Vol. 274, Issue 3, R741-R745, March 1998
TNF-
tolerance blocks LPS-induced hypophagia but LPS
tolerance fails to prevent TNF--induced hypophagia
M. H.
Porter,
M.
Arnold, and
W.
Langhans
Institute for Animal Sciences, Physiology and Animal Husbandry,
Swiss Federal Institute of Technology, 8092 Zurich, Switzerland
 |
ABSTRACT |
To
investigate the role of tumor necrosis factor-
(TNF-) in
bacterial lipopolysaccharide (LPS)-induced hypophagia, we tested whether a cross tolerance between LPS and TNF- exists with respect to their anorectic effects. Only the first of three subsequent intraperitoneal injections of LPS (100 µg/kg body wt) given every second day at dark onset (12:12-h light-dark cycle) led to a
significant reduction of food intake in male rats. Likewise,
intraperitoneal injections of human recombinant TNF- (150 µg 
3 × 106 U/kg body wt) also
resulted in tolerance to its hypophagic effect. LPS tolerance did not
alter the hypophagic response to subsequently injected TNF-
(n = 14). However, TNF-
pretreatment completely blocked the hypophagic response to LPS
(n = 14). The results
demonstrate that tolerance to the hypophagic effect of exogenous
TNF- is sufficient to eliminate LPS-induced hypophagia. This is
consistent with the hypothesis that endogenous TNF- plays a major
role in LPS-induced hypophagia. The ineffectiveness of LPS tolerance to attenuate TNF--induced hypophagia is compatible with findings demonstrating that reduced TNF- production is an important feature of LPS tolerance.
tumor necrosis factor-; lipopolysaccharide; anorexia; cytokine; endotoxin; food intake; feeding
| |
INTRODUCTION |
ACUTE BACTERIAL INFECTIONS serve as the impetus for a
host defense reaction known as the acute phase response. Anorexia is often observed during the acute phase response and seems to be an early
mechanism of host defense. In support of a positive role for the
hypophagia during infection, the force feeding of experimentally infected mice decreased survival time and increased mortality (21).
Hypophagia may serve to reduce the availability of nutrients essential
for the survival of pathogenic microorganisms.
Lipopolysaccharides (LPS) from gram-negative bacterial cell walls are
major promoters of the acute phase response and reduce food intake
after parenteral administration in animals (14, 16). Many of the
physiological effects of LPS are mediated by cytokines, like tumor
necrosis factor- (TNF-) and interleukin (IL)-1, which are
released from activated cells of monocyte/macrophage lineage (3, 5, 20,
22). TNF-, IL-1, and IL-1
potently reduce food
intake after either peripheral or central administration in rats and
mice (15, 24) and are therefore implicated in the hypophagic effect of
LPS.
Repeated exposure to LPS results in the rapid development of tolerance
to various LPS effects, including hypophagia, in experimental animals
(2, 10, 14). LPS tolerance is accompanied by the absence of an increase
in serum TNF- in response to subsequent LPS stimulation, whereas
IL-1 and IL-6 are usually still synthesized (10, 14). Accordingly,
LPS-tolerant macrophages do not produce TNF- during in vitro LPS
restimulation but retain the ability to produce and even augment the
production of IL-1 (17, 28). The blunted TNF- response during LPS
tolerance suggests that downregulation of TNF- production plays a
role in the cessation of LPS hypophagia. Repeated injections of TNF-
also result in tolerance to TNF- (7, 9, 29). TNF- tolerance
protects against some of the effects of LPS and vice versa. For
example, TNF- tolerance attenuates the thermal response to LPS in
guinea pigs, whereas LPS tolerance protects against a lethal dose of TNF- in rats (7, 9). Therefore, a cross tolerance between LPS and
TNF- appears to exist, but its role in regard to food intake and
hypophagia has not been thoroughly examined.
To address the role of endogenous TNF- in LPS hypophagia, the
present study investigated whether a cross tolerance between LPS and
TNF- exists with respect to their hypophagic effects. The first
experiment examined the hypophagic effect of exogenously administered
TNF- in rats made LPS tolerant by three subsequent intraperitoneal
LPS injections. The second experiment tested the hypophagic effect of
exogenously administered LPS in rats made TNF- tolerant.
| |
METHODS |
Animals and housing conditions.
Adult male Sprague-Dawley rats (Institut für Labortierkunde,
Universität Zürich Irchel, Zürich, Switzerland) were
used in the experiments. They were individually housed in stainless steel-drawer cages with wire bottoms in temperature-controlled (22 ± 2°C) colony rooms. The rats were kept on an artificial
12:12-h light-dark cycle, with the lights on from 2200 to 1000, and
were fed a ground rat chow diet (Nafag, Gossau, Switzerland).
Food intake was measured by manually weighing (±0.1 g) the feeding
cups at various times after injections (see the following paragraphs).
Spillage was collected on paper spread beneath the cages and was also
measured. Food and tap water were available ad libitum. Before
experiments, the rats were adapted to diet and experimental conditions
for at least 2 wk. Each experiment was performed with a different group
of rats. All procedures and protocols were approved by the Kanton of
Zurich's Animal Use and Care Committee.
Test procedures.
On test days, groups of rats were matched for food intake and body
weight during the preceding dark phase. Drug solutions were freshly
prepared before injections. LPS (from
Escherichia coli serotype no. 0111:B4, L-2630;
Sigma, St. Louis, MO) was dissolved (100 µg LPS/ml) in isotonic,
pyrogen-free saline. Recombinant human TNF- (rhTNF-) (specific
activity as determined by L929 assay
107 U/mg; Knoll, Ludwigshafen,
Germany) was diluted in a buffer consisting of human serum albumin,
Hanks' balanced salt solution, and pyrogen-free saline, in a ratio of
0.1:2:7.9 and was administered at a dosage of 300 µg 3 × 106 U/kg body wt. Both were
injected intraperitoneally at dark onset. Control injections consisted
of an equivalent volume of saline or vehicle solution.
In the first experiment, the effect of repeated injections of LPS on
food intake and on the feeding response to TNF- was tested in 28 rats (mean body wt 292 g) that were distributed into two groups
(n = 14) as described. Injections of
LPS (100 µg/kg body wt) or saline were administered at dark onset on
days
1, 3,
and 5 of the experiment. Food intake
was measured at 6, 12, and 24 h after each injection. On the
noninjection days
2, 4, and 6, food intake was measured at 12 and 23 h. The feeding cups were refilled shortly before injections on
days
1, 3,
5, and
7. On
day 7 of the experiment, seven of the LPS-pretreated rats and seven of the
saline-pretreated rats received an injection of TNF- (300 µg 3 × 106 U/kg body wt). The
remaining rats (7 LPS-pretreated and 7 saline-pretreated rats) received
an injection of vehicle. Food intake was measured as described for
days
1, 3,
and 5.
In the second experiment, the effect of repeated injections of TNF-
on food intake and on the feeding response to LPS was tested in 28 other rats (mean body wt 284 g) by essentially the same procedure as
described above, except for the following changes. The rhTNF-
(specific activity as determined in the L929 assay 2 × 107 U/mg, Endotel) was dissolved
in a buffer consisting of sterile-filtered, phosphate-buffered solution
containing 0.1% pyrogen-free bovine serum albumin and was administered
at a dosage of 150 µg 3 × 106 U/kg body wt. Control
injections consisted of an equivalent volume of vehicle. In addition,
the second experiment included a crossover experiment on
day 9 (same as experimental day
7) after another noninjection day
(day
8).
Statistical evaluation.
Differences between group means were tested using Student's
t-test or an analysis of variance
followed by a modified t-test (11)
when appropriate. P values <0.05
were considered significant.
| |
RESULTS |
Food intake was significantly reduced after the first injection of 100 µg LPS/kg body wt on experimental
day 1 (Fig. 1). The two subsequent injections of
LPS on days
3 and
5 did not affect food intake
significantly (Fig. 1). On days without injections (experimental
days
2, 4,
and 6), food intakes of LPS- and
saline-injected rats did not differ significantly (not shown). On
day
7, TNF- (300 µg/kg body wt)
similarly reduced food intake in both LPS and saline-pretreated rats at
6, 12, and 24 h (Fig. 2). TNF--induced hypophagia seemed to be more pronounced after saline pretreatment than
after LPS pretreatment. However, this difference did not reach
statistical significance (Table 1).
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Fig. 1.
Development of tolerance to the hypophagic effect of lipopolysaccharide
(LPS, 100 µg/kg body wt) from
Escherichia coli with repeated injections.
A, B,
and C: first, second, and third
injections, respectively. Each value represents the mean ± SE of 14 rats. * P < 0.05 between LPS
and saline values (Student's
t-test).
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Fig. 2.
Effect of LPS tolerance on the hypophagic response to tumor necrosis
factor- (TNF-, 300 µg/kg body wt). Each value represents the
mean ± SE of 7 rats. * Values of both TNF- groups are
significantly lower than the corresponding control values
[P < 0.05, modified
t-test after significant analysis of
variance (ANOVA)].
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Similar to LPS tolerance, repeated injections of TNF- also resulted
in tolerance to its hypophagic effect, which had fully developed on the
third injection day (day
5) (Fig.
3). Again, food intakes of TNF--injected
and vehicle-injected rats did not differ significantly on days without
injections (experimental days
2, 4,
6, and
8; not shown). On
days
7 and
9 (Fig.
4), food intake was reduced
(P < 0.001) at all time points in
the 3× buffer-LPS treatment group compared with all other groups.
Accordingly, LPS-induced suppression of food intake was significantly
greater after vehicle pretreatment than after TNF- pretreatment at
every time period (Table 2).
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Fig. 3.
Development of tolerance to the hypophagic effect of TNF- (150 µg/kg body wt) with repeated injections. Each value represents the
mean ± SE of 14 rats. A,
B, and
C: first, second, and third
injections, respectively. * P < 0.05 between LPS and saline values (Student's
t-test).
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Fig. 4.
Effect of TNF- tolerance on the hypophagic response to LPS (100 µg/kg body wt). Each value represents the mean ± SE of 14 rats.
* Values of the 3 × vehicle/LPS group are significantly
lower than the values of the other groups
(P < 0.05, modified
t-test after significant ANOVA).
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| |
DISCUSSION |
In accordance with previous studies (14, 29), repeated administration
of either LPS or TNF- resulted in tolerance to the hypophagic
effects of these compounds. The new finding in the present study is the
partial cross tolerance that was observed between LPS and TNF- with
respect to their hypophagic effects: LPS tolerance did not affect the
hypophagia in response to TNF-, but TNF- tolerance blocked
LPS-induced hypophagia. These results are compatible with the
hypothesis that LPS-induced anorexia depends on the action of
endogenous TNF-.
The mechanism of LPS tolerance has not been fully elucidated. The rapid
onset of tolerance to the hypophagic effect of LPS in rats never before
experimentally exposed to LPS indicates that LPS tolerance is not due
to antibody formation (4). Also, LPS tolerance is not a result of
downregulation of the CD14-LPS receptor (33, 34). Numerous studies
suggest that alteration of macrophage secretory function, including a
decrease in TNF- production, plays a prominent role in LPS tolerance
(6, 17, 19, 26, 28, 34). Several explanations have been put forth to
explain impaired TNF- production during LPS tolerance. For example,
LPS tolerance alters G proteins that may serve to regulate the
synthesis of TNF- (1, 18). In addition, the
upregulation of the anti-inflammatory cytokine IL-10 during LPS
tolerance has been demonstrated to downregulate the expression of
TNF- (8, 25). Furthermore, decreased TNF- production during LPS
tolerance may be related to alterations in TNF- transcription and
translation (12, 19, 28, 33) or production of a TNF- inhibitor in
tolerant animals (27). Finally, under certain conditions, receptors for
TNF- can be downregulated during LPS tolerance (32).
Administration of exogenous TNF- reduced food intake similarly in
LPS-tolerant rats and in saline-pretreated rats. This observation lends
support to the hypothesis that LPS loses its hypophagic effect with
repeated administration because of a decrease in macrophage TNF-
production. LPS tolerance has been shown to alter the hyperthermic effect of peripherally administered TNF- and to protect against its
lethal effect (7, 9, 23). The present results therefore indicate that
the hypophagic effect of TNF- is not directly related to its
hyperthermic or potentially lethal effects. Previous studies in our
laboratory demonstrated that LPS tolerance did not change the
hypophagic effects of IL-1 (16) and muramyl dipeptide (14). Taken
together, these data suggest that the mechanism of LPS tolerance is
located before any potential common final pathway in the hypophagic response to these immunomodulators. The results are also an indicator of the complexity of interactions between bacterial products and cytokines in the hypophagia during bacterial infections.
Similar to LPS, repeated injections of TNF- also induced tolerance
to its hypophagic effect. Again, the mechanisms of this phenomenon
remain largely unknown. TNF- tolerance developed more slowly than
LPS tolerance in the present experiments, indicating that the
mechanisms of LPS and TNF- tolerance are different. The observed
time course for the development of tolerance to the hypophagic effect
of TNF- roughly corresponds to the time course for the development
of TNF- tolerance reported by others (7, 29). TNF- tolerance is
not the result of an altered absorption or clearance of TNF-,
because serum TNF- activity is equivalent in TNF--exposed
tolerant and naive animals (7). The lack of antibody production in
response to TNF- administration argues against the idea that a
humoral immune response contributes to TNF- tolerance (7, 29).
Finally, changes in circulating soluble TNF- receptors or a
downregulation in the number of TNF- receptors on target cells does
not seem to be involved in the tolerance to TNF- (30). Nevertheless,
some evidence indicates that TNF- tolerance is due to a 55-kDa
TNF- receptor-triggered blockade of the 75-kDa TNF- receptor
pathway (31).
Tolerance to TNF- has been shown to attenuate the histopathological
alterations induced by administration of high LPS doses (7), to protect
against LPS lethality (7), and to alter the hyperthermic effects of LPS
administration (9). The present study adds the elimination of the
hypophagic effect of LPS to that list of cross reactions. The fact that
TNF- tolerance is sufficient to block LPS-induced hypophagia
indicates that endogenous TNF- is a necessary contributor to LPS
hypophagia. This finding is also consistent with reports of a blunted
TNF- response during LPS tolerance (6, 17, 19, 28, 34).
Interestingly, TNF- pretreatment has been shown to dramatically
increase LPS-induced TNF- production in vivo (23). Therefore, a
decreased LPS-induced production of TNF- cannot explain the lack of
a hypophagic response to LPS in TNF--tolerant rats. Together, these
data demonstrate that the crucial mechanism that blocks the hypophagic
effect of LPS in TNF- tolerance is located downstream of monocyte
and/or macrophage TNF- production, perhaps at the receptor
or postreceptor level (31). A blockade of the action of endogenous
TNF- in response to LPS injection is the most plausible explanation
for the elimination of the hypophagic effect of LPS in TNF--tolerant rats. Alternatively, endogenous TNF- and some other endogenous mediator of LPS-induced hypophagia might share a common pathway that is
blocked in TNF- tolerance. The present data do not allow exclusion
of this possibility. For instance, tolerance to TNF- may also affect
a postreceptor signalling pathway of IL-1 (31). However, it is worth
mentioning in this context that previous studies failed to reveal any
indication of a cross tolerance between the hypophagic effects of LPS
and IL-1 (16).
In conclusion, a partial cross tolerance was observed between LPS and
TNF- with respect to their hypophagic effects. LPS tolerance did not
affect the hypophagia in response to TNF-, but TNF- tolerance
blocked LPS-induced hypophagia. Whether this phenomenon would occur in
humans and might be clinically relevant is unknown because species
sensitivity to LPS varies considerably (13).
Perspectives
Several cytokines and other substances are supposed to play a role as
endogenous mediators of the hypophagic effects of bacterial products
such as LPS. LPS and the endogenous mediators certainly do not act only
sequentially to inhibit feeding. Rather, the food intake reduction
during bacterial infections is most likely the result of complex
neural, neurohumoral, and endocrine interactions between bacterial
products and endogenous mediators in the periphery as well as in the
brain. Further work will be necessary to fully understand these complex
interactions and to identify the most promising tools for therapeutic
intervention, when needed. However, the present finding that tolerance
to the hypophagic effect of exogenous TNF- completely eliminates the
hypophagic effect of intraperitoneally injected LPS points to TNF-
as a major player in the hypophagia during bacterial infections and may
provide some leads for the development of promising strategies for a
therapeutic intervention. It is possible that the use of LPS or TNF-
tolerance to prevent hypophagia during severe infection could be
beneficial when induced before sepsis occurs. This might be applicable
to several clinical settings, including those in which patients are undergoing major surgery or receiving chemotherapy.
| |
ACKNOWLEDGEMENTS |
This work was supported by Swiss Federal Institute of Technology
Grant 020-096-95. A preliminary report of the data was given at the 1997 meeting of the Society for the Study of Ingestive Behavior
in Baltimore, MD.
| |
FOOTNOTES |
Address for reprint requests: M. H. Porter, Institut für
Nutztierwissenschaften der ETHZ, Physiologie und Tierhaltung,
Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
Received 1 August 1997; accepted in final form 31 October 1997.
| |
REFERENCES |
1.
Altavilla, D.,
F. Squadrito,
P. Canale,
M. Ioculano,
G. M. Campo,
G. Squadrito,
G. Urna,
A. Sardella,
and
A. P. Caputi.
Endotoxin tolerance impairs a pertussis-toxin-sensitive G-protein regulating tumour necrosis factor release by macrophages from tumour-bearing rats.
Pharmacol. Res.
33:
203-209,
1996[Medline].
2.
Beeson, P. B.
Tolerance to bacterial pyrogens: factors influencing its development.
J. Exp. Med.
86:
29-37,
1947[Abstract].
3.
Beutler, B.,
D. Greenwald,
and
J. D. Hulmes.
Identity of tumor necrosis factor and the macrophage-secreted factor cachectin.
Nature
316:
552-554,
1985[Medline].
4.
Cook, J. A.,
T. S. Rogers,
W. C. Wise,
and
P. V. Halushka.
Agents which modulate reticuloendothelial function and affect endotoxin sensitivity.
In: Handbook of Endotoxin, Cellular Biology of Endotoxin, edited by L. J. Berry. Amsterdam, Holland: Elsevier, 1985, p. 303-339.
5.
Dinarello, C. A.
Biological basis for interleukin-1 in disease.
Blood
87:
2095-2147,
1996[Abstract/Free Full Text].
6.
Erroi, A.,
G. Fantuzzi,
and
P. Ghezzi.
Differential regulation of cytokine production in lipopolysaccharide tolerance in mice.
Infect. Immun.
61:
4356-4359,
1993[Abstract/Free Full Text].
7.
Fraker, D. L.,
M. C. Stovroff,
M. J. Merino,
and
J. A. Norton.
Tolerance to tumor necrosis factor in rats and the relationship to endotoxin tolerance and toxicity.
J. Exp. Med.
168:
95-105,
1988[Abstract/Free Full Text].
8.
Frankenberger, M.,
H. Pechumer,
and
H. W. Ziegler-Heitbrock.
Interleukin-10 is upregulated in LPS tolerance.
J. Inflamm.
45:
56-63,
1995[Medline].
9.
Goldbach, J. G.,
J. Roth,
B. Storr,
and
E. Zeisberger.
Repeated infusions of TNF- cause attenuation of the thermal response and influence LPS fever in guinea pigs.
Am. J. Physiol.
270 (Regulatory Integrative Comp. Physiol. 39):
R749-R754,
1996[Abstract/Free Full Text].
10.
Greisman, S. E.,
E. J. Young,
and
W. E. Woodward.
Mechanisms of endotoxin tolerance: specificity of the pyrogenic refractory state during continuous intravenous infusions of endotoxin.
J. Exp. Med.
124:
983-1000,
1966[Abstract].
11.
Holm, S. A.
A simple sequentially rejective multiple test procedure.
Scand. J. Stat.
6:
65-70,
1979.
12.
Labeta, M. O.,
J. J. Durieux,
G. Spagnoli,
N. Fernandez,
J. Wijdenes,
and
R. Hermann.
CD14 and tolerance to lipopolysaccharide: biochemical and functional analysis.
Immunology
80:
415-423,
1993[Medline].
13.
Langhans, W.
Bacterial products and the control of ingestive behavior: clinical implications.
Nutrition
12:
303-315,
1996[Medline].
14.
Langhans, W.,
G. Balkowski,
and
D. Savoldelli.
Differential feeding responses to bacterial lipopolysaccharide and muramyl dipeptide.
Am. J. Physiol.
261 (Regulatory Integrative Comp. Physiol. 30):
R659-R664,
1991[Abstract/Free Full Text].
15.
Langhans, W.,
G. Balkowski,
and
D. Savoldelli.
Further characterization of the feeding responses to interleukin-1 and tumor necrosis factor.
In: Endocrine and Nutritional Control of Basic Biological Functions, edited by H. Lehnert,
R. Murison,
and H. Weiner. Seattle, WA: Hogrefe & Huber, 1993, p. 135-142.
16.
Langhans, W.,
D. Savoldelli,
and
S. Weingarten.
Comparison of the feeding responses to bacterial lipopolysaccharide and interleukin-1.
Physiol. Behav.
53:
643-649,
1993[Medline].
17.
Li, M. H.,
S. C. Seatter,
R. Manthei,
M. Bubrick,
and
M. A. West.
Macrophage endotoxin tolerance: effect of TNF or endotoxin pretreatment.
J. Surg. Res.
57:
85-92,
1994[Medline].
18.
Makhlouf, M.,
S. H. Ashton,
J. Hildebrandt,
N. Mehta,
T. W. Gettys,
P. V. Halushka,
and
J. A. Cook.
Alterations in macrophage G proteins are associated with endotoxin tolerance.
Biochim. Biophys. Acta
1312:
163-168,
1996[Medline].
19.
Marchant, A.,
C. Gueydan,
and
L. Houzet.
Defective translation of tumor necrosis factor mRNA in lipopolysaccharide-tolerant macrophages.
J. Inflamm.
46:
114-123,
1996[Medline].
20.
Marinkovic, S.,
G. P. Jahreis,
and
G. G. Wong.
IL-6 modulates the synthesis of a specific set of acute phase proteins in vivo.
J. Immunol.
142:
808-812,
1989[Abstract].
21.
Murray, M. J.,
and
A. B. Murray.
Anorexia of infection as a mechanism of host defense.
Am. J. Clin. Nutr.
32:
593-596,
1979[Abstract/Free Full Text].
22.
Nathan, C. F.
Secretory products of macrophages.
J. Clin. Invest.
79:
319-326,
1987.
23.
Norton, J. A.,
and
D. L. Fraker.
Tolerance to tumor necrosis factor.
Nutrition
5:
131-135,
1989[Medline].
24.
Plata-Salaman, C. R.
Immunoregulators in the nervous system.
Neurosci. Biobehav. Rev.
15:
185-215,
1991[Medline].
25.
Randow, F.,
U. Syrbe,
C. Meisel,
D. Krausch,
H. Zuckermann,
C. Platzer,
and
H. D. Volk.
Mechanism of endotoxin desensitization: involvement of interleukin-10 and transforming growth factor beta.
J. Exp. Med.
181:
1887-1892,
1995[Abstract/Free Full Text].
26.
Roth, J.,
J. L. McClellan,
M. J. Kluger,
and
E. Zeisberger.
Attenuation of fever and release of cytokines after repeated injections of lipopolysaccharide in guinea pigs.
J. Physiol. (Lond.)
477:
177-185,
1994[Abstract/Free Full Text].
27.
Schade, F. U.,
J. Schlegel,
K. Hofmann,
H. Brade,
and
R. Flach.
Endotoxin-tolerant mice produce an inhibitor of tumor necrosis factor synthesis.
J. Endotoxin Res.
3:
455-462,
1996.[Abstract/Free Full Text]
28.
Seatter, S. C.,
T. Bennet,
M. H. Li,
M. P. Bubrick,
and
M. A. West.
Macrophage endotoxin tolerance: tumor necrosis factor and interleukin-1 regulation by lipopolysaccharide pretreatment.
Arch. Surg.
129:
1263-1270,
1994[Abstract/Free Full Text].
29.
Socher, S. H.,
A. Friedman,
and
D. Martinez.
Recombinant human tumor necrosis factor induces acute reductions in food intake and body weight in mice.
J. Exp. Med.
167:
1957-1962,
1988[Abstract/Free Full Text].
30.
Takahashi, N.,
P. Brouckaert,
M. H. Bemelmans,
W. A. Buurman,
and
W. Fiers.
Mechanism of induction of tolerance to tumor necrosis factor (TNF): no involvement of modulators of TNF bioavailability or receptor binding.
Cytokine
6:
235-242,
1994[Medline].
31.
Takahashi, N.,
P. Brouckaert,
and
W. Fiers.
Mechanism of tolerance to tumor necrosis factor: receptor-specific pathway and selectivity.
Am. J. Physiol.
269 (Regulatory Integrative Comp. Physiol. 38):
R398-R405,
1995[Abstract/Free Full Text].
32.
Van der Poll, T.,
S. M. Coyle,
A. Kumar,
K. Barbosa,
J. M. Agosti,
and
S. F. Lowry.
Down-regulation of surface receptors for TNF and IL-1 on circulating monocytes and granulocytes during human endotoxemia: effect of neutralization of endotoxin-induced TNF activity by infusion of a recombinant dimeric TNF receptor.
J. Immunol.
158:
1490-1497,
1997[Abstract].
33.
Ziegler-Heitbrock, H. W.,
M. Frankenberger,
and
A. Wedel.
Tolerance to lipopolysaccharide in human blood monocytes.
Immunobiology
193:
217-223,
1995[Medline].
34.
Ziegler-Heitbrock, H. W.,
A. Wedel,
and
W. Schraut.
Tolerance of lipopolysaccharide involves mobilization of nuclear factor 
B with predominance of p50 homodimers.
J. Biol. Chem.
269:
17001-17004,
1994[Abstract/Free Full Text].
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Abstract
Introduction
