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Divisions of 1 Pulmonary and
Critical Care Medicine and
7 Infectious Disease, Fever is a phylogenetically ancient
response that is associated with improved survival in acute infections.
In endothermic animals, fever is induced by a set of pyrogenic
cytokines [tumor necrosis factor-
fever; body temperature; tumor necrosis factor- FEVER IS A key element in the acute-phase response (23)
and is generally beneficial in bacterial, fungal, and viral infections (23). Fever accelerates the resolution of human viral infections (14)
and shigellosis (25) and is positively correlated with survival in
patients with gram-negative bacteremia (10). Studies of induced
hyperthermia in infected animals suggest that an increase in core
temperature may enhance immune defenses. For example, housing herpes
virus-infected mice in a 38°C ambient environment increased their
core temperature by ~2°C and increased survival to 100% compared
with 0% survival in infected mice maintained at normal laboratory
temperature (4). Bell and Moore (6) reported similar protection of
passive warming in rabies-infected mice. However, the mechanisms
through which an increase in core temperature can improve survival in
the infected host are incompletely understood.
The acute-phase response during bacterial infection is a dynamic
process that sets into motion the transition from activated innate
defenses to antigen-specific immune defenses (5). In sepsis,
dysregulation of this tightly orchestrated host response leads to both
life-threatening multiple-organ injury and impaired host defenses (27).
Although these processes are incompletely understood, it is generally
accepted that the pattern and timing as well as the magnitude of
cytokine expression are important in determining the course of disease
(12, 27). Specifically, survival in the infected host may be enhanced
by early expression of the proinflammatory cytokines tumor necrosis
factor- Whereas IL-1 and TNF- Temperature shifts from basal to febrile ranges have been reported to
influence expression of proinflammatory cytokines in vitro (19). We
recently found that increasing murine core temperature from basal
(36.5-37.5°C) to febrile (39.5-40°C) levels enhanced early TNF- Reagents
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(TNF-), interleukin
(IL)-1, and IL-6] that are also essential for survival in acute
infections. We studied the influence of core temperature on cytokine
expression using an anesthetized mouse model in which core temperature
was adjusted by immersion in water baths. We showed that raising core
temperature from basal (36.5-37.5°C) to febrile
(39.5-40°C) levels increased peak plasma TNF- and IL-6
levels by 4.1- and 2.7-fold, respectively, and changed the kinetics of
IL-1
expression in response to lipopolysaccharide challenge. TNF-
levels were increased predominantly in liver, IL-1 levels were
higher in lung, and IL-6 levels were widely increased in multiple
organs in the warmer mice. This demonstrates that the thermal component
of fever may directly contribute to shaping the host response by
regulating the timing, magnitude, and tissue distribution of cytokine
generation during the acute-phase response.
; interleukin-1; interleukin-6; Kupffer cells; heat shock proteins
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(TNF-) and interleukin (IL)-1 (12). Characterization of
TNF--deficient mice revealed that TNF- is not only essential for
recruiting antimicrobial defenses but that failure to express TNF-
causes dysregulation of these processes, resulting in persistent and lethal systemic inflammation (26). However, high or persistent exposure
to TNF- (30) or simultaneous exposure to TNF- and IL-1 (34) or
interferon-
(13) can cause host injury and death.
are predominantly proinflammatory, the biology
of IL-6 is more complex. IL-6 consistently appears at high levels in
plasma of septic individuals (33), it enhances nonspecific immune
processes as well as the acute-phase response (17), and stimulates
lymphocyte proliferation and differentiation (20). On the other hand,
IL-6 also limits inflammation by blocking IL-1 and TNF- expression
(1). New studies in IL-6 knockout mice clearly demonstrate that IL-6
has anti-inflammatory effects (35). These data suggest that IL-6 may
serve as a transition cytokine between innate and antigen-specific defenses.
generation predominantly by Kupffer cells but decreased its duration after challenge with bacterial endotoxin
[lipopolysaccharide (LPS)]. The objective of this study was
to determine how shifting core temperature from basal to febrile levels
modifies the early cytokine response to LPS. Using an anesthetized,
temperature-clamped mouse model, we found that increasing core
temperature from 37 to 39.5-40°C caused an early, amplified,
but self-limited pulse of TNF- expression and persistent enhancement
of IL-6 production in most tissues while preventing coexpression of
TNF- and IL-1 expression. In contrast with TNF- expression,
which was largely confined to the hepatic Kupffer cells, IL-6
expression was widely enhanced in the warmer animals. Finally, we
showed that the temperature-dependent changes in cytokine expression
were associated with only a partial activation of heat shock protein
(HSP)-72 expression.
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Temperature Clamping
Six- to eight-week-old male CD-1 mice, weighing 25-30 g, were purchased from Harlan Sprague Dawley (Indianapolis, IN), housed in the University of Maryland, Baltimore, animal facility under the supervision of a full-time veterinarian, and used within 4 wk. All animal protocols were approved by the Institutional Animal Care and Use Committee of the University of Maryland, Baltimore. Mice were anesthetized with 30 mg/kg tribromoethanol (Sigma) administered subcutaneously. The anesthetized animals were suspended in water baths (VWR; temperature variation <0.2°C) to the level of the axillae. Body temperature was continuously monitored with rectal thermistors. When body temperature reached bath temperature, 0.25 ml of a dose of LPS (see RESULTS for dose used in each experiment) or vehicle (pyrogen-free saline) was administered as an intraperitoneal injection. To control for the effects of anesthesia and water immersion, we also studied a group of conscious, unrestrained mice at normal laboratory temperatures (22-24°C). To model endotoxemia or bacteremia in the setting of established infection in febrile hosts, we increased core temperature to febrile levels before administering LPS. Core temperature reached water bath temperature in <10 min and varied by <0.2°C during the experiments. To avoid the influence of diurnal cycling, all experiments were started at approximately the same time each day (between 8:00 AM and 10:00 AM).Plasma Cytokine Levels
Mouse TNF-, IL-1, and IL-6 were measured in the University of
Maryland, Baltimore, Cytokine Core Laboratory using standard two-antibody ELISA with commercial antibody pairs and recombinant standards (TNF- and IL-6 from Endogen, Boston, MA; and IL-1 from
Genzyme, Cambridge, MA). Polystyrene plates (Maxisorb; Nunc) were
coated with capture antibody in PBS overnight at 25°C. The plates
were washed four times with 50 mM Tris, 0.2% Tween 20, pH 7.2 and then
blocked for 90 min at 25°C with assay buffer (PBS containing 4%
BSA and 0.0 1% thimerosal, pH 7.2). The plates were washed, and 50 µl of assay buffer were added to each along with 50 µl of sample or
standard prepared in assay buffer and incubated at 37°C for 2 h.
After the plates were washed, strepavidin-peroxidase polymer in casein
buffer (Research Diagnostics, Mount Pleasant, NJ) was added and
incubated at 25°C for 30 min. The plate was washed, and 100 µl
substrate (TMB; Dako, Carpinteria, CA) were added and incubated for
20-30 min. The reaction was stopped with 100 µl 2 N HCl, and the
absorbance at 450 nm (minus absorbance at 650 nm) was read on a
microplate reader (Molecular Devices, Sunnyvale, CA). The data were
analyzed using a computer program (SoftPro; Molecular Devices). These
assays had lower detection limits of 8, 3, and 1.5 pg/ml, respectively.
Organ-Specific Cytokine Analysis
Spleen, lungs, liver, and kidney were collected and snap-frozen after flushing the circulation with 10 ml of 4°C PBS containing protease inhibitors (4 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, and 1 µg/ml leupeptin) injected through the left ventricle and drained from the left atrium. Organs were powdered under liquid nitrogen, homogenized in 1 ml lysing buffer (150 mM NaCl, 25 mM Tris, pH 7.4, 1% Nonidet P-40, 4 mM EDTA, and protease inhibitors), and cleared by centrifugation. Total protein concentration in the homogenate supernatants was measured using a commercial reagent (Bio-Rad, Mountainview, CA) with BSA (Sigma) as a standard. To minimize the background signal from endogenous biotin-containing proteins, 50 µl of a 3 mg/ml avidin solution (Sigma) in PBS was added to 470 µl of each homogenate supernatant. The treated homogenates were analyzed by ELISA as described above except for an additional 20-min incubation with 20 µg/ml free biotin (Sigma) in PBS added just before the detecting antibody. This method reduced background noise by >99% without affecting specific cytokine signal. Cytokine concentrations in homogenate supernatants were standardized to total protein concentrations.Immunoblot Analysis of HSP-72
Homogenates were prepared from liver and kidney exactly as described for the organ ELISA analysis. Homogenates containing 200 µg total protein were separated on 12% Laemli SDS-PAGE under reducing conditions, electrostatically transferred to polyvinylidene difluoride membrane (Stratagene), blocked with 5% dry milk in PBS-0.01% (vol/vol) Tween 20 overnight at 4°C, and incubated with 1:16,000 dilution of anti-HSP-70 (product no. SPA-810; StressGen, Victoria, BC, Canada) in blocking buffer for 2 h at room temperature. Bands were detected using 1:2,000 dilution of goat anti-mouse IgG peroxidase conjugate (Transduction Laboratories, Lexington, KT) in blocking buffer for 1 h at room temperature and a chemiluminescence detection system (New England Nuclear, Boston, MA). Intensities of autoradiograph bands were quantified using an Ambis (Billerica, MA) biological image analysis system. Sonicates from L929 cells incubated at 42°C for 90 min and then at 37°C for an additional 18 h were used as a positive control for HSP-72.Experimental Protocols
Experiment 1: Effect of core temperature on plasma cytokine levels after LPS challenge. Three groups of six mice each were studied. One group of animals ("unclamped") was injected intraperitoneally with 50 µg LPS and returned to the cages housed at normal ambient temperature (22-24°C). These mice maintained core temperatures of 35.5-36°C during the course of the experiment. A second group of mice was temperature clamped at 37°C and treated with 50 µg LPS. A third group of mice was temperature clamped at 40°C and treated with 50 µg LPS. Temperature clamping was continued until death. Animals were killed after 1, 2, 3, 4, or 5 h, and plasma cytokine levels were analyzed by ELISA. Control animals were subjected to the same protocol but received PBS instead of LPS.Experiment 2: Effect of core temperature on LPS dose
response for plasma TNF- and IL-6 expression. Groups
of five mice were temperature clamped at either 37 or 40°C and
received an intraperitoneal injection of a single dose of LPS between 1 and 250 µg. Temperature clamping was continued until death after 1 or
3 h for analysis of plasma TNF- or IL-6, respectively.
Experiment 3: Effect of intermediate core temperatures
on plasma TNF- and IL-6 expression. Groups of five
mice were temperature clamped at either 37, 38, 39, 39.5, or 40°C
and injected intraperitonally with 50 µg LPS. Temperature clamping
was continued until death after 1 or 3 h for analysis of plasma TNF-
or IL-6, respectively.
Experiment 4: Effect of transient shifts in core
temperature on plasma TNF- and IL-6 expression.
Groups of four mice were temperature clamped at 37 or 40°C for only
1 h after receiving 50 µg LPS and then were allowed to recover from
anesthesia. They were dried under a heat lamp to prevent transient
hypothermia, returned to cages at 22-24°C, and killed 5 h
later for analysis of plasma TNF- and IL-6 expression.
Experiment 5: Effect of core temperature on levels of
organ-associated cytokines. Three groups of mice were
challenged with 50 µg LPS: 1) unclamped mice, 2) mice
clamped at 37°C, and 3) mice clamped at 40°C.
Control mice were clamped at 37 or 40°C but received
PBS injection instead of LPS. Animals were killed before LPS (0 h) or 1 or 3 h after LPS treatment. The spleen, liver, lungs, and one
kidney were removed and snap-frozen in liquid nitrogen for analysis of
tissue TNF-, IL-1, and IL-6 content by ELISA.
Experiment 6: Effect of Kupffer cell depletion on temperature-dependent cytokine expression. Kupffer cells were depleted by injecting 0.1 ml liposome-encapsulated clodronate prepared as previously described (32) via the tail vein 2 days before temperature clamping and LPS challenge. Control mice received 0.1 ml pyrogen-free sterile saline via tail vein injection.
Experiment 7: Effect of temperature clamping on expression of HSP-72. Each pair of mice was temperature clamped at either 37 or 39.5°C for 3 h, allowed to recover, and returned to 22-24°C cages for an additional 3 h. A positive in vivo heat-shock control group was temperature clamped at 42°C for 20 min and returned to 22-24°C cages for an additional 5 h and 40 min. All animals were killed 6 h after initiation of temperature clamping. Livers and kidneys were collected and snap-frozen for immunoblot analysis of HSP-72.
Statistics
Data are displayed as means ± SE. Differences among more than two groups were analyzed by applying Fisher's protected least-squares difference test to a one-way ANOVA. Differences between two groups were tested using an unpaired t-test.| |
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Effect of Core Temperature on LPS-Induced Cytokine Expression
The influence of core temperature on expression of early response cytokines was studied using the LPS-challenged, temperature-clamped mouse model. Peak plasma TNF- levels were
4.1-fold higher and peaked 1 h earlier in the 40°C mice
compared with the 37°C animals (Fig.
1A).
Circulating TNF- levels were similar in the unclamped and the
37°C clamped mice. As expected, circulating IL-6 appeared 1-2
h after TNF-. Raising core temperature from 37 to 40°C increased peak plasma IL-6 levels 2.7-fold (Fig.
1D) but did not alter the kinetics
of IL-6 expression. The effect of raising core temperature on
circulating IL-1 expression was more complex. In 37°C clamped mice, circulating IL-1 expression was biphasic, with peaks occurring 1 and 4 h after LPS challenge (Fig. 2).
Increasing core temperature to 40°C attenuated the early IL-1
peak and delayed the late IL-1 peak, thereby temporally separating
TNF- and IL-1 expression.
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Plasma TNF-, IL-6, and IL-1 were not detectable in control mice
temperature clamped at either 37 or 40°C without LPS treatment, suggesting that core temperature changes could modify but not directly
induce proinflammatory cytokine expression in the absence of pyrogen.
Influence of Core Temperature on LPS Dose Response for
Plasma TNF- and IL-6 Expression
and IL-6 was flat
between 50 and 250 µg in 37°C clamped mice (Fig. 1,
B and E), but the dose response remained
steeply positive over this dose range in the 40°C animals. In mice
injected with 250 µg LPS, peak plasma TNF- levels were 12.3-fold
higher and IL-6 levels were 3.9-fold higher in the 40 vs. 37°C animals.
Effect of Intermediate Core Temperatures on Plasma IL-6 Expression
To define the threshold temperature required to amplify TNF- and
IL-6 expression, we compared plasma TNF- and IL-6 levels 1 or 3 h
after LPS challenge, respectively, in mice maintained between 37 and
40°C (Fig. 1, C and
F). The threshold temperature for
enhancing plasma levels of both TNF- and IL-6 consistently occurred
between 39 and 39.5°C, a temperature within the murine febrile
range (18).
Effect of Transient Shifts in Core Temperature on Plasma
TNF- and IL-6 Expression
was not
detectable at this time point in either group.
Effect of Core Temperature on Levels of Organ-Associated Cytokines
We previously demonstrated that hepatic Kupffer cells were the predominant temperature-dependent source of LPS-induced TNF- production. To compare the potential effects of fever on tissue distribution of IL-1, IL-6, and TNF-, we measured concentrations of these cytokines in homogenates of liver, spleen, kidney, and lung
obtained from the LPS-challenged, temperature-clamped animals (Fig.
3). These organs were selected for study
because they are either important sources of systemic cytokine
expression or are frequently injured in sepsis (8). As we previously
found (21), the liver was the only tissue in which TNF- levels were
increased in 40 vs. 37°C mice after LPS challenge (Fig.
3A). By comparison, LPS-induced IL-6
levels were higher in spleen (2.6-fold) and lung (3.4-fold) as well as
in liver (15-fold) in the 40°C mice compared with the 37°C
animals (Fig. 3B). Raising core
temperature from 37 to 40°C increased IL-1 levels in the lungs
but not in the liver, spleen, or kidneys of LPS-challenged mice (Fig.
3C). Clamping core temperature at
40°C without LPS challenge caused a slow increase in hepatic
TNF- content but did not affect TNF- levels in spleen, lung, or
kidney and did not alter expression of IL-6 or IL-1 in any of the
tissues studied (data not shown).
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Role of Kupffer Cells in Temperature-Dependent Cytokine Expression
We previously reported that Kupffer cells were virtually the sole source of hepatic TNF- and the predominant source of
temperature-dependent plasma TNF- generated in the LPS-challenged
mouse (21). To determine if Kupffer cells were also essential for the
enhanced IL-6 expression in the warmer mice, we analyzed plasma
cytokine levels in temperature-clamped, LPS-challenged mice after
depleting their Kupffer cells with intravenous liposome-encapsulated
clodronate (31). This treatment has been shown to virtually eliminate
Kupffer cells and reduce the number of splenic macrophages without
affecting circulating monocytes or other tissue macrophages (31).
Pretreatment with clodronate decreased plasma TNF- levels by 87% in
the 37°C mice compared with sham-depleted 37°C controls,
demonstrating that the Kupffer cell is the predominant source of
TNF- in LPS-challenged mice. Kupffer cell depletion reduced the
excess plasma TNF- levels generated in the 40°C mice by 81%
(Table 1). In contrast, plasma IL-6 levels
were comparable in 37°C control and 37°C Kupffer cell-depleted mice, implicating sources other than Kupffer cells in the generation of
circulating IL-6. However, the increase in plasma IL-6 levels that
occurred in 40°C sham-depleted mice was abrogated in the Kupffer
cell-depleted mice.
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Effect of Temperature Clamping on Expression of HSP-72
We previously reported that the temperature threshold for modifying TNF- expression in the RAW 264.7 mouse macrophage cell line is at
least 2°C below the threshold for inducing the heat-shock response
in vitro (15). To determine if the temperature threshold for modifying
cytokine production (39-39.5°C) was distinct from the
threshold for the heat-shock response in vivo, we measured HSP-72 in
liver and kidney homogenates from temperature-clamped mice by
immunoblot analysis (Fig. 4). Temperature
clamping at 39.5°C for 3 h (Fig. 4,
lanes 3 and
4) increased hepatic and renal HSP-72 levels compared with 37°C mice (lanes
1 and 2), but HSP-72 levels in the 39.5°C animals reached only one-half the levels achieved in the positive control mice warmed to 42°C for 20 min (lanes 5 and
6).
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In this study, we showed that an increase of 2-2.5°C above
basal core temperature and within the murine febrile range (18) profoundly altered the magnitude, kinetics, and tissue distribution of
TNF-, IL-6, and IL-1 in LPS-challenged mice. These changes included 1) earlier and higher peaks
in plasma and liver TNF- levels;
2) higher circulating and
tissue-associated IL-6 levels; 3)
attenuation of the early plasma IL-1 peak and a delay in the late
peak, preventing simultaneous exposure to TNF- and IL-1; and
4) enhanced pulmonary expression of
IL-1.
Mice have similar basal and febrile temperatures as humans (18), but
their partially ectothermic nature (2) makes them particularly useful
for studies requiring manipulation of core temperature. Armstrong (4)
and Bell and Moore (6) demonstrated that murine core temperature could
be maintained ~2°C above basal levels for several days by housing
conscious mice in a warm environment. In the present study, we used an
anesthetized temperature-clamping model rather than conscious mice for
the following reasons. First, this was a short-term study focused on
events occurring within 5 h of LPS challenge, during which
anesthesia could be safely maintained. Second, the use of anesthesia
avoided the potentially profound immunomodulatory effects of physical
stress imposed by handling and LPS challenge (22). Third, anesthesia
and immersion in water baths provided much more rapid and precise
control of core temperature than is possible in conscious mice. This
model was intended to isolate the effects of the core temperature
increase from the other components of the febrile response, and our
results should be interpreted in this context. Although anesthesia
itself may potentially disturb the normal immune responses (9), we previously showed that comparable increases in core temperature caused
similar changes in LPS-induced TNF- expression in anesthetized and
conscious mice (21). In the present study, circulating and organ-associated cytokine levels after LPS challenge were similar in
the anesthetized 37°C mice and in the conscious control animals, which maintained similar core temperatures. These data do not exclude
immunosuppressive effects of some anesthetic agents but indicate that
the anesthetic protocol used in this study did not significantly affect
the measured generation of cytokines.
Three previous studies have reported that raising core temperature in
rodents either reduced (11, 22) or had no effect (7) on circulating
TNF- and IL-1 expression. However, in these studies the animals were
warmed to temperatures above the normal febrile range and within the
heat-shock range (
41°C). Furthermore, the core temperature
increase in these studies either preceded LPS challenge by 6-7 h
(7) or 24 h (22) or followed LPS challenge (11). We previously reported
that the core temperature increase must occur before or coincident with
LPS challenge to enhance early TNF- expression (21). Delaying the
increase in core temperature for 30 min after injection of LPS
abrogated its effects on TNF- expression. Taken together, these data
suggest that the effect of increasing core temperature on TNF-
expression is determined by both the magnitude of the temperature
increase and the timing of the core temperature change relative to
challenge with an injurious stimulus. In the present study, mice were
challenged with LPS immediately after target core temperature was
reached. This schedule models recurrent endotoxemia and bacteremia
occurring in the setting of fever, which often occurs during serious
bacterial infections (29).
We previously showed that Kupffer cells were the major source of
circulating TNF- in 37°C clamped, LPS-challenged mice, as well
as the source of the excess circulating TNF- present in the 40°C
animals (21). In this study, we found that, while enhanced TNF-
levels were restricted to the liver in the 40°C mice, IL-6 levels
were severalfold higher in most tissues studied in the warmer animals.
Thus it was not surprising that Kupffer cell depletion, which markedly
attenuated TNF- generation, did not reduce plasma IL-6 levels in
LPS-challenged 37°C mice. However, the increase in plasma IL-6
levels that occurred in 40°C mice was abrogated by prior Kupffer
cell depletion. We have considered two possible explanations for the
loss of excess IL-6 generation in the Kupffer cell-depleted 40°C
mice. The Kupffer cell may be the predominant source of the excess IL-6
generation in the febrile mouse. Although IL-6 levels increased in most
tissues studied in the 40°C mice, the greatest relative increase in
IL-6 expression occurred in the livers of the warmer animals.
Alternatively, Kupffer cells may release a factor that stimulates a
widespread increase in IL-6 expression in the warmer animals. TNF-
is the most obvious candidate for this Kupffer cell-generated,
IL-6-inducing factor. TNF- is a potent inducer of IL-6 expression
(28), and circulating levels of TNF- were greatly reduced in the
Kupffer cell-depleted mice. However, IL-6 expression at 37°C was
comparable in the control and Kupffer cell-depleted mice even though
circulating TNF- levels were reduced by 87% in the Kupffer
cell-depleted animals. Furthermore, LPS can directly induce IL-6
expression in the absence of TNF- (3). It may also be possible that
tissues are more responsive to the IL-6-stimulating action of TNF-
in the warmer animals. We are presently using a murine TNF-
knockout model to determine the role of TNF- in mediating the
enhanced IL-6 expression that occurs in warmer animals.
In this study, a core temperature increase of 2-2.5°C above
basal temperature was sufficient to modify the generation of
acute-phase cytokines. Increases in core temperature of this magnitude
commonly occur during infections as well as during vigorous physical
exercise, in response to stress, and as a result of exposure to high
ambient temperatures in many species, including humans and mice (24). We previously reported that the temperature threshold for modifying TNF- expression in vitro was lower than that for inducing heat shock
in cultured macrophages (15, 16). In this study, we found that the
temperature threshold for modulating cytokine generation in vivo was
only sufficient to induce submaximal HSP-72 expression in kidney and
liver, suggesting the two processes are likely to be distinct.
Survival of the infected host depends on a delicate balance between
enhanced antimicrobial host defense mechanisms and collateral tissue
injury (12). We previously showed that an elevation in core temperature
such as occurs in fever may tip the balance toward enhanced
antimicrobial defense by amplifying expression of the proinflammatory
cytokine TNF- (21). In this study, we showed that fever exerts
effects on cytokine expression that may also reduce the risk of host
injury. First, while fever may enhance early TNF- expression, it
limits its toxicity by reducing the duration of its expression and
preventing simultaneous expression of TNF- and IL-1 (34). Second,
fever caused enhanced generation of IL-6 in most tissues. Although IL-6
enhances the acute-phase response (17), it has recently been shown to
have important anti-inflammatory actions (35) that are caused, in part,
by the downregulation of IL-1 and TNF- expression (1). We speculate that the net effects of fever on expression of TNF-, IL-1, and IL-6 may serve to enhance a restricted early host response to infection, while facilitating the transition between innate and antigen-specific defenses.
The implications of these results are far reaching. Models of the acute-phase response that fail to consider the thermal component of fever may not accurately represent the normal host response. Therapeutic interventions that interfere with normal thermoregulation in infected patients may inadvertently defeat a precisely orchestrated and optimized host response, which is required for survival. A more complete understanding of the interactions among core temperature and immunological processes may not only improve management of fever in infected hosts but also provide a novel therapeutic modality for manipulating immunological processes in vivo.
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ACKNOWLEDGEMENTS |
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We thank Drs. Matthew Kluger, Alan Cross, and Sheldon E. Greisman for valuable time and helpful comments.
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FOOTNOTES |
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This project was supported by Veterans Association Merit Review Award No. 128-44-4284-0005, National Cancer Institute Grant R29CA-52741, and an SRIS grant from the University of Maryland.
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 correspondence and reprint requests: J. D. Hasday, Rm. 3D127, Baltimore VA Medical Center, 10 N. Greene St., Baltimore, MD 21201 (E-mail: jhasday{at}umaryland.edu).
Received 20 October 1998; accepted in final form 22 February 1999.
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INTRODUCTION
METHODS
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P < 0.02 vs. unclamped
mice. § P < 0.001 vs.
37°C clamped and unclamped mice. B
and E: LPS dose response for plasma
TNF-
