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-induced fever
Department of Neurochemistry and Neurotoxicology, Arrhenius Laboratories for Natural Sciences, Stockholm University, S-10691 Stockholm, Sweden
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Tumor necrosis
factor-
(TNF-) is a pleiotropic cytokine that orchestrates an
array of local and systemic effects. For instance, acute exposure to a
high dose of TNF- results in septic shock and fever. We have used
interleukin-1
(IL-1)- and interleukin-6 (IL-6)-deficient mice,
along with their wild-type equivalents, to define a role for TNF- in
fever. Briefly, the mice produced prostaglandin
E2-dependent fevers in response to
recombinant murine TNF- (rmTNF-). Furthermore, rmTNF- (12 µg/mouse ip) triggered a febrile response in IL-1-deficient mice
as well as in their corresponding wild-type controls. In contrast, the
IL-6-deficient mice were resistant to rmTNF- (4.5 µg/mouse ip),
although their wild-type counterparts readily mounted a fever. In the
IL-6-deficient mice, moreover, the febrile response to rmTNF- could
be restored by a central administration of rat recombinant IL-6 (500 ng/mouse icv). We thus conclude that TNF- can trigger fever
independent of IL-1 but dependent on IL-6. We also suggest that
central, rather than peripheral, IL-6 (plasma IL-6 was measured 2 h
after pyrogenic challenge) is essential in TNF--induced fever.
interleukin-1; interleukin-1-deficient mice; interleukin-6-deficient mice; lipopolysaccharide; indomethacin
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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FEVER IS A SYSTEMIC response that is initiated when an
organism is invaded by pathogens (12, 13). Hence, the febrile response can, at least in part, be mimicked through the use of an exogenous pyrogen such as lipopolysaccharide (LPS), a carbohydrate from the cell
wall of gram-negative bacteria. When LPS is injected into experimental
animals, it instigates a cascade of endogenous pyrogens, which in turn
induces fever (21). Some of these endogenous pyrogens are interleukin
(IL)-1/, IL-6, and tumor necrosis factor (TNF)- (29). Their
respective interrelations in the cascade are, however, far from clear,
since cytokines commonly induce each other. For instance, IL-1 and
IL-1 are known inducers of TNF- (1, 3). Therefore, a few years
ago, our laboratory set out to map the cytokine cascade in fever (1, 4,
17, 22, 30). The present study also specifically aims at elucidating the role of TNF- in the febrile response.
The TNF- protein is a 157-amino acid, acidic polypeptide that forms
a trimer during native conditions. The murine variant is glycosylated,
which is not the case for the human form (9). As for its biologic
properties, TNF- is a pleiotropic cytokine, known to orchestrate
many local and systemic responses. For instance, chronic TNF-
exposure in low doses causes cachexia, and acute exposure to high doses
of TNF- results in a number of effects, such as septic shock
syndrome and fever (28). Although TNF- can bind two receptors, p55
and p75 (8), certain protective qualities of the protein are probably
mediated through the p55 receptor. For example, mice lacking the p55
receptor succumb to infection of at least one type of bacteria (23,
25), suggesting that this receptor is important in host defense.
To study the cytokine cascade in fever, a number of transgenic mice
strains, deficient in different cytokines or cytokine receptors, have
been generated: IL-1-deficient mice (31), IL-6-deficient mice (24),
IL-1 type I receptor (IL-1RI)-deficient mice (17), IL-1 receptor
accessory protein (IL-1RAcP)-deficient mice (5), and TNF
receptor-deficient mice (2, 6, 19). With use of these transgenic
strains and reasonably low doses of the pyrogens, it has been shown
that an intraperitoneal injection of LPS can trigger a fever,
independent of whether the strain is deficient in IL-1RI (17), IL-1RAcP
(30), or IL-1 (1, 16). This is suggestive of a route to fever onset
that is not dependent on IL-1. A likely candidate in this context is
TNF-. In addition, we previously showed that IL-6 is necessary in
LPS fever (4). In other words, in LPS fever, an aspirant endogenous
pyrogen in the cascade (such as TNF-) should, if injected
intraperitoneally, be sensitive to a null mutation in the IL-6 gene,
unless it acts downstream of IL-6 in the mechanism. Following this line
of argument, TNF- should further be a pyrogen when injected
intraperitoneally into IL-1-deficient mice; otherwise it would not
represent an alternate route in the cascade.
Consequently, in this study we have injected IL-1- and
IL-6-deficient mice, as well as their wild-type counterparts, with recombinant murine TNF- (rmTNF-). We show that IL-1 is not a
requirement, although IL-6, most likely a central source of the
cytokine, is necessary in TNF- fever.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Materials.
Recombinant murine (rm) and recombinant human (rh) TNF- were kind
gifts from Dr. Charles A. Dinarello. Recombinant rat (rr) IL-6 was
acquired from European Union, Concerted Actions (Dr. Stephen Poole).
Indomethacin was purchased from Dumex, xylazine (Rompun) from Bayer
(Leverkusen, The Netherlands), and ketamine (Ketalar) from Parke-Davis
(Barcelona, Spain). All substances were diluted in pyrogen-free saline solution.
Animals.
IL-6- and IL-1-deficient male mice, as well as their wild-type
counterparts, were used in this study (8-12 wk old). The
generation of the IL-1-deficient strain of mice, on a C57BL/6J
background, has been described previously (31), as has the generation
of the IL-6-deficient strain of mice, on a B6CBA background (24). The
mice were housed one per cage, in a temperature-controlled room, with
food and water ad libitum and under a 12:12-h light-dark cycle (lights
on at 8:00 AM). The temperature in the room was kept at 30 ± 1°C, which is within the thermoneutral range of mice. The animals
were acclimated for 
1 wk after surgery before any experimental
procedure was started. The experiments started when the mice reached a
body weight of ~30 ± 5 g. Mice were used only once for each experiment.
Measurement of body temperature.
A battery-operated radiotransmitter (model XM-FH, Mini-Mitter) was
inserted into the mouse peritoneal cavity under anesthesia with
ketamine (50 mg/kg) and xylazine (10 mg/kg); all incisions were sealed
with stitches, and all wounds were treated with antibiotics. The core
body temperature and the activity (data not shown) of the animals were
measured using receivers under each cage (Mini-Mitter). Body
temperature was recorded at 10-min intervals beginning 24 h before
the injection of rmTNF-, rrIL-6, or indomethacin and continued for
48 h after the injections. Injections began between 8:30 and 10:00 AM
during the light period. In all cases the mean baseline temperature
before injection was compensated to equal the average temperature
during the light period, when animals were undisturbed. All
intraperitoneal injection volumes were 0.15 ml.
Intracerebroventricular injection. The intracerebroventricular injections were performed under ether anesthesia with 3.5-mm needles. The site of injection was 2 mm to the right of the midline, on a line drawn through the anterior base of the ears (7). The volume of the central injection was 0.01 ml. After the experiment the brains were removed and examined with respect to the site and consequence of the intracerebroventricular injection.
Statistical analysis. Values are means ± SE, unless stated otherwise. A repeated-measures ANOVA was used to analyze statistical differences of fever curves; the thermal data were grouped in 20-min intervals. The data in Table 1 were analyzed with one-way ANOVA, followed by Fisher's protected least significant difference test.
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ELISA for murine IL-6. The ELISA kit was purchased from R & D Systems (Minneapolis, MN), and the assay was performed according to the manufacturer's instructions.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Analyses of in vivo doses of rmTNF-.
We have studied the ability of rmTNF- to induce fever in IL-1-
and IL-6-deficient mice, as well as in their respective wild-type equivalents. First, the rmTNF- doses were tested in the wild-type mice: 0.05-12 µg/mouse in IL-1 wild-type mice and 0.11-6
µg/mouse in IL-6 wild-type mice. The doses found to induce fever were
12 and 4.5 µg/mouse, respectively (Fig.
1).
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IL-1-deficient and wild-type mice.
An injection of rmTNF- (12 µg/mouse ip) caused a reproducible
fever response in the IL-1 wild-type mice starting ~2 h after stimulus and with a duration of ~7 h (Fig.
2A). As
a control, indomethacin [600 µg/mouse, 20 ± 0.75 (SD) mg/kg
ip] was administered 2 h before the injection of pyrogen. This
treatment blocked rmTNF- fever efficiently throughout the entire
temperature peak (Fig. 2A). The
average core temperature was also significantly higher in the
rmTNF--injected IL-1-deficient mice (12 µg/mouse ip) than in
saline-injected mice (Fig. 2B).
Moreover, the fever onset was delayed ~1 h compared with the
wild-type animals, whereas the amplitude and length of the fever were
similar in the wild-type and knockout mice (Fig. 2).
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IL-6-deficient and wild-type mice.
A reproducible fever response was induced in IL-6 wild-type mice after
injection of rmTNF- (4.5 µg/mouse ip). The temperature increased
~3 h after injection and remained elevated for ~4 h (Fig.
3A).
Furthermore, the febrile response was efficiently blocked by an
injection of indomethacin [600 µg/mouse, 19 ± 1.4 (SD)
mg/kg ip] 2 h before rmTNF- injection (Fig.
3A). In contrast, the IL-6-deficient mice were unable to respond with fever when challenged with rmTNF- (Fig. 3B; 4.5 µg/mouse ip). A brief
hypothermia (lasting ~3 h) was seen instead (Fig.
3B).
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Hypothermic responses.
We also found that many animals exhibit more-or-less nocturnal
hypothermia on the night after the experiments. First, in the IL-1
wild-type mice a hypothermia was observed during the switch from light
to dark when animals injected with rmTNF- were compared with their
saline-injected controls (7:00-9:00 PM;
P < 0.05; data not shown).
Similarly, sporadic periods of nocturnal hypothermia for most of the
night after injection was observed in the rmTNF--treated IL-1-deficient mice compared with their saline-injected equivalents (8:20 PM-2:40 AM, most intervals;
P < 0.05; data not shown). When the
two rmTNF--injected groups mentioned above were compared, the
IL-1- knockout animals displayed the lowest temperature (10:40 PM-1:40 AM, divided on 2 significant periods;
P < 0.05; data not shown). The IL-6
wild-type mice did not exhibit a clear hypothermia after peripheral
rmTNF- injection; there was a mere tendency toward lower body
temperatures during the night after treatment. The IL-6-deficient mice,
however, show a long-lasting hypothermia starting at 7:40 PM and
continuing to 12:00 PM, with intermittent temperature increases
(rmTNF- vs. saline-injected,
P < 0.05; data not shown).
There was, however, no difference between the IL-6 knockout and the
IL-6 wild-type when only rmTNF--injected animals were compared.
Injection of rhTNF-.
Recombinant human TNF- is often used as an endogenous pyrogen in
rodents. Because our results have been obtained with the murine form of
TNF-, we also injected the animals with rhTNF- simply for the
sake of comparison. The IL-1- wild-type mice were injected with
0.4-12 µg/mouse ip, whereas the IL-6 wild-type mice were
injected with 0.4-6.0 µg/mouse ip. In the IL-1 wild-type mice, rhTNF- at 3 µg/mouse was sufficient to induce fever (data not shown). In the wild-type counterparts to the IL-6-deficient mice,
all rhTNF- doses tested (0.4, 3, and 6 µg/mouse) first elicited
hypothermic reactions (0-4 h). rhTNF- at 6 µg/mouse also
induced a temperature elevation at 4-8 h (data not shown).
Measurement of peripheral IL-6 levels.
Because IL-6 appeared to be necessary for rmTNF- fever in mice, we
measured IL-6 levels in plasma within the time frame of fever onset (2 h after injection). The IL-6 levels were 50 times higher in the
rmTNF--treated IL-6 wild-type mice (4.5 µg/mouse ip) than in the
saline controls (Table 1). Likewise, an rmTNF- injection in the
IL-1-deficient and IL-1 wild-type mice (12 µg/mouse ip)
increased the IL-6 levels 229- and 37-fold, respectively (Table 1).
Reestablishment of rmTNF- fever in IL-6-deficient
mice.
We further examined whether a central administration of IL-6 could
restore the febrile response to an intraperitoneal injection of
rmTNF- in the IL-6-deficient mice. rrIL-6 was injected at 500 ng/mouse [16 ± 0.67 (SD) µg/kg icv] 1 h
before the injection of rmTNF- (4.5 µg/mouse ip). The injection of
rrIL-6 plus rmTNF- causes an elevation in body temperature compared
with IL-6-deficient mice injected with saline intracerebroventricularly
and intraperitoneally (Fig.
4A).
This temperature curve was significantly different from that elicited
in IL-6-deficient animals by rmTNF- (open circles in Fig.
4A compared with open squares in Fig.
3B, P < 0.05; between 4 h 20 min and 5 h 40 min). When analyzed similarly, there was also no statistical difference between rmTNF- fever in
IL-6 wild-type mice (Fig. 3A, open
circles) and the fever elicited in IL-6-deficient mice that received
rrIL-6 and rmTNF- (Fig. 4A, open
circles), suggesting that the febrile response in the IL-6-deficient
mice had indeed been restored. It is noteworthy, however, that IL-6
injected alone (icv) causes a small general elevation of the body
temperature compared with control (Fig. 4B); this temperature curve was
statistically indistinguishable from that triggered in mice that were
stimulated with rmTNF- and IL-6 (Fig.
4A).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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In the past few years, new tools in fever research have become
available, namely, transgenic mice that lack cytokine or cytokine receptor genes (2, 5, 6, 17, 19, 24, 31). With this in mind, the first
step in analyzing the cytokine cascade in LPS fever is naturally to
inject LPS into mice that are deficient in specific cytokines or
cytokine receptors. We have, however, not injected LPS into any of the
animals, since this has been done in previous studies. The
IL-1-deficient mice have been stimulated with LPS in two independent
laboratories (1, 17). The findings were somewhat contradictory: after
treatment with Escherichia coli LPS,
Kozak and colleagues (16) observed a fever of lower magnitude in
IL-1-deficient mice, whereas Alheim and co-workers (1) found that
IL-1-deficient mice mounted a higher fever than wild-type controls.
Nevertheless, it is clear that IL-1 is not the only endogenous
mediator in LPS-induced fever, since both groups report febrile
responses in IL-1-deficient mice, albeit with varying amplitudes. In
contrast, the IL-6-deficient mice that were injected with LPS (4) were
unable to respond with fever, suggesting that IL-6 is a necessary
endogenous mediator in the febrile response to LPS, at least with use
of a relatively low dose (50 µg/kg ip). Injection of a 50 times
higher dose of LPS (2.5 mg/kg ip), potentially triggering nonspecific
effects, elicited a febrile response in IL-6 knockout animals (15).
The next step in clarifying the cytokine cascade in LPS fever is to
inject known endogenous pyrogens that are elevated by LPS (29) into the
different transgenic mouse strains. Part of this work has been done (4,
17, 30). For instance, it has been shown that IL-1 triggers fever
through IL-1RI (17) and IL-1RAcP (30). Now, the finding that LPS can
trigger fever independent of IL-1 (see above) suggests an alternate
signaling route, possibly through TNF-. In support of this theory is
the finding that LPS and IL-1 induce TNF- (1). Furthermore, TNF
p55/p75 double receptor-deficient mice have been shown to exhibit an
exacerbated fever in response to LPS (19), implying an upregulation of
other cytokines (possibly the IL-1 system) in the absence of proper TNF
signaling. The present work, however, which shows that TNF- acts as
an endogenous pyrogen in IL-1- but not IL-6-deficient mice (Figs. 2
and 3), is an important piece in the "LPS puzzle." It is not
altogether clear which TNF receptor is involved in LPS fever. To our
knowledge, fever studies on single TNF receptor-deficient mice (2, 6)
have not been carried out. There are, however, some indications as to
which receptor is important in fever. Work on p55-deficient mice, for
instance, shows that this receptor is essential for a TNF--induced
IL-6 response (2). This, coupled with the fact that IL-6 is necessary
for the induction of TNF- fever (present study), suggests that the
p55 receptor is essential in TNF- fever. Also, it has been suggested
that human TNF- only activates the p55 receptor in rodents (20).
Linking this to our results, which show that human TNF- can induce
fever in mice, further indicates that the p55 receptor is important for
TNF--induced febrile responses.
In summary (Fig. 5), we argue that LPS can
trigger fever through IL-1 or TNF-, not of course excluding other
candidates. IL-1 signals through IL-1RI (17) and IL-1RAcP (30),
whereas TNF- possibly utilizes the p55 receptor to signal its
effects. Then both pathways converge onto the cytokine IL-6 (present
study; 4). This leads to fever via prostaglandin
E2, since LPS, IL-1, TNF-,
and IL-6 fevers are sensitive to cyclooxygenase inhibitors (present
study; 10, 14, 18). The picture is likely to be more complicated than
this, but for now, it is a well-supported working theory. For instance,
during fever onset, at least IL-6 and prostaglandin E2 most likely need to operate in
a very limited surrounding: on the right side of the blood-brain
barrier, perhaps in an extracellular space, between an endothelial
cell, a glial cell, or a neuron.
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This brings us to a major flaw of this model: it does not specify where
in the animal any of these cytokines act. Are these endogenous pyrogens
acting locally at the site of injection or elsewhere, such as in the
brain, where the body thermostat resides (27)? In an attempt to answer
this question, we monitored IL-6 levels in plasma (Table 1) within the
time frame of fever onset. The IL-6 levels were elevated, as expected
if IL-6 was to act locally. There was one discrepancy, however. The
fever in IL-1-deficient mice was ~1 h later in onset than in their
wild-type controls, whereas the peripheral IL-6 levels 2 h after
injection were about twice as high (Table 1; IL-6 levels in
IL-1-deficient vs. IL-1 wild-type mice after rmTNF- injection,
P < 0.05). If peripheral IL-6 was
the primary mediator of fever, one could expect circulating IL-6 levels
to correspond better with the febrile response
(criterion 2 in Ref. 13). Hence, we
proceeded to analyze whether an injection of central IL-6 could restore
fever in IL-6-deficient mice, an experiment that proved successful. In
other words, intraperitoneal rmTNF- was unable to trigger a febrile
response in IL-6-deficient mice (Fig.
3B), whereas intracerebroventricular
injection of IL-6 together with intraperitoneal injection of rmTNF-
in IL-6 knockout animals elicited a febrile response (Fig.
4A). This fever was statistically
similar to the fever elicited in rmTNF--injected IL-6 wild-type
mice. However, a central injection of IL-6 (500 ng/mouse) was slightly
pyrogenic in itself in these animals (Fig. 4B). This is not surprising, since
it has been reported that central, but not peripheral, IL-6 is
pyrogenic (4, 18, 26).
Briefly, at the doses tested, our data suggest that IL-1 is not a
requirement, but IL-6 is necessary, in TNF- fever. We also suggest
that a central, rather than a peripheral, pool of IL-6 is important in
the TNF--induced febrile response. This is in accordance with other
reports showing that hypothalamic concentrations of IL-6 are increased
during LPS-induced fever (11) and that IL-6 administered centrally
produces a fever (18, 26).
Perspectives
Although fever is a systemic response that is familiar to all of us, it is not well known in molecular terms. Even the simplest questions await better understanding of fever-triggering mechanisms before any answers may be offered; for instance, why does acetylsalicylic acid suppress fever by 2-3°C but have no effect on normal body temperature when taken for a headache? In addition, studies of endogenous pyrogens and the cell types that produce them may provide important new information on processes that are involved in head trauma, stroke, encephalitis, and major neurodegenerative disease. In other words, fever research and its spinoff effects could provide a better understanding of how to reduce brain damage after insults to the brain or hints as to which anti-inflammatory drugs could slow neurodegeneration. Future investigations in this field would include further elucidation of mechanisms behind the febrile response, closer studies on the "thermostat" in the brain, and merits and demerits of cytokines in the central nervous system.| |
ACKNOWLEDGEMENTS |
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We thank Dr. S. Gatti for valuable comments on the manuscript and Drs. H. Zhen and V. Poli for providing the animals.
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FOOTNOTES |
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A. K. Sundgren-Andersson and P. Östlund contributed equally to this work.
This study has been supported by the Swedish Medical Research Council and by the European Community Biomed Program.
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 reprint requests to T. Bartfai.
Received 12 January 1998; accepted in final form 29 July 1998.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Temp). Each point represents 1 animal. Dose
(x-axis) is reported as µg
rmTNF-
, 12 µg/mouse, 0.15 ml ip,
n = 5) or saline (
, 0.15 ml ip,
n = 5) at 0 h in IL-1
, 600 µg/mouse, 0.15 ml ip,
n = 3) 2 h before injection of
rmTNF-
, 12 µg/mouse, 0.15 ml ip,
n = 5) or saline (
, 0.15 ml ip,
n = 6) at 0 h in
IL-1
1 h; intraperitoneal injections were done at 0 h.
A: central injection of rrIL-6
followed by an intraperitoneal injection of rmTNF-