermore, at the time
of death (2 h), LPS significantly increased IL-1 protein levels in
the liver [F(3,51) = 114.553, P < 0.0001; Fig. 4B]. There were no significant
differences in endotoxin levels in peritoneal lavage fluid or
IL-1 levels in liver between Sham and Vag rats.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In control rats, all three doses of LPS increased circulating LPS
levels at the earliest time point examined (15 min) and circulating
levels remained elevated for the duration of the experiment (2 h).
These data indicate that LPS quickly gains access to the general
circulation but is not rapidly cleared from the circulation despite the
clearing ability of the liver Kupffer cells (11). Furthermore, LPS dose
dependently increased circulating IL-1 and IL-6, increased
corticosterone beginning at 60 min after the injection, and increased
liver IL-1 levels 2 h after the injection. These data are in
agreement with the concept that cytokines are critical mediators in
signaling the central nervous system to orchestrate the cascade of
endocrine, autonomic, and behavioral processes collectively termed the
acute phase response.
In addition, the current results do not support the hypothesis that
vagotomy inhibits brain-mediated illness responses because it inhibits
peripheral cytokine production (30). In contrast, with the two lower
doses (10 and 50 µg/kg) of intraperitoneal LPS, no significant
differences were found in circulating levels of LPS or in the
production of serum IL-1, IL-6, or corticosterone between Sham and
Vag animals. Thus it does not appear that vagotomized rats are
endotoxin tolerant. However, it is important to note that the
vagotomy-associated bacterial translocation previously reported was
only examined 7 days after surgery (7). The current experiments began
~5 wk after surgery, which is a similar recovery period used in prior
vagotomy studies that found a blockade of various sickness behaviors by
vagotomy (17, 28). Furthermore, there were no significant differences
in circulating LPS levels in saline-injected Sham and Vag rats, which
indirectly suggests that there is not an increase in bacterial
translocation at this time. Nevertheless, it is not known whether
vagotomy would alter cytokine production 1 wk after surgery when the
increased bacterial translocation was reported to occur (7).
The 100-µg/kg dose of LPS resulted in many similar effects between
Sham and Vag rats. However, there was a reduction in LPS-induced serum
IL-1 and IL-6 at the 90- and 120-min time points. These differences
in serum cytokines at the highest dose of LPS were not likely the
result of endotoxin tolerance; rather, the decreases in serum IL-1
and IL-6 in Vag rats were likely due to the significant reduction in
the amounts of LPS in the circulation at the earlier time points (e.g.,
15 min; Fig. 1C). It remains unknown as to why differences in
the transport of LPS from the peritoneal cavity occurred in this group,
whereas no differences in transport were seen with the two lower doses
of LPS. One possible explanation of these results is that the Vag rats
in the highest-dose group (100 µg/kg) were in relatively "poor
shape" compared with Vag rats in the lower-dose LPS groups. However,
analysis of individual food intake and body mass data between the
different groups of Vag rats did not reveal any differences between the
groups, which allows us to exclude the possibility that the current
results were due to poor health of the Vag rats in the highest-dose
group or incomplete vagotomy in the two lower-dose groups. In addition, these differences at 100 µg/kg may be uncharacteristic, because in a
similar study using 100 µg/kg LPS intraperitoneally, we did not find
any significant differences in circulating levels of LPS or IL-1
between Sham and Vag rats (unpublished data). Furthermore, although
differences in circulating IL-1 and IL-6 were found with the
100-µg/kg dose of LPS, there were no differences in serum corticosterone between Sham and Vag rats, suggesting that the differences in serum cytokines were not likely physiologically relevant
differences. Also, there were no differences in liver IL-1 levels
after any dose of LPS between Sham and Vag rats, suggesting that immune
cells of liver, the Kupffer cells, are not tonically suppressed.
Regardless of these considerations, it remains unknown whether the
reduction in circulating cytokines observed in the current study at the
100-µg/kg dose of LPS would lead to differences in other brain
activation measures or sickness behaviors commonly examined. Thus it is
advisable to determine unequivocally whether circulating levels of LPS
and/or cytokines are elevated equally in this type of experiment.
The current data also support earlier studies suggesting that vagotomy
does not block or reduce cytokine-to-brain communication by means other
than afferent interruption. Subdiaphragmatic vagotomy inhibits brain
production of IL-1 mRNA in response to intraperitoneal IL-1, yet
does not alter liver IL-1 mRNA production (17). Vagotomy also does
not alter plasma IL-1 levels or pituitary IL-1 mRNA, yet blocks
IL-1 mRNA in the brain of mice in response to intaperitoneal LPS
(21). In addition, vagotomy does not block fever in response to an
intracerebroventricular injection of PGE2 (23) or
behavioral effects of intracerebroventricular IL-1 (4), suggesting
that vagotomy does not disrupt sickness responses by interrupting
effector pathways or by impairing the direct sensitivity of the brain
to immune signals. Finally, fever in response to intraperitoneal LPS is
blocked by vagotomy in well-nourished rats, rejecting the possibility
that the vagotomy-induced febrile nonresponsiveness is due to
malnutrition (27). Collectively, these data support a direct action of
vagal afferents in cytokine-to-brain communication and argue against
several of the alternative hypotheses as to why vagotomy is blocking
centrally controlled illness responses.
The lack of effect of vagotomy on circulating corticosterone requires
comment, because vagotomy does blunt HPA activation to a variety of
intraperitoneally administered immune-activating agents (9, 10, 12,
18). Vagotomy reduced corticosterone levels in response to
intraperitoneal IL-1 and tumor necrosis factor- (9, 10). In these
studies, however, the blockade of corticosterone was only partial. In
addition, in response to intraperitoneal LPS or IL-1, vagotomy
blocked adrenocorticotropin hormone secretion, yet had no effect on
circulating corticosterone (12, 18). Finally, it is possible that
direct action of IL-1 on the adrenal gland may contribute to
corticosterone production (1), thus making the effects of vagotomy on
corticosterone variable and difficult to interpret.
In conclusion, the suppressive effects of subdiaphragmatic vagotomy on various aspects of the acute phase response are not likely due to differences in the distribution of endotoxin in the circulation or in the peripheral production of cytokines. Rather, these data support the hypothesis that vagal afferent signaling is likely one mechanism by which cytokines can signal the brain to regulate centrally controlled aspects of the acute phase response.
Perspectives
The role of vagal afferents in cytokine-to-brain communication remains a topic of much debate. It is clear, however, that peripheral cytokines do signal the brain, and it is likely that this occurs through multiple routes. Alternative pathways include other vagal afferents that are still intact, other peripheral nerves, as well as various other routes of communication between the blood and brain, such as active transport mechanisms, passage at sites that lack a true blood-brain barrier (e.g., circumventricular organs), and barrier-cell mediated pathways (2, 29, 33). It is likely that peripheral cytokines use different routes of communication under specific circumstances. For example, the majority of the data suggests that vagal afferents likely contribute to cytokine-to-brain communication during relatively small challenges in the physiological range (16, 28), whereas other routes of communication may be more important during times of pathology when increases in cytokines gain access to sites closely linked to brain sites.| |
ACKNOWLEDGEMENTS |
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We thank Stephanie Daniels and Debra Berkelhammer for excellent technical assistance.
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FOOTNOTES |
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This work was supported, in part, by National Institute of Mental Health grants MH-5045, MH-5283, MH-0314, and MH-1558.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. K. Hansen, Dept. of Psychology, Univ. of Colorado at Boulder, Campus Box 345, Boulder, CO 80309-0345 (E-mail: mhansen{at}psych.colorado.edu).
Received 9 June 1999; accepted in final form 3 September 1999.
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TOP
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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