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-induced fever is dependent on dose
1 Department of Psychology and Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309; and 2 Department of Psychology, University of Virginia, Charlottesville, Virginia 22904
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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It has been suggested that proinflammatory
cytokines communicate to the brain via a neural pathway involving
activation of vagal afferents by interleukin-1
(IL-1), in
addition to blood-borne routes. In support, subdiaphragmatic vagotomy
blocks IL-1-induced, brain-mediated responses such as fever.
However, vagotomy has also been reported to be ineffective. Neural
signaling would be expected to be especially important at low doses of
cytokine, when local actions could occur, but only very small
quantities of cytokine would become systemic. Here, we examined core
body temperature after intraperitoneal injections of three doses of recombinat human IL-1 (rh-IL-1). Subdiaphragmatic vagotomy
completely blocked the fever produced by 0.1 µg/kg, only partially
blocked the fever produced by 0.5 µg/kg, and had no effect at all on
the fever that followed 1.0 µg/kg rh-IL-1. Blood levels of
rh-IL-1 did not become greater than normal basal levels of
endogenous rat IL- until the 0.5-µg/kg dose nor was IL-1
induced in the pituitary until this dose. These results suggest that
low doses of intraperitoneal IL-1 induce fever via a vagal route and
that dose may account for some of the discrepancies in the literature.
cytokines; vagotomy; immune-to-brain communication; rat
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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PROINFLAMMATORY
CYTOKINES [interleukin (IL)-1
and -, tumor necrosis
factor-, and IL-6] are released by peripheral immune cells in
response to pathogenic challenge (20). These
cytokines play a local role at the site of infection in mediating
immune defense, but they also signal the central nervous system,
thereby initiating the brain-mediated components of host defense such as fever. Thus the peripheral administration of cytokines such as
IL-1 leads to fever and other brain-mediated, host-defensive responses (21) as well as a distinctive pattern of neural
activation (4, 10) and neurochemical changes
(7). Analogously, the peripheral blockade of receptors for
IL-1 blocks or reduces the neural activation and host-defensive
responses (6) that follow challenge with immune-activating
agents such as lipopolysaccharide (LPS; a constituent of the
cell walls of gram-negative bacteria). In addition, this
immune-to-brain signaling induces behavioral changes characteristic of
depressed mood (38) as well as other changes not typically
associated with host defense (23).
Although it is clear that cytokines such as IL-1 signal
the brain, the pathway(s) by which this communication is accomplished remains a matter of controversy. Because there are receptors for IL-1 and other cytokines in the brain (1), it is
natural to suggest that blood-borne cytokines enter the brain and bind
to their receptors, thereby initiating the neural cascade. However, cytokines are large peptides and are unlikely to cross the
blood-brain barrier in significant quantities. This has led to
suggestions that blood-borne cytokines 1) are carried into
the brain by specific active transport mechanisms (2),
2) initiate signaling at regions of the brain where the
blood-brain barrier is weak or absent (3), and
3) bind to receptors on the inside of the cerebral
vasculature, thereby leading to the release of other second-order
messengers (e.g., prostaglandins) on the "brain side" of the
vasculature (9).
Alternatively, it has recently been suggested that
cytokines also communicate to the brain via a neural route. It has been argued that cytokines such as IL-1 bind to receptors located on
afferent vagal terminals or structures closely associated with afferent vagal fibers (14), thereby activating
afferent vagal fibers (12) that terminate in the nucleus
of the solitary tract (NTS) and initiate the neural cascade. The most
compelling evidence for vagal signaling comes from studies in which
IL-1 has been injected intraperitoneally in animals in which the
vagus has been severed at the subdiaphragmatic level. The frequent
result has been that subdiaphragmatic vagotomy blocks both the changes
in the brain (e.g., norepinephrine release) and the host-defensive responses (e.g., fever) that would normally follow the IL-1
administration (see Ref. 22 for a review).
However, the vagotomy experiments have been controversial, and a number
of failures to find any effects of vagotomy on neurally mediated
responses to IL-1 has been reported (see below). Although there is a
large number of factors that might influence the outcome of abdominal
deafferentation studies, the assumption that there exist both
blood-borne and neural pathways of immune-to-brain communication
suggests that cytokine dose is likely to be a critical factor. This is
because only very small amounts of cytokine might be expected to become
systemic after the intraperitoneal injection of small doses, thereby
yielding a balance that relies on vagal communication. In contrast,
larger quantities may become systemic after larger intraperitoneal
doses, thereby shifting the balance to blood-borne signaling. Dose may
even play the same role after intravenous injection, with most of the
cytokine being retained in the liver after small intravenous doses
(26), with the hepatic branch of the vagus then taking on
a primary signaling role (33, 37). It is thus of interest
that vagotomy has been reported to block the sleep-promoting effects of
intraperitoneal recombinant human IL-1 (rh-IL-1) only at a very
low 0.1-µg/kg dose (16). However, blood levels of
rh-IL-1 were not measured, and so it is difficult to interpret the
effects of dose in this study. Fever has been the most often measured
outcome of peripheral IL-1, although IL-1 dose has not been
manipulated in a vagotomy/fever study, and dose has varied over a wide
range in reported studies. The present studies examined the effects of
subdiaphragmatic vagotomy on the fever produced by different doses of
intraperitoneal rh-IL-1 as well as the entry of rh-IL-1 into
blood and the induction of pituitary IL-1 at these doses.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Adult male Sprague-Dawley rats (250 g at purchase; Harlan Sprague Dawley, Indianapolis, IN) were used in all studies. All animals (n = 76) were individually housed in plastic cages at 25 ± 1°C with a 12:12-h light-dark cycle (lights on at 0800), and standard rat chow and water were freely available. Care and use of the animals were in accordance with protocols approved by the University of Colorado Institutional Animal Care and Use Committee.
Subdiaphragmatically vagotomized (Vag) and sham-operated (Sham) rats were prepared under halothane anesthesia as previously described in detail (37). In addition, precalibrated radio transmitters (MiniMitter, Sun River, OR) for measuring core body temperature (CBT) were implanted in the peritoneal cavity at the time of surgery. During the immediate postsurgical period (~2 days), Sham and Vag rats were maintained on highly palatable food and received acetaminophen (0.5 mg/ml) in their drinking water. Verification of vagotomy was performed using food-intake analysis and stomach weight measurements as previously described (15).
Experimental testing occurred ~4 wk after surgery. At the time of
experimental testing, all animals were gaining weight (Sham: 365 ± 5 g; Vag: 329 ± 8 g) and appeared healthy. Each rat
(Sham: n = 24; Vag: n = 16) was
injected with vehicle (sterile, pyrogen-free saline) on a control day,
and CBT was measured for 6 h after the injection using standard
telemetry techniques. On the next day, each rat was injected with one
dose (0.1, 0.5, or 1 µg/kg) of rh-IL-1 (provided by the Biological
Response Modifiers Program, National Cancer Institute). These doses
were chosen on the basis of a pilot experiment designed to determine
the minimum dose that would produce fever. A dose of 0.1 µg/kg
produced fever, whereas a dose of 0.05 µg/kg did not. All
injections were performed 2 h after light onset in an injection
volume of 1 ml/kg. After the rh-IL-1 injections, CBT measurements
were again taken for 6 h after which all rats were killed by
decapitation. At the time of death (6 h after rh-IL-1 injection),
pituitary samples were collected, snap-frozen in liquid nitrogen, and
stored at 
80°C until processed. In addition, pituitary samples were
collected from a separate group of Sham and Vag rats (n = 8) that received saline injections on both the control and test day.
The pituitary samples were processed for endogenous rat IL-1
measurements as previously described (27). Briefly, the
pituitary tissue was sonicated in a sonication buffer, centrifuged
(10,000 rpm, 10 min, 4°C), and supernatants were collected and stored at 20°C until assayed. Bradford protein assays were performed to
determine total protein concentrations. Pituitary IL-1 protein levels were measured using a commercially available ELISA kit (R & D
Systems, Minneapolis, MN) as previously described
(18). Cross-reactivity with rh-IL-1 is 1.6%.
In a second experiment, rats (n = 28) received either
vehicle (pyrogen-free saline), 0.05, 0.1, or 0.5 µg/kg rh-IL-1.
Rats were killed 15 and 30 min later by decapitation, blood was
collected in sterile tubes, and serum was obtained by centrifugation
(3,000 rpm, 20 min, 4°C) and stored at 20°C until assayed. Serum
rh-IL-1 protein levels were measured using a commercially available
ELISA kit for human IL-1 (R & D Systems). There is no significant
cross-reactivity with rat IL-1.
The effects of vagotomy and rh-IL-1 on CBT were analyzed by
repeated-measures ANOVA. The effects of rh-IL-1 on blood levels of
human IL-1 and pituitary rat IL-1 were evaluated with a two-way ANOVA. Post hoc analysis was done, when appropriate, using the Student-Newman-Keuls multiple-comparison test. In all tests, an -level of P < 0.05 was accepted as indication of
statistical significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The rh-IL-1 produced a dose-dependent fever
[F(2,21) = 14.33, P < 0.0001], with both the 0.5- and 1.0-µg/kg doses producing greater
elevations in CBT than did the 0.1-µg/kg dose. The 0.5- and
1.0-µg/kg doses did not differ. Figure
1A presents the CBT after the
control saline and the 0.1-µg/kg rh-IL-1 injections in Vag and
Sham subjects. There was no difference in CBT between the Vag and Sham
subjects on the saline day (F < 1.0), indicating that
vagotomy did not alter basal CBT. The low dose of 0.1 µg/kg rh-IL-1 produced fever that was completely blocked by vagotomy. The
0.1-µg/kg rh-IL-1 injection, relative to saline, did not lead to
increased CBT in the Vag subjects [F(1,7) = 3.70, P > 0.13], but it did produce fever in the
Sham subjects [F(1,7) = 242.32, P < 0.0001]. Thus CBT after rh-IL-1 injection
differed between Sham and Vag groups
[F(1,11) = 6.58, P < 0.03]. Figure 1B presents the data for the low dose
expressed as a difference between CBT on the saline and rh-IL-1 days
for the Vag and Sham subjects. As is evident, the 0.1-µg/kg dose did
not produce fever in the Vag subjects, but it did so in the Sham group
[F(1,11) = 18.29, P < 0.002].
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The pattern of data following 0.5 µg/kg rh-IL-1 was quite
different (Fig. 2). Again, there were no
differences between groups on the saline day (F < 1.0). However, vagotomy produced only a marginal attenuation in the
increase in CBT produced by rh-IL-1. Sham subjects responded
strongly to rh-IL-1 [F(1,7) = 84.18, P < 0.0001], whereas the fever in Vag subjects was
marginal [F(1,4) = 5.95, P < 0.08]. The difference between Sham and Vag
subjects after the rh-IL-1 injection was also marginal
[F(1,11) = 3.65, P < 0.09]. The data expressed as change from baseline (Fig. 2B) also indicate only a blunting of the increase in CBT produced by
vagotomy [F(1,11) = 4.09, P < 0.07].
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The 1.0-µg/kg dose yielded a yet different pattern (Fig.
3). In this case, Vag animals displayed a
slightly, but not significantly, lower CBT after saline injection than
did Sham subjects [F(1,12) = 4.11, P < 0.07]. For this dose, vagotomy had no effect at
all on the fever after the rh-IL-1 injection. Both Sham
[F(1,7) = 293.47, P < 0.0001] and Vag [F(1,5) = 64.89, P < 0.0005] groups responded to the rh-IL-1, and
the two groups showed an equal increase in CBT from baseline
(F < 1.0).
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Blood levels of rh-IL-1 15 and 30 min after intraperitoneal
injection of saline or rh-IL-1 are shown in Fig.
4. Measurable blood levels were present
even after the 0.05-µg/kg dose that does not produce fever. A further
small increase was evident after 0.1 µg/kg and a much larger increase
after 0.5 µg/kg [F(3,20) = 74.21, P < 0.0001].
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The differences in blood levels after the 0.5-µg/kg dose compared with both the 0.05- and 1.0-µg/kg doses were significant, whereas the difference between the 0.05- and 1.0-µg/kg doses was not significant.
Pituitary IL-1 levels (Fig. 5) were
increased after intraperitoneal injection of rh-IL-1 in a
dose-dependent manner [F(3,38) = 22.92, P < 0.0001]; there were large increases after 1.0 µg/kg, moderate increases after 0.5 µg/kg, and no increases at all
after 0.1 µg/kg. Vagotomy neither altered pituitary IL-1
[F(1,38) < 1] nor did it reduce the
effect of rh-IL-1 injection (F < 1.0).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study demonstrates that whether or not
subdiaphragmatic vagotomy will block the effects of intraperitoneal
IL-1 on fever does indeed depend on the dose of IL-1. Vagotomy
completely blocked fever at a dose of 0.1 µg/kg, the lowest dose at
which intraperitoneal IL-1 produced increased CBT in pilot work.
Vagotomy had a partial effect at 0.5 µg/kg and no effect at all at
1.0 µg/kg. It is difficult to compare doses across studies because there are large differences in the biological activity of rh-IL-1 across different lots and sources (unpublished observations). However,
it can be noted that Hansen and Krueger (16) found vagotomy to almost completely block the somnogenic effects of 0.1 µg/kg, to only mitigate the effects of 0.5 µg/kg, and to have no
effect after 2.5 µg/kg. It can also be noted that Porter et al.
(29) and Schwartz et al. (31), who failed to
detect an effect of vagotomy on intraperitoneal IL-1-induced
decreases in feeding, used a single dose of 2 µg/kg. Dose is also
likely to be a critical issue in intraperitoneal LPS studies. Vagotomy has been reported to have no effect on intraperitoneal LPS-induced fever (5) and anorexia (29, 31), with the
single dose used being 50 and 100 µg/kg, respectively. However, even
1.0 µg/kg ip LPS produces substantial fever
(15). Indeed, the fever produced by 1.0 µg/kg ip
LPS was as large as that produced by 50 µg/kg, although it was not as
persistent. In keeping with the argument made here, vagotomy did not
reduce the fever produced by 1.0 µg/kg ip LPS (15), and
lower doses are currently being explored.
The argument being made is that at low intraperitoneal doses, very
little IL-1 enters the circulation, and so the fever or other end
point being measured is generated by abdominal vagal input to the
brain. This input could arise either from direct IL-1 action in the
abdomen (serosal or draining lymphatic actions) or by circulating
IL-1 acting on vagal afferents in the liver or other organs. Under
these conditions, subdiaphragmatic vagotomy would naturally have a
major impact. At higher doses, significant quantities of IL-1 become
systemic, and the end point is then produced by a combination of vagal
and other signaling that result from blood-borne cytokines (e.g., entry
at circumventricular organs). Here, vagotomy should have less and less
impact the higher the dose. The blood levels of rh-IL-1 measured
after 0.05, 0.01, and 0.5 µg/kg rh-IL-1 adminstration are
consistent with this argument. The 0.05-µg/kg injection led to very
little rh-IL-1 in blood; only 14 pg/ml were present at 15 min. To
place this amount in context, normal blood levels of endogenous IL-1
in untreated rats are in the 25- to 50-pg/ml range
(18). Thus, neither the blood level of rh-IL-1
nor the degree of vagal activation produced by 0.05 µg/kg is
sufficient to produce fever. Although blood levels of rh-IL-1 were
slightly higher (38 pg/ml at 15 min) after the 0.1-µg/kg dose, the
difference was not statistically significant. Moreover, these levels
were still quite small relative to normal basal levels of endogenous
rat IL-1, and so blood-borne rh-IL-1 was unlikely to be the
source of the fever after this dose. Rather, the fever was likely
generated by abdominal vagal activation, and thus subdiaphragmatic
vagotomy completely blocked the fever. The 0.5-µg/kg dose led to a
much larger quantity of circulating rh-IL-1 (164 pg/ml), and so
vagotomy naturally had less impact. Although not measured, 1.0 µg/kg
would have doubtlessly been followed by very high blood levels of
rh-IL-1, and so abdominal vagal deafferentation had no effect at all.
Pituitary IL-1 was measured because induction of IL-1 in the
pituitary by intraperitoneal rh-IL-1 injection almost certainly is
mediated via blood-borne transmission of the rh-IL-1 to the pituitary. Indeed, vagotomy had no effect on the induction of IL-1
in the pituitary at any dose. The important finding, however, was that
the 0.1-µg/kg dose did not induce IL-1 in the pituitary. This
supports the contention that the quantity of rh-IL-1 that enters the
blood after this intraperitoneal dose is insufficient to produce
signaling and that the fever that follows this dose is likely to be
mediated independently of IL-1 in the blood. It might be argued that
the present study examined only a 6-h time point and that pituitary
IL-1 would have been elevated at some other time after the
0.1-µg/kg dose. This is, of course, possible.
This line of reasoning suggests that dose should be critical after
intravenous administration as well. Small quantities of intravenously
injected LPS, and perhaps rh-IL-1 as well, should be rapidly cleared
from the circulation by the liver (26), and the liver is a
particularly rich source of abdominal vagal afferents and local
cytokine production and release from Kupffer cells. Thus intravenously
injected substances would be able to generate a vagal signal to the
brain at the liver (32). However, hepatic filtration would
become saturated at higher doses, resulting in more sustained
circulation of cytokines or LPS. Thus, as with intraperitoneally
administered agents, subdiaphragmatic vagotomy should only be effective
at low doses. Indeed, Romanovsky et al. (30) have reported
that subdiaphragmatic vagotomy blocks the fever that follows 1.0 µg/kg iv LPS but not the fever that follows 10 to 1,000 µg/kg iv
LPS. Indeed, experiments that have found vagotomy to have no effect
after intravenous LPS (5, 35, 36) have employed doses
ranging from 20 to 400 µg/kg, whereas a negative intravenous
rh-IL-1 experiment (9) used a single dose of 1.87 µg/kg.
It should be noted that there is a large amount of additional evidence
for vagal transmission of immune-to-brain signals. 1)
IL-1-binding sites are located on structures associated with abdominal
vagal terminals (14), and IL-1 receptor mRNA is present in
the cell bodies of afferent vagal fibers (8).
2) Macrophages and other immune cells, some constitutively
expressing IL-1, are intermingled with and surround abdominal vagal
fibers (13), thereby providing a mechanism whereby LPS or
pathogenic agents can lead to local IL-1 production and release onto
vagal terminals. 3) These lymphoid cells associated with the
abdominal vagus rapidly increase IL-1 expression after intraperitoneal
administration of immune-activating agents (13).
4) Intraperitoneally and intravenously administered IL-1
and LPS activate afferent vagal fibers as indicated by measurement of
electrical activity (28) and c-fos expression in the cell bodies of afferent vagal fibers (11, 12).
5) There is a rapid increase in extracellular levels of
glutamate in the NTS after intraperitoneal administration of LPS
(25), and glutamate is known to be released by vagal
terminals at their site of termination in the NTS (34).
6) Peripheral electrical stimulation of the vagus leads to
neural alterations characteristic of peripheral immune activation by
LPS and other agents (19).
The present data, along with those summarized above, indicate that the vagus nerve can carry the immune-to-brain signal that initiates neurally mediated host defense and that blood-borne extra vagal communication is not necessary. The critical importance of dose is consistent with the proposal that neural signaling routes are important early in an infection before significant blood levels of cytokines have developed or under conditions in which neither the infectious agent nor locally produced cytokines become systemic (24). Later, when blood levels of cytokines or the infectious agent itself become systemic, blood-borne routes may come to play the dominant role. However, even here the vagus may play a role. Circulating cytokines will have access to vagal afferents in the liver and in regions such as the lungs that are not deafferented by subdiaphragmatic vagotomy. Whether vagal activation by blood-borne, rather than locally acting, cytokines is a factor in immune-to-brain communication remains to be determined.
Perspectives
The pathways used in cytokine-to-brain communication remain a topic of lively debate. Strong arguments have been made for both blood-borne and neural routes, but it seems clear that multiple-communication routes are used. This would seem entirely appropriate for a function so important for host defense during infection. The present results, along with those of Hansen and Kruger (16) and Romanovksy et al. (30), firmly suggest that whether vagotomy will block the effects of peripherally administered IL-1 or LPS depends on dose, and so subsequent studies
of vagal deafferentation should be attentive to this issue. It is clear
that it is possible to administer sufficiently large doses of IL-1
or LPS such that subdiaphragmatic vagotomy is no longer effective in
reducing the impact of the injected substance. An understanding of the
functional significance of this dose dependency will require studies
similar to those conducted here, however, with the use of infectious
agents rather than bolus injections of cytokines or LPS. We (15,
24) and Romanovsky et al. (30) have suggested that
vagal afferents are likely to be an especially important pathway early
in an infection and in response to small challenges in the
physiological range, and the present data are fully supportive of this suggestion.
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ACKNOWLEDGEMENTS |
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This research was supported by National Institutes of Health Grants MH-55283, MH-45045, MH-00314, and MH-0155.
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. F. Maier, Dept. of Psychology, Univ. of Colorado at Boulder, Campus Box 345, Boulder, CO 80309-0345 (E-mail: smaier{at}psych.colorado.edu).
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. Section 1734 solely to indicate this fact.
Received 5 September 2000; accepted in final form 21 November 2000.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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