Departments of
* Immunology and
Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York
Correspondence: Dr. Elizabeth Repasky, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail: Elizabeth.Repasky{at}RoswellPark.org
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(TNF-), interleukin-6
(IL-6), IL-1ß, and the acute phase proteins (APPs) 1-acid
glycoprotein and haptoglobin were analyzed. WBH alone did not affect
serum concentrations of these cytokines or APPs when compared with
controls. In contrast, when WBH was applied just after intraperitoneal
administration of lipopolysaccharide (LPS), serum concentrations of
TNF- and IL-6 were greater than or equal to threefold higher in
BALB/c mice compared with LPS-treated controls. LPS-induced IL-6 levels
were also enhanced in WBH-treated C57BL/6 mice. However, APP levels
were prolonged only in WBH-treated BALB/c mice. It is interesting that
in vitro hyperthermia treatment of LPS-stimulated
peritoneal cells resulted in decreased cytokine production compared
with controls. These results suggest that fever-range hyperthermia
regulates acute inflammation in a mouse strain-specific manner that is
more complex than that observed in vitro.
Key Words: acute phase reactants • cytokines • immunomodulators
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Much is known about the inflammatory mediators involved in generating
fever [5
] and the other inflammatory responses such as
neutrophil recruitment and vasodilation. These physiological changes
are mediated by local or systemic elevations of inflammatory cytokines
such as tumor necrosis factor (TNF-), interleukin-6 (IL-6), and
IL-1ß. Platelets and professional phagocytes (i.e., neutrophils and
monocytes/macrophages) that have been stimulated by their damaged and
infected environment release these cytokines locally. The IL-1 and TNF
activate adjacent stroma and endothelium to release a second wave of
TNF, IL-6, and IL-1 as well as chemotactic cytokines such as IL-8 and
monocyte chemotactic protein (MCP) [6
]. These cytokines
culminate in the sera at various times, but in a sequential order
(e.g., TNF- first, followed by IL-6, then IL-1ß) and then recede
gradually to baseline levels in a relatively short period of time
(i.e., within 24 h) [1
].
Not only do these cytokines mediate local inflammation, but they also
induce systemic responses such as the stimulation of liver hepatocytes
to synthesize and release acute phase proteins (APPs). These APPs can
be categorized into two groups, based on the cytokines that are
responsible for their induction. IL-1-like cytokines, such as TNF-
and IL-1ß, and IL-6-like cytokines, such as IL-6, IL-11, and
oncostatin M, are required for maximum induction of Type I APPs [e.g.,
1 acid glycoprotein (AGP) and C-reactive protein (CRP)]
[6
]. Type II APPs [e.g. haptoglobin (Hp) and
fibrinogen] are maximally induced by IL-6-like cytokines, and
inhibited by IL-1-like cytokines [6
]. In general, these
APPs exert protective functions that assist in the resolution of
inflammation [7
, 8
]. As alluded to above,
the inflammatory cytokines TNF-, IL-6, and IL-1ß also act as
endogenous pyrogens, affecting the temperature-regulating mechanism of
the hypothalamus [6
]. Yet, despite the natural
occurrence of increased body temperature in association with immune
challenge, temperature is not a variable in most experimental
immunological investigations.
Those few studies that have examined the effector or immunoregulatory role of fever-range hyperthermia, in turn, have resulted in considerable controversy. For example, different laboratories have shown that elevated temperatures either enhance [9 10 11 12 13 14 15 16 17 ] or inhibit [14 , 16 , 18 19 20 21 22 23 ] the cytolytic activity of T lymphocytes and natural killer (NK) cells. It is interesting that the disparity in results from these studies might easily be explained by the variations in hyperthermia protocols performed by different laboratories. The majority of studies looking at the effects of elevated temperatures on acute phase response mediators have been performed in vitro with temperatures ranging from 39 to 42°C. The results of such in vitro studies have been fairly consistent in describing hyperthermia as a negative regulator of mitogen-induced TNF, IL-1, and IL-6 production [24 25 26 27 28 29 30 ], supposedly by altering the posttranscriptional processing of the cytokine mRNA [29 , 30 ]. However, recent work by Jiang et al. suggests that in contrast to the effects of elevated temperatures in vitro, in vivo hyperthermia may up-regulate inflammatory cytokine expression [31 ]. Thus, there is a clear need for further studies regarding the effects of hyperthermia on acute inflammatory responses in vivo.
The paucity of knowledge regarding the immunoregulatory role of
increased in vivo body temperatures, especially with regard
to innate immune activities such as the acute phase reaction, led us to
directly evaluate the effects of the thermal component of fever on an
in vivo acute inflammation model through the use of
intraperitoneal (i.p.) injections of low-dose LPS. Here we report on
the effects of a fever-range whole-body hyperthermia (WBH) protocol
(39.8 ± 0.2°C for 6 h) on serum TNF-, IL-6, IL-1ß,
Hp, and AGP content in mice. Because C57BL/6 mice are known to be less
responsive to LPS than BALB/c mice [32
], the effects of
WBH on both of these mouse strains were also analyzed.
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Fever-range whole-body hyperthermia
To prevent dehydration, mice were injected with 1 mL sterile
saline i.p. [33
] immediately before being placed in
microisolator cages preheated to 38.8°C. The cages (five mice per
cage) were then placed in a gravity convection oven with preheated
incoming fresh air (Memmert model BE500, East Troy, WI). Within 20 min
the average core body temperatures of the mice were raised from
37.5°C (normal core temperature of mice) to 39.8°C (±0.2°C), and
this body temperature was maintained for up to 6 h by adjusting
the incubator temperature (see Fig. 1B
and D
). Core temperatures in each cage
were monitored with the Electronic Laboratory Animal Monitoring System
from Biomedic Data Systems (Maywood, NJ) using non-experimental BALB/c
mice that had 14 x 2.2-mm microchip transponders subcutaneously
implanted into the dorsal thoracic area. Previous studies have shown
that if all mice in a cage have transponders implanted in them, the
variations in temperature readings between animals are reproducibly
within 0.2°C of the mean. Control mice were kept at room temperature
and subjected to the same handling, i.p. saline administration, and
temperature measurement manipulations as that of the heated mice. To
avoid the possible influence of diurnal cycling, all experiments were
started at approximately the same time each day (7:30 AM to
9:30 AM).
 View larger version (37K): [in a new window] |
Figure 1. Representative core body temperatures of mice for all acute phase
response experiments. BALB/c (A and B) and C57BL/6 (C and D) mice that
were left as room temperature controls (A and C) or underwent WBH
treatment (B and D) were injected i.p. at 0 h with either 1 mL
sterile saline (filled squares) or 1 mL of saline containing 10 µg
LPS (open circles), and the resulting body temperatures were measured.
Duration and desired temperature range of WBH treatment is indicated by
shaded areas in B and D. All core body temperature readings returned to
baseline within 24 h (not shown).
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Sample collection
Sera were collected from the blood of the retroorbital venous
plexus 5 days before WBH treatment (t =0), and various
times during and after WBH treatment. All mice were divided into groups
so that each mouse was bled a maximum of once per day.
Resident peritoneal cells were collected from untreated mice that were killed by cervical dislocation. Upon exposure of the peritoneal cavity (PerC), 10 mL of PerC wash solution [1x phosphate-buffered saline (PBS), 0.1% bovine serum albumin (BSA), 10 U/mL heparin, 0.54 mM EDTA] was injected into the PerC using a 27G1/2; needle, and the resulting hole at the injection site was clamped. The bloated cavity was then agitated using a blunt instrument to tap each side of the peritoneal lining 10 times, and the mouse and surgery board were inverted 10 times. Using a 22G11/2 needle, the same syringe was then used to collect the peritoneal wash fluid, generally resulting in a 7- to 9-mL cell suspension.
In vitro hyperthermia
Resident peritoneal cells were cultured at 1 x
105/well with or without 10 µg/mL LPS in RPMI medium with
10% FBS to a total volume of 200 µL/well. For the first 6 h of
culture, plates were divided between 37 and 40°C incubators, each
with 5% CO2. The rest of the culture time was continued at
37°C. One hundred sixty microliters of supernatant were then
collected from fresh wells at various timepoints.
Enzyme-linked immunosorbent assays (ELISAs)
All sera and supernatant samples from an individual experiment
were run simultaneously using QuantikineTM M ELISA Kits (R
& D Systems, Minneapolis, MN) for mouse IL-6, IL-1ß, and TNF-. The
sera samples collected between 2 and 4 h required further
dilutions ranging between 1:250 and 1:2000 for IL-6 measurements; all
other sera dilutions were 1:2. The 2- and 4-h supernatant samples for
IL-6 required 1:2 dilutions, the 6- and 12-h samples for IL-6 required
1:50 dilutions, and all other supernatant samples were not diluted.
Plates were read at 450 nm using an MRX microplate reader with Biolinx
software (Dynex Technologies, Chantilly, VA), and cytokine
concentrations in picograms per milliliter were determined using the
kit standards. The detection limits for these TNF-, IL-6, and
IL-1ß ELISAs are less than 5.1, 3.1, and 3 pg/mL, respectively.
Western analyses
For APP analysis, 0.1, 0.05, and 0.025 µL of each serum sample
were loaded per well and subjected to 10% sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred
onto immobilon-P membrane (Millipore). Membranes were blocked with 5%
nonfat dry milk in PBST (1x PBS, 0.05% Tween-20) for 1 h at room
temperature followed by a 2-h incubation with either of the following
primary antibodies in 5% nonfat dry milk, PBST: goat polyclonal
anti-Hp (ICN Pharmaceuticals, Aurora, OH) or rabbit polyclonal anti-AGP
(Roswell Park Cancer Institute, formally Springville Laboratories,
Buffalo, NY), diluted 1/5,000 and 1/10,000, respectively. After washing
with PBST, membranes were incubated with horseradish peroxidase
(HRP)-conjugated rabbit anti-goat IgG or goat anti-rabbit IgG (ICN
Pharmaceuticals). Immunoreactivity was detected by the enhanced
chemiluminescence detection system (Amersham, Arlington Heights, IL),
and a computer densitometer with ImageQuantTM software
(Molecular Dynamics, Sunnyvale, CA) was used to measure the
densitometry of the resulting bands. Relative amounts of APPs were
determined by analysis of the serial dilutions of sera and
normalization to the respective bands of pretreatment sera.
Statistical analysis
Control values were compared to the experimental values at each
time point during and after WBH treatment through the use of unpaired
Student’s t tests. P values less than 0.05 were
considered to represent statistically significant differences.
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, IL-6, and IL-1ß levels by
ELISA, and Hp and AGP levels by Western (data not shown). No difference
in serum cytokine or APP levels was seen between the WBH-treated and
control mice of either strain.
Fever-range WBH has differential effects on LPS-induced serum
cytokine levels in BALB/c and C57BL/6 mice
Because WBH alone did not appear to induce an acute inflammatory
response, we next examined the adjuvant potential of fever-range WBH
with LPS, a known inducer of the acute phase reaction. Specifically, a
39.8 ± 0.2°C body temperature was initiated and maintained for
6 h directly after low-dose LPS administration intraperitoneally,
and sera were analyzed at various times during and after WBH for
inflammatory cytokine concentrations (Fig. 2
). In BALB/c mice, serum levels of TNF- and IL-6 were
significantly enhanced up to three- and fourfold, respectively, at
multiple timepoints during WBH treatment (Fig. 2A
and 2B)
. However,
WBH treatment did not appear to significantly affect sera IL-1ß
levels in either BALB/c or C57BL/6 mice (Fig. 2C
and 2F)
. Nor were
sera levels of TNF- significantly altered in the WBH-treated C57BL/6
mice (Fig. 2D)
. Levels of IL-6 were enhanced four- to sevenfold at
various timepoints in the C57BL/6 mice (Fig. 2E)
. However, the
WBH-induced levels of serum IL-6 were not as pronounced in the C57BL/6
mice as that seen in the BALB/c mice.
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Figure 2. Effects of fever-range WBH on LPS-induced cytokine levels. WBH-treated
(open circles) and control (filled squares) BALB/c (A–C) and C57BL/6
(D–F) mice were bled 5 days before LPS injection and initiation of the
WBH protocol (represented by time 0), and various timepoints
(hours) during and after these treatments. Sera concentrations of
TNF- (A, D), IL-6 (B, E), and IL-1ß (C, F) were determined by
ELISA. Inset, panel B, is a magnification of the IL-6 concentration at
the 6-h timepoint. Shaded region, time frame for WBH procedure;
*P< 0.05 when WBH-treated mice were compared to controls
through the use of Student’s unpaired t test;
n = 4–12 mice per group, per time point. Data
represent three separate experiments.
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and IL-6 seen in these mice. It is interesting that, besides
the prolonged sera Hp elevation in the BALB/c mice, it was also
consistently noticed that the initial levels of Hp in the sera of these
mice were consistently delayed by 6–12 h (Fig. 3B)
. In contrast, even
though the C57BL/6 mice also displayed enhanced sera levels of IL-6,
they did not display any alterations in AGP or Hp (Fig. 3C and 3D)
. In
both cases, LPS-induced sera AGP and Hp levels in the WBH-treated C57BL/6 mice were similar to LPS-treated controls.
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Figure 3. Effects of fever-range WBH on LPS-induced acute phase protein levels.
WBH-treated (open circles) and control (filled squares) BALB/c (A, B)
and C57BL/6 (C, D) mice were bled 5 days before LPS injection and
initiation of the WBH protocol (represented by time 0), and
various time points after these treatments. Relative concentrations of
AGP (A, C) and Hp (B, D) were determined by serial-dilution Western
blot and densitometry followed by normalization to the respective band
densities of the pretreatment serum. Inset, panel B, is a magnification
of the Hp concentration at the 6-h (0.25 day) timepoint. Shaded region,
time frame for WBH procedure; *P < 0.05 when
WBH-treated mice were compared to controls through the use of
Student’s unpaired t test; n = 3–7 mice
per group, per time point. Data represent three separate experiments.
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, IL-6, and IL-1ß levels by ELISA (Fig. 4
). In vitro hyperthermia-treated cells from either
BALB/c or C57BL/6 mice were found to produce consistently lower levels
of cytokine compared with controls. Thus, these data contrast
significantly with the effects of in vivo WBH on sera levels
of LPS-induced TNF- and IL-6.
 View larger version (48K): [in a new window] |
Figure 4. Effects of in vitro hyperthermia on LPS-induced cytokine
production of PerC lavage cells. Resident PerC lavage cells from BALB/c
(A–C) and C57BL/6 (D–F) mice were incubated with 10 µg/mL LPS at
either 40°C (open circles) or 37°C (filled squares) for the first
6 h of culture, and then all cultures were placed at 37°C.
Supernatants were collected at various times during and after
hyperthermia treatment to determine the concentrations of TNF- (A,
D), IL-6 (B, E), and IL-1ß (C, F) production by ELISA. Shaded region,
time frame for 40°C treatment; *P < 0.05 when
hyperthermia-treated cells were compared to controls through the use of
Student’s unpaired t test; n = 3 mice per
group, per time point. Data represent three separate experiments.
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and IL-1ß by binding to their promoters
[34
, 35
]. However, the conclusions drawn by
these in vitro studies, namely that the thermal element of
fever acts as a negative regulator of acute inflammation, is shown to
be inaccurate when an in vivo model system is used. The
fever-range WBH induced changes of LPS-induced cytokine levels seen in
the sera of BALB/c and C57BL/6 mice is comparable to that seen by Jiang
et al. in anesthetized CD-1 mice using a temperature clamping
H2O bath WBH method [31
]. Thus, although
both in vitro and in vivo protocols reveal the
immunoregulatory potential of hyperthermia in the acute inflammatory
response, the results of the in vitro studies might be
considered misleading because they are in direct contrast to what is
observed in vivo. The results described in these in
vivo WBH studies are thus of particular importance because they
provide a larger picture of the potential adjuvancy of fever-range
hyperthermia in the acute inflammatory response.
Although unable to induce a systemic acute phase response on its own,
our studies do not preclude the potential effect of fever-range WBH on
microenvironmental changes in proinflammatory cytokines. We have
revealed, however, that fever-range WBH enhances LPS-induced serum IL-6
in both BALB/c and C57BL/6 mice. It is interesting that the WBH-induced
enhancement of this cytokine did not appear as dramatic in the C57BL/6
strain of mice as compared with that of the BALB/c strain of mice.
Other strain-specific effects of WBH regulation of the acute
inflammatory response include the enhancement of serum TNF- in
BALB/c mice but not in C57BL/6 mice. In addition, although WBH-treated
BALB/c mice displayed prolonged elevations of both type I and type II
APPs in their sera, corresponding to the enhanced cytokine levels,
WBH-treated C57BL/6 mice showed no enhancement of sera APP levels.
These strain-specific effects of WBH may be related to the differential
LPS responsiveness seen in BALB/c and C57BL/6 mice [32
].
Indeed, our results are congruous with previously identified
differences between BALB/c and C57BL/6 mice in their immune responses
to a variety of stimuli, such as that seen in the Th1 vs. Th2 responses
of the Leishmania model [36
].
The observed effects of WBH on LPS-induced serum cytokine levels could
have many implications. TNF- is an important mediator of cellular
immunity against bacteria and parasites, and it is a stimulator of
neutrophils. IL-6 also plays a key role in stimulating lymphocytes.
Thus, enhancement of TNF- and IL-6 could reflect increased
potentiation of immune activity against infection. Alternatively, high
levels of TNF- and other immediate pro-inflammatory cytokines could
be undesirable, due to their role in some of the severe effects of
sepsis. However, IL-6, which does not cause shock or capillary leakage
like other pro-inflammatory cytokines, has an anti-inflammatory role by
reducing TNF production via negative feedback. Therefore, it may be
hypothesized that the fever-range WBH-induced enhancement of these
LPS-induced cytokine levels are overall beneficial to the host.
Serum APP levels observed in these mice depend on the production,
circulation, usage, and turnover of these proteins. Because the 6-h WBH
treatment occurs before the APPs really begin to accumulate in the
serum, it is reasonable to suggest that WBH predominantly affects APP
production, potentially through the regulation of the mediators that
stimulate the liver. For example, the significantly higher levels of
TNF- and IL-6 in WBH-treated BALB/c mice appear to have long-term
effects on lasting elevations of APPs. However, the lack of Hp
enhancement in the WBH-treated C57BL/6 mice and the apparent delay in
Hp production in WBH-treated BALB/c mice were unexpected and
contradictory to the enhanced sera levels of IL-6 seen in both strains
of mice. Because mouse Hp is a type II APP, and thus regulated
predominantly by IL-6-like cytokines [6
], it is possible
that WBH has a negative effect on hepatocyte IL-6 signaling pathways in
the BALB/c mice. Intracellular STAT3 in particular is activated by
tyrosine phosphorylation in response to IL-6 [37
,
38
]. However, upon examination of the liver tissue at
early timepoints (i.e., 30 min, 1 h, and 2 h) after LPS
administration, statistically significant differences in STAT3
phosphorylation were not observed in either the C57BL/6 or BALB/c mice
between WBH-treated and control groups (data not shown). This suggests
that other regulators of the liver APP response, such as
glucocorticoids and growth factors [6
], may be affected
by WBH in a manner that would result in the observed effects on Hp.
These systemic APPs are known to take a protective role in the resolution of inflammation, presumably after an infection has been controlled by the acute inflammatory response [7 , 8 ]. Thus, the observed WBH-induced prolonged elevation of LPS-induced APPs seen in the BALB/c mice is suggestive of prolonged repair and anti-inflammatory activity. In contrast, the WBH-induced delay in Hp levels seen in the BALB/c mice could have various implications in this model of acute inflammation. Hp protects against hemoglobin-directed peroxidation [39 ] and is also thought to take part in angiogenesis and the inhibition of lymphocyte and neutrophil activity [40 41 42 ]. Thus, the WBH effects on LPS-induced Hp may reflect a general delay (in BALB/c mice), of anti-inflammatory mediators. In the BALB/c mice there is also the prolonged elevation of both AGP and Hp, which suggest that APP-mediated anti-inflammatory control of acute phase immune responses is maintained if not enhanced.
In conclusion, although this study suggests that body temperatures
similar to that experienced during a fever are capable of modulating
immune responses, it is important to realize that WBH treatment cannot
be directly compared to a naturally occurring fever. For example, this
externally applied mild, long-duration hyperthermia treatment bypasses
the biochemical, neurological, and immunological events that normally
lead to fever [5
]. Arguments may even be made that
exogenous heat is unlikely to cause changes in vasoregulation and
tissue metabolism that are representative of the temperature effects
seen with true fever. Yet, upon consideration of the various
observations made using ectotherms, the relevance of exogenous heating
mechanisms in survival against infections cannot be denied
[2
, 3
]. A more recent study using a mouse
model of bacterial peritonitis has also revealed the importance of
increased core body temperatures for optimal antimicrobial host defense
[43
]. It is interesting that although hyperthermia
improved survival and reduced the bacterial load in mice infected with
Klebsiella pneumoniae peritonitis, it also was shown to
suppress or delay plasma TNF- and interferon-
levels
[43
]. This brings to light the importance of delineating
differences in the effects of mild hyperthermia between endotoxin
challenge vs. infection with replicating pathogen. In any case,
in vivo studies such as ours highlight a largely
underappreciated immunoregulator (i.e., elevated body temperature) that
may in particular affect immune activities that involve the same
cytokines and effector cells that take part in the acute inflammatory
response. Indeed, one may speculate that the effects of elevated body
temperatures are beneficial to the host and may be clinically utilized
as an adjuvant for the treatment of disease.
Received March 23, 2000; revised July 11, 2000; accepted July 14, 2000.
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transcription in macrophages exposed to febrile range temperature J. Biol. Chem. 271,9841-9848This article has been cited by other articles:
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