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1 Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque 87131; 2 Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87185; and 3 Department of Physiology and Endocrinology, Medical College of Georgia, Augusta, Georgia 30912
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We have previously
reported that heat conditioning augments lipopolysaccharide
(LPS)-induced fever in rats, which is accompanied by an accumulation of
heat shock protein (HSP) in the liver and the reduction of the plasma
level of tumor necrosis factor (TNF-
) (Kluger MJ, Rudolph K,
Soszynski D, Conn CA, Leon LR, Kozak W, Wallen ES, and Moseley PL.
Am J Physiol Regulatory Integrative Comp Physiol 273:
R858-R863, 1997). In the present study we have tested whether
inhibition of protein synthesis in the liver can reduce the effect of
this heat conditioning on the LPS-induced febrile response in the rat.
D-galactosamine (D-gal) was used to selectively
inhibit liver protein synthesis. D-gal (500 mg/kg) or PBS
as control was administered intraperitoneally 1 h before heat
stress. LPS (50 µg/kg ip) was injected 24 h post-heat exposure. Treatment with D-gal blunted the febrile response to LPS.
Moreover, heat-conditioned rats treated first with D-gal
and subsequently with LPS demonstrated a profound fall in core
temperature 10-18 h post-LPS. A significant increase of serum
TNF- accompanied this effect of D-gal on fever.
Heat-conditioned animals receiving D-gal showed an
inhibition in inducible HSP-70 in the liver. These data support the
role of hepatic function in modulating the febrile response to LPS.
heat shock proteins; liver; heart; kidney; tumor necrosis
factor-, interleukin-6, temperature regulation; fever; lipopolysaccharide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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HEAT STRESS PROVOKES metabolic adaptations in the whole organism. One such response is the production of heat shock proteins (HSPs) (26). The accumulation of HSPs within cells helps both cells and the whole organism survive subsequent, otherwise lethal, thermal stress. Interestingly, heat conditioning sufficient to cause cellular HSP accumulation has also been shown to be protective in a subsequent, otherwise lethal, endotoxin challenge (30).
Several studies have demonstrated that HSPs regulate cytokine
production in peripheral blood monocytes. Intracellular HSP accumulation is associated with a decrease in synthesis of tumor necrosis factor- (TNF-) and interleukin (IL)-1
(6,
32). Impaired HSP production causes enhanced TNF-induced
cytotoxicity in cells (27), whereas overexpression of
HSP-70 is associated with a decrease of TNF-induced cytotoxicity
(13). We have shown that heat stress sufficient to induce
liver HSP in the rat resulted in significant augmentation of
LPS-induced fever compared with non-heat-stressed animals
(15). This amplifying effect of heat conditioning on fever
was accompanied by a suppression of LPS-induced plasma TNF- and no
change in LPS-induced elevation of plasma IL-6. Based on these data, we
postulated that induction of HSPs in the liver may be associated with
the heat conditioning-induced alterations of the response to LPS
injection in rats.
Whereas heat conditioning is protective, pretreatment with
D-galactosamine (D-gal) increases sensitivity
to subsequent LPS (2, 10). D-gal inhibits
protein synthesis primarily in the liver (20, 35). Based
on these data, we used D-gal to test the hypothesis that
inhibition of protein synthesis in the liver would alter the effect of
heat exposure on induction of liver HSPs and the subsequent LPS-induced
fever in rats. The first aim of this study was to examine the ability
of D-gal to block the cellular accumulation of HSP-70 in
the liver compared with other organs. The second aim was to determine
whether D-gal blocked the effect of heat conditioning on
LPS-induced fever and cytokine production. We report that
D-gal inhibited the febrile response to LPS both in
heat-stressed and nonstressed rats, selectively blocked the expression
of inducible type of HSPs in the liver, and increased the concentration
of circulating TNF-.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental animals. Male Sprague-Dawley rats weighing 200-220 g on arrival were obtained from Harlan (Indianapolis, IN). Rats were housed one per cage in a room maintained at 24-25°C with 12:12-h light-dark cycle and were provided with ad libitum tap water and laboratory rodent chow (Teklad rodent diet W8604). All experimental procedures were approved by the Lovelace Respiratory Research Institute Institutional Animal Care Committee.
Measurement of body temperature. Core body temperature (±0.1°C) was monitored using a Datacol 3 biotelemetry system (Mini-Mitter, Sunriver, OR) (15). Seven days before the experiments, the animals were anesthetized with halothane for intra-abdominal implantation of the Mini-Mitter transmitters (15). Body temperature was recorded at 5-min intervals, beginning at least 24 h before experimental procedures and continuing until the animals were killed. After each experiment, the transmitters were recalibrated to ensure that recorded temperatures were accurate.
Reagents. Purified LPS (Escherichia coli endotoxin 0111:B4, L2630, Sigma, St. Louis, MO) was dissolved in sterile pyrogen-free saline and injected intraperitoneally at a dose of 50 µg/kg. This dose causes robust, but not maximal, fever in control rats (15). D-gal (G0500, Sigma) was dissolved in sterile pyrogen-free PBS and injected intraperitoneally at a dose of 500 mg/kg.
Tissue preparation and Western blot analysis.
At 24 h after heat or sham exposure (experimental protocol
1) or 4 h after LPS injection (experimental protocol
2), tissue samples from the liver, kidney, and brain were quickly
removed and frozen in liquid nitrogen and then stored at 
20°C for
subsequent analysis. Samples were homogenized with a Potter-Elvehjem
tissue grinder in an equal volume of ice-cold NaHCO3 (10 mM) for 30 s, subjected to three freeze-thaw cycles, then
centrifuged to remove undissolved material. Protein was quantitated
using the Bradford method. Fifteen micrograms of each sample was
separated on a 12.5% SDS-PAGE and transferred to nitrocellulose. The
membranes were blocked by a 3 h exposure to 10% fetal calf serum
(FCS) and 10% BSA in Tris-buffered saline (TBS; 10 mM Tris, 150 mM
HCl, pH 8.0) at room temperature. The membranes were rinsed once in TBS
with 0.05% Tween 20 (Fisher Scientific, Fair Lawn, NJ) and then twice with TBS alone. The rinsed membranes were exposed for 1 h on
monoclonal antibodies specific for either the inducible HSP-70 (72 kDa)
or the constitutive heat shock cognate protein (HSC)-70 (73 kDa) (StressGen Biotechnologies, Victoria, BC, Canada). The blots were then rinsed in TBS with 0.05% Tween 20, followed by three rinses in
TBS alone. After the final rinse, the membranes were incubated for
1 h with an alkaline phosphate linked anti-mouse IgG (for inducible) or anti-rat IgG (for constitutive), then incubated in 0.45 mM 5-bromo-4-chloro-3-indolyl phosphate (Sigma) and 0.27 mM
nitrobluetetrazolium (Fisher Biotech) in alkaline phosphatase buffer (100 mM Tris, 100 mM NaCl, and 5 mM MgCl2, pH 9.5)
until the bands developed a blue color.
Measurement of IL-6.
IL-6 plasma levels were measured 4 h after intraperitoneal
injection of LPS (50 µg/kg) or saline (experimental
protocol 2). Blood was withdrawn into syringes by heart puncture.
After centrifugation, recovered plasma was stored at 20°C until
assayed. IL-6 concentration was determined using an ELISA kit
(Bio-Rad Laboratories, Hercules, CA).
Measurement of TNF-.
TNF- serum levels were measured 1 h after intraperitoneal
injection of LPS (50 µg/kg) or saline (experimental protocol
2). Blood was withdrawn into syringes by heart puncture. After
centrifugation, recovered serum was stored at 20°C until assayed.
TNF- concentration was determined using an ELISA kit (R&D
Systems, Minneapolis, MN).
Experimental protocol 1. All experiments were begun between 0800 and 0830 to minimize circadian variation. Rats were removed from their cages (25°C ambient temperature) and placed in new cages in a climatic chamber (44°C ambient temperature) for heat conditioning. Before exposure to the warm ambient temperature, the average body temperature of the animals was ~37°C. When the body temperature reached 42°C, animals were removed from the warm chamber and returned to their home cages. Control rats were paired with the heat-stressed rats and treated similarly: they were removed from their home cages and placed into new ones in the 25°C room and returned to their home cages when the heat-treated rats were returned to their cages. One hour before the heat or sham exposure, all rats were injected with either D-gal or PBS. Changes in HSP level in the liver, kidney, and brain were measured.
Experimental protocol 2. Rats were treated with D-gal or PBS and exposed to heat (see Experimental protocol 1). At 24 h after heat or sham exposure, animals were injected with either LPS or saline. To check effects of LPS on rat body temperature, recordings were continued for 24 h. Changes in HSP level in the liver, kidney, and brain were measured.
Data analysis. Separate statistical analyses were performed for the temperature data from experimental protocols 1 and 2 and for the cytokine data. For all analyses, the data were analyzed using ANOVA. Depending on experimental protocol, the ANOVA had two or three factors with interactions. The possible factors were: heat stress (yes or no), D-gal treatment (yes or no), and LPS treatment (yes or no). If the overall model F for the ANOVA was statistically significant (P < 0.05), then the factor and interaction term F tests were examined for statistical significance. If any interaction terms were observed to be statistically significant and there were more than two comparison groups, subtesting was performed using t-tests. If a factor was statistically significant, there was no need for further subtesting as each factor had only two possible comparison groups. In that case, the factor F test and the subtest t-test would have the same P values, making the subtesting redundant.
The temperature measurements were made at 5-min intervals. For the purpose of the figures, the data from experimental protocol 2 were collapsed into 1-h averages, and the data from experimental protocol 2 were collapsed into 20-min averages. For the purposes of the statistical analyses, the data were averaged as follows. There were three time intervals of interest in experimental protocol 1: before heat stress (or sham heat stress) and D-gal (or sham) injection, to ensure that all animals in the experiment had similar body temperatures before any treatments were performed (0600-0800); post-heat stress during the afternoon when the animals might be expected to be less active (1200-1700); and during the night (1800-0600). The temperatures were averaged for each individual animal corresponding to each of these three periods. The two-factor with interaction ANOVAs were performed separately for each time period. There were five time intervals of interest in experimental protocol 2: before LPS (or sham) injection (0900-1040), the first fever peak (1300-1420), the second fever peak (1520-1720), the night (1900-0500), and the following morning (0520-0900). For the two fever peaks, the maximum temperature was used rather than the average; however, for the other three time points, the averages were calculated for each animal. The three-factor with interactions ANOVAs were performed separately for each of the five periods.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of D-gal and heat stress on changes in body
temperature.
Before heat (44°C) or sham-heat (25°C) exposure, animals were
injected with D-gal or PBS. Heat stress caused an immediate increase in body temperature (Fig. 1).
When the body temperature reached 42°C, animals were removed to their
home cages (25°C) and a decrease in body temperature was observed.
Figure 1 shows 1-h temperature averages. The average body temperatures
were 40.11 and 40.59°C for D-gal and PBS-treated rats,
respectively (P = not significant). Shortly after heat
stress (1300-1700), PBS-treated animals had significantly higher
temperatures compared with three other groups (PBS-control,
D-gal-control, D-gal-heat stress;
P < 0.01). During the dark period (1800-0600),
body temperatures of the heat-conditioned animals pretreated with
either PBS or D-gal were higher than sham-heated rats
(P < 0.01). D-gal had no effect on changes
in body temperature during the dark period.
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Effect of D-gal and heat stress on LPS-induced fever.
Rats were injected with D-gal or PBS 1 h before
exposure to heat or sham heat. Twenty-four hours later animals were
subjected to 50 µg/kg ip of LPS or saline. The patterns of body
temperature changes after LPS and saline injection are shown in Fig.
2 and Fig.
3, respectively. Biphasic fever was
recorded after LPS injection in both heat-stressed and
sham-heat-stressed animals that had been injected (1 h before heat
conditioning) with PBS. However, D-gal-treated rats with or
without heat conditioning did not develop the second phase of fever to
50 µg/kg LPS (P < 0.01) compared with control (PBS
treated) animals exposed to heat or sham heat, respectively.
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Effect of D-gal and heat stress on changes in
inducible and constitutive HSP in accumulation.
One hour after D-gal or PBS injection, animals were
exposed to heat. Twenty-four hours later tissues (liver, kidney, and
brain) were harvested, and HSP-70 and HSC-70 were measured. In liver tissue D-gal suppressed the inducible type of HSP-70 (Fig.
4, top), with no effect on the
constitutive type of HSC-70 (Fig. 4, bottom), synthesis that
normally occurs even in unstressed cells. In the brain and kidney,
however, accumulation of both HSP-70 and HSC-70 were unchanged (data
not shown).
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Cytokine production.
One hour before heat stress or sham heat stress, rats were injected
with D-gal or PBS. Twenty-four hours after heat or sham exposure, the rats were given LPS or saline. At 1 h and 4 h
after injection, blood from the heart was harvested, and serum TNF- (1 h) and plasma IL-6 (4 h) were measured. Plasma IL-6 concentration (Fig. 6) was significantly elevated
(P < 0.01) in LPS-treated animals that had been
subjected to PBS and sham heat stress, compared with the three other
groups of animals also treated with LPS. IL-6 was absent in the plasma
of sham-LPS-treated (saline treated) animals 24 h after heat
exposure or sham heat exposure, with or without D-gal.
Similarly, in the sham-LPS-injected (saline injected) animals serum
TNF- was not detected (Fig. 7). On the
other hand, TNF- concentration increased in LPS-treated rats that
were subjected to D-gal and heat stress, relative to the
three other LPS-treated groups. A trend toward an increase of the
TNF- level was also observed in LPS-treated nonheated (25°C)
animals compared with their heat-stressed (44°C) counterparts. But
these differences were not statistically significant (P = 0.2).
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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 D-gal given
shortly before heat conditioning dramatically alters the response to
LPS in rats. D-gal treatment before heat conditioning not
only blocks the augmented febrile response to LPS, but actually results
in a drop in body temperature. We also demonstrate that
D-gal effectively blocks the accumulation of inducible
HSP-70 in the liver, but not in other organs we studied, in response to
heat. Finally, we show that D-gal coupled with heat
actually augments the TNF- response to LPS. These data are
consistent with our earlier reports (15, 30),
demonstrating a protective effect of heat conditioning on subsequent
LPS stress and extend the model to support the hypothesis that
inhibition of hepatocyte function before heat conditioning and LPS
exposure changes the heat conditioning from a protective to an additive stress.
D-gal is thought to alter hepatic function by inhibiting
hepatic mRNA synthesis through depleting uridine phosphates and uridine diphosphate sugars (14). This results in an
inability of the cells to produce important components of the cell
membrane, leading to cell damage. The Kupffer cells are thought to play
a major role in the response to inflammatory agents, mainly to those
entering the circulation from the gut, which, in turn, promotes the
expression of TNF- (33). LPS-induced TNF- may be
responsible for pathogenesis of liver injury and increase in mortality
in D-gal-sensitized mice (2, 21, 31).
Moreover, anti-TNF- inhibits the lethal activity of killed
gram-negative and gram-positive bacteria in D-gal-sensitized mice (9) and rhesus monkeys
(8). This cytokine is considered a key factor inducing
hepatocellular apoptosis after exposure to LPS in
D-gal-treated mice (1, 34).
We demonstrate that D-gal inhibits the production of inducible HSP in the liver of animals that had been exposed to heat, whereas synthesis of the inducible type of HSP-70 in the kidney and brain was unaltered (data not shown). Levels of constitutive HSC-70 were not affected by D-gal either in heat-stressed or in sham-exposed animals in the examined organs. Morikawa et al. (25) have found that D-gal or LPS injections alone were not able to significantly alter the synthesis of HSC-70 and HSP-70 in mice. However, simultaneous treatment with D-gal and LPS led to overexpression of the inducible type of HSP-70 and suppression of constitutive HSC-70 in the liver. In our experiments we used D-gal (1 h before heat stress) to prevent the synthesis of HSPs in the liver.
We have previously shown (15) a heat stress-associated increase in HSP synthesis accompanied by an enhanced febrile response after LPS injection. The present experiments demonstrate that D-gal exposure blocks the second phase of the LPS-induced fever in both heated and nonheated rats (Fig. 2). This effect was accompanied by the augmented TNF level (Fig. 7). Ferreira et al. (7) reported that D-gal did not significantly affect the febrile response induced by LPS injection. However, in their studies they measured changes in body temperature during the 6 h after simultaneous treatment with D-gal and LPS.
There is strong support to the hypothesis that IL-6 plays an important role in modulating febrile response. However, some aspects of its action remain unknown. IL-6 was shown to be a necessary component of febrile response in mice (3) and rats (18). But administering higher doses of IL-6 has a smaller effect on body temperature (29). Moreover, recent studies have shown anti-inflammatory properties of IL-6 (36). Heat stress causes some structural abnormalities: obstruction of hepatic sinusoids, local hepatic hemorrhages, and necrosis of the liver; these changes per se may lead to decreased IL-6 production in liver macrophages and epithelial cells, which represent the main sources of the cytokine. Moreover, the activation of circulating monocytes by LPS is mediated by plasma LPS-binding proteins (LBP), which are released by liver. We speculate that both heat conditioning and D-gal could be responsible for decreased accumulation of these proteins and consequently blunted febrile response. On the other hand, Lamping et al. (19) showed that a high level of LBP, as seen during the acute phase response, inhibits LPS effect. Heat stress and D-gal could lack this protection.
In humans (23), baboons, and mice (22), it has been shown that IL-6 exists in the form of complexes with other proteins. Activity of IL-6 that is bound to the other molecules is markedly altered. We suppose that D-gal may change the interaction between IL-6 and its chaperoning molecules and finally change its biological function.
Finally, we propose that the reduced febrile response to LPS in animals pretreated with heat stress and D-gal can result from blunted production of IL-6 (Fig. 2).
During endotoxemia (5, 16, 28), stroke (24),
exposure to organophosphate pesticides (12), and terminal
liver failure (11), a fall in body temperature is often
observed. TNF is thought to be involved in endotoxin-induced decrease
in body temperature in rats (4) and in mice
(17). Moreover, impaired HSP production enhances
TNF-induced cytotoxicity in cells (27). From these data we
speculate that loss of the HSP-70 response in the liver and subsequent
increased concentration of TNF- in D-gal-sensitized rats
might be key factors responsible for the long-lasting reduction in body
temperature observed in Fig. 2. Based on in vitro studies (6,
32), it is possible that these are linked phenomena, given the role of HSP production in blocking LPS-associated TNF transcription.
In summary, in the present study we demonstrate that the febrile response in D-gal-sensitized and heat-conditioned rats was dramatically changed, whereas heat-conditioned animals in the absence of D-gal showed increased febrile response to LPS. D-gal exposure combined with heat conditioning not only resulted in reduction of fever, but also in a long-lasting drop in body temperature. We also show that D-gal effectively blocks liver HSP accumulation in heat-exposed animals. Finally, we demonstrate augmented concentration of TNF to LPS in D-gal-sensitized rats with heat exposure. In conclusion, these data are consistent with our earlier study demonstrating a protective effect of heat conditioning on subsequent LPS stress and extend the model to support the hypothesis that inhibition of hepatocyte function changes the heat conditioning from protective to additive stress.
Perspectives
Expression of HSP, which is one of the most basic and highly conserved mechanisms of protection, affects many physiological functions on cells and organisms. Our recent studies have shown that heat conditioning, accompanied by an accumulation of HSP-70, augments LPS-induced fever in rats. In our present study, we have shown that the treatment with D-gal blunted the febrile response to LPS. Moreover, heat-conditioned animals treated first with D-gal and then exposed to LPS demonstrated a profound fall in body temperature. Although the exact mechanism responsible for the effect remains to be determined, we speculate that overexpression of TNF may be one possible explanation. Further studies will be needed to determine the role of proteins synthesized in liver on the development of fever or anapyrexia (fall in body temperature). Moreover, we hope such further study will help us figure out whether the LPS-induced drop in body temperature during liver disfunction that we observed here might have had physiological and protective effects or whether it was only a sign of disease. Answering that question may contribute to our understanding of the role of fever and anapyrexia in hepatic disease and find some practical applications.| |
ACKNOWLEDGEMENTS |
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Karol Dokladny thanks Dr. Michal Caputa, and Dr. Andrzej Tretyn (N. Copernicus University, Torun, Poland) for help.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants AR-40771, AG-14687, HL-61389, and AI-27556.
Address for reprint requests and other correspondence: P. L. Moseley, Dept. of Internal Medicine, Univ. of New Mexico, 5-ACC 2211 Lomas Blvd., N.E., Albuquerque, NM 87131 (E-mail: pmoseley{at}salud.unm.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 28 March 2000; accepted in final form 20 September 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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in the time axis). During
nighttime, heat-stressed (HS) rats (injected with PBS or
D-gal) had higher body temperature compared with
sham-heat-exposed animals. The solid line just above axis represents
the hours of darkness in the room. Values are means ± SE 1-h
averages; n, numbers of rats in each group. cont, Control.
