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Infection and Immunity, September 2000, p. 5026-5029, Vol. 68, No. 9
Department of Molecular Biology, Flanders
Interuniversity Institute for Biotechnology and University of
Ghent, B-9000 Ghent, Belgium
Received 24 February 2000/Returned for modification 24 April
2000/Accepted 15 June 2000
The proinflammatory cytokine tumor necrosis factor alpha (TNF- Tumor necrosis factor alpha
(TNF- In order to study TNF- We are interested in identifying endogenous protective molecules and
are focusing on the possible protective roles of acute-phase proteins.
In this context, we already described protection conferred by
As IL-1 Animals.
SAP0/0 mice were kindly provided by M. Botto and M. B. Pepys (Immunological Medicine Unit, Royal
Postgraduate Medical School, London, United Kingdom). The
SAP0/0 allele was backcrossed in a C57BL/6 background for
seven generations, after which heterozygotes were intercrossed;
homozygous SAP0/0 animals and homozygous wild types were
identified by SAP enzyme-linked immunosorbent assay (ELISA). No SAP was
detected in the serum of SAP0/0 mice by ELISA
(3). ELISA has a sensitivity of approximately 10 ng/ml,
whereas normal basal levels found in wild-type C57BL/6 mice are
approximately 10 µg/ml. Mutant and wild-type mice were then further
bred as inbred couples. Female offspring was used at the age of 8 to 12 weeks. The animals were housed in a temperature-controlled, air-conditioned room with 12-h light-dark cycles and received food and
water ad libitum.
Reagents.
mTNF- Injections, blood collections, and SAP ELISA.
Before
injection, all reagents were diluted in lipopolysaccharide-free
phosphate-buffered saline (PBS). Intraperitoneal (i.p.) injections were
0.5 ml, and intravenous (i.v.) injections were 0.2 ml. Subcutaneous
(s.c.) injections of TNF-
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
The Major Acute-Phase Protein, Serum Amyloid P Component, in
Mice Is Not Involved in Endogenous Resistance against Tumor
Necrosis Factor Alpha-Induced Lethal Hepatitis, Shock, and
Skin Necrosis
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
)
induces lethal hepatitis when injected into
D-(+)-galactosamine-sensitized mice on the one hand or
systemic inflammatory response syndrome (SIRS) in normal
mice on the other hand. We studied whether serum amyloid P component
(SAP), the major acute-phase protein in mice, plays a
protective role in both lethal models. For this purpose, we used
SAP0/0 mice generated by gene targeting. We studied the
lethal response of SAP0/0 or SAP+/+ mice to
both lethal triggers but found no differences in the sensitivity of
both types of mice. We also investigated whether SAP is involved in
establishing two types of endogenous protection: one using a single
injection of interleukin-1
(IL-1) for desensitization and clearly
involving a liver protein, the other by tolerizing mice for 5 days
using small doses of human TNF-. Although after IL-1 or after
tolerization the SAP levels in the serum had risen fourfold in
the control mice and not in the SAP0/0 mice, the same
extents of desensitization and tolerization were achieved. Finally, we
observed that the induction of hemorrhagic necrosis in the skin of mice
by two consecutive local injections with TNF- was not altered in
SAP0/0 mice. We conclude that the presence or absence of
SAP has no influence on the sensitivity of mice to TNF--induced
hepatitis, SIRS, and hemorrhagic necrosis or on the endogenous
protective mechanisms of desensitization or tolerization.
INTRODUCTION
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
) is a pleiotropic cytokine which exhibits a pronounced
antitumor activity in vitro as well as in vivo
(2). However, administration of TNF- has proven to induce
a systemic inflammatory response syndrome (SIRS) (41). Administration of TNF- in humans and in experimental animals gives
rise to a shock-like response associated with hypotension and liver
damage (5, 8, 19, 36). So far, the application of TNF- in
a systemic treatment remains impossible. Local treatment, however, has
been achieved with considerable success using the technique of isolated
limb perfusion (23, 30). Also, the use of TNF- in
isolated hepatic perfusion has recently been reported (10,
24).
-induced hepatitis and SIRS, we used
murine TNF- (mTNF-) in D-(+)-galactosamine
(GalN)-sensitized or normal mice. GalN is a hepatotoxin which
specifically inhibits transcription and translation in hepatocytes
(9). In combination with TNF-, extreme apoptosis
and necrosis of hepatocytes are observed (22, 25, 42). The
mice die about 6 to 8 h after the challenge. TNF- injection
into normal mice leads to lethal SIRS characterized by hypotension. In
normal mice, TNF- causes lethality between 24 and 48 h after
the challenge, by a process resembling septic shock.
1-acid glycoprotein (25) and
1-antitrypsin (29). To induce feedback
systems, we use two different methods: (i) injection of a single dose
of interleukin-1 (IL-1), which causes "desensitization," which is most pronounced against TNF--GalN (28, 43), and (ii) injection of a low dose of human TNF- (hTNF-) twice daily for 5 days, which leads to "tolerization" against TNF--induced SIRS (37). The mechanism of IL-1-induced desensitization
is not fully understood but clearly involves induction of one or more
factors in the liver. An involvement of the liver in establishing tolerization has not yet been demonstrated.
is a strong inducer of acute-phase proteins and since serum
amyloid P (SAP) component is one of the major acute-phase proteins in
mice, we investigated the role of SAP in both TNF- models and in the
induction of desensitization and tolerization. We also studied the
effect of SAP presence or absence in the induction of hemorrhagic
necrosis by TNF-. To this end, we used recently generated
SAP0/0 mice that have no circulating SAP but are fertile
and develop normally (3). When such mice are treated with
casein, they do not display amyloid deposition, which is a typical
feature of Alzheimer's disease (3).
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
and hTNF- were expressed in
Escherichia coli, produced and purified to homogeneity in
our laboratory, and had specific activities of 8.0 × 107 and 1.8 × 107 IU/mg, respectively.
The endotoxin levels, assessed with a chromogenic Limulus
amebocyte lysate assay (Coatest; Chromogenix, Stockholm, Sweden), were
less than 10 endotoxin units (EU)/mg for both cytokine preparations.
mIL-1 was expressed in E. coli, was purified at our
facilities, and had a specific activity of 3.65 × 108
U/mg and an endotoxin contamination of <10 EU/mg of protein. GalN was
purchased from Sigma Chemical Co. (St. Louis, Mo.).
were 0.1 ml. Mice were bled at the
retroorbital plexus under light ether anesthesia. Serum was kept at
20°C.
into shaved
mice. To this end, mice were anesthetized using Avertine (tribromoethanol), and their backs were shaved using an electric shaver
and Veet 3 days before the injections.
Body temperatures and skin necrosis lesion size. Rectal body temperatures were recorded with an electronic thermometer (model 2001; Comark Electronics, Littlehampton, United Kingdom). The size of the skin lesions (in square millimeters) was determined using calipers; the largest diameter and the perpendicular diameter were measured and multiplied.
Statistics.
Mean values and the standard deviations were
compared using an unpaired Student's t test. Final
lethality was evaluated with a 
2 test.
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RESULTS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Response of SAP0/0 mice to TNF--induced lethality in
GalN-sensitized and normal mice.
Before we studied the involvement
of SAP in desensitization and tolerization, we examined the effect of
SAP deficiency in both models of TNF--induced lethality. Therefore,
mice were treated with 20 mg of GalN given i.p. in combination with
different doses of mTNF-. In C57BL/6 mice, the 100% lethal dose
(LD100) is usually obtained with 0.3 to 0.5 µg of TNF-
per mouse. In Table 1, we show that both
SAP+/+ and SAP0/0 mice are killed by TNF- in
combination with GalN. No sensitization or protection were observed by
the deletion of SAP.
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(without GalN sensitization),
SAP+/+ and SAP0/0 mice were injected i.v. with
2.5, 10, 20, or 30 µg of mTNF- (the LD100
for C57BL/6 mice is usually around 20 µg per mouse). Both
SAP+/+ and SAP0/0 mice appeared to be equally
sensitive to mTNF--induced lethal shock (Table 1). These data show
that the absence of SAP does not lead to a changed response of mice to
TNF--induced hepatitis or TNF--induced lethal SIRS.
Role of SAP in IL-1-induced desensitization.
Desensitization of mice to TNF--GalN is obtained by pretreatment
with IL-1 12 h before the lethal challenge. As demonstrated in
Fig. 1, serum levels of SAP are
significantly (P < 0.0001) increased, 12 h after
injection of 0.3 µg of IL-1, in SAP+/+ mice only. In
order to study the role of SAP in IL-1-induced desensitization,
SAP+/+ and SAP0/0 mice were injected i.p. with
PBS or different doses of IL-1 (3 to 300 ng per mouse), followed
12 h later by an i.p. injection with 0.5 µg of mTNF-/20 mg of
GalN. For this batch of mice, this dose appeared to be slightly less
than LD100. As demonstrated in Table
2, SAP0/0 mice can be
desensitized just as well as SAP control mice. Also, regarding
protection against a TNF--GalN-induced drop in body temperature,
IL-1 was as active in SAP0/0 mice as in
SAP+/+ mice (data not shown). These data indicate that in
the absence of SAP, IL-1 is also perfectly able to desensitize to
TNF--GalN-induced lethal hepatitis.
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SAP is not involved in hTNF--induced tolerization.
Repetitive injections of small doses of TNF- for 1 week result in
tolerance to a normally lethal dose of TNF- for a period of about 10 days (37). Tolerization was induced by hTNF- injection (6 µg per injection) twice per day (9 a.m. and 6 p.m.) for 5 consecutive days (Monday to Friday). The lethal challenge was given on
day 8 (Monday). Just before the challenge, blood was withdrawn and the
serum SAP levels were measured. As demonstrated in Fig. 1, SAP levels
had significantly risen (P = 0.001) in
SAP+/+ mice and not in SAP0/0 mice.
Furthermore, SAP+/+ mice were indeed found to resist
mTNF--induced lethality by tolerization. In Table
3 we demonstrate that hTNF- is also
able to induce tolerance in SAP0/0 mice. These data
indicate that SAP is not a necessary serum factor for the induction of
tolerance to TNF--induced SIRS.
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Effect of SAP deficiency on TNF--induced hemorrhagic skin
necrosis.
Two s.c. injections (with a 24-h interval) of 1 µg of
mTNF- into the back of mice resulted in the appearance of a local
hemorrhagic necrotic spot 24 h after the second injection. This is
a variation of the Shwartzman reaction as previously described
(33). We treated SAP+/+ as well as
SAP0/0 mice and measured the size of necrosis. We found
that both types of mice equally developed the typical erythema
formation 24 h after the first injection, which developed further
to a necrotic spot 24 h after the second challenge. The size of
the spot was slightly (but not significantly, P = 0.1774) less in SAP0/0 mice than in controls (data not shown).
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DISCUSSION |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Phase I and phase II clinical trials, but also experiments using
laboratory animals, have revealed that the major dose-limiting toxicities of a treatment with TNF- are hypotension, liver damage, and bowel necrosis (5, 8, 19, 36, 41). TNF- is indeed a
powerful proinflammatory cytokine, and inhibition of its
inflammation-inducing properties will most likely also lead to an
increased therapeutic value of TNF- in cancer treatment. In our
laboratory, we are predominantly studying two different mouse models of
TNF--induced lethality. In the first model, recombinant mTNF- is
administered i.v. This leads to SIRS associated with hypotension,
hypothermia, massive adhesion to the endothelium of neutrophils, and
bowel necrosis, eventually leading to lethal shock about 24 h
after the challenge. In the second model, mice are treated with a
combination of TNF- and GalN, a liver-specific inhibitor of
transcription (9). In this model, mice are extremely
sensitized to TNF-, and lethality appears to be the result of
apoptosis and necrosis of the liver (22, 42). This
model resembles viral hepatitis (11, 20).
We believe that, in mammals, several endogenous feedback mechanisms
exist that are capable of reducing or preventing (TNF--induced) inflammation and lethality. Because of the extremely sensitizing effect
of GalN (13, 21, 27) and of partial hepatectomy
(14), we hypothesize that at least part of these feedback
systems are located in the liver.
We are studying the molecular basis of two independent protective
feedback systems: desensitization and tolerance. Desensitization is a
short period of resistance to TNF- or TNF--GalN by a single injection of either TNF- itself or IL-1 (28, 43). We
found that, very likely, IL-1-induced desensitization is the result of induction of one or more proteins in the liver (28). In
the liver, IL-1 is a strong inducer of the acute-phase reaction, both by inducing IL-6 and by inducing glucocorticoids (16, 26, 31,
40, 45). IL-6 is a cytokine that directly provokes an acute-phase
reaction and that induces glucocorticoids (34). But the
latter also induce an acute-phase response (1). Induction, by IL-1, of both IL-6 and glucocorticoids simultaneously leads to a
synergistic effect on the induction of the acute-phase response (7). We previously determined that indeed two of the
acute-phase proteins, viz., 1-acid glycoprotein and
1-antitrypsin, protect against both models of
TNF--induced lethality (25, 29, 42). Tolerance is induced
by repetitive treatment with TNF- itself, given twice per day, for 5 days. After this treatment, mice are resistant to TNF-- but not to
TNF--GalN-induced lethality. An involvement of the liver has not
been described (37, 38).
We describe here our efforts to further characterize the factors that mediate the induction of desensitization as well as tolerization. We have focused our attention on SAP because the latter is, together with serum amyloid A protein, the major acute-phase protein in the mouse. SAP belongs to the family of pentraxins, which have been conserved throughout vertebrate evolution. The homology to C-reactive protein, the classical acute-phase protein in humans, is about 51%. In the mouse, SAP is an acute-phase reactant, while it is constitutively present in humans, with a maximal twofold increase during sepsis (12). SAP shows calcium-dependent binding to DNA (35), chromatin (18), and glycosaminoglycans (17). SAP has also been described to play a role in the complement cascade (4, 6, 15, 44). SAP0/0 mice were found to be protected against induction of amyloidosis by injection of casein (3).
Using SAP0/0 mice, we found that the presence of SAP is
irrelevant to the sensitivity of the animals to a lethal challenge of TNF--GalN or TNF-. These data do not exclude a role of SAP in the induction of protection by desensitization or tolerization. In
fact, we found that after injection of a desensitizing dose of IL-1,
as well as after tolerizing, at the moment the challenge is given,
serum SAP levels are significantly increased (4- and 3.5-fold,
respectively) in SAP+/+ mice only. However, like
SAP+/+ mice, SAP0/0 mice could very well be
desensitized and tolerized, despite the absence of SAP. These data
illustrate that SAP, though a major acute-phase reactant in the mouse
and a potential candidate as a mediator for desensitization and
tolerance, is not involved in both protective mechanisms.
We were also interested in studying the effect of SAP deficiency in a
model of TNF--induced skin hemorrhagic necrosis since it has been
reported that several strains of mice (BALB/c, DBA/2, and A/J) had
>10-fold-higher basal serum levels of SAP compared to C57BL/6 mice
(32) and that these strains failed to develop typical
necrosis (C. Libert, unpublished data). However, a further decrease in
SAP levels to zero in C57BL/6 mice by gene targeting and subsequent
backcross in a C57BL/6 background did not lead to increased sensitivity
to this TNF- effect as previously described.
In conclusion, we found no evidence for a protective role of SAP in
several models of TNF--induced inflammation or lethal shock. Also,
the induction of endogenous protection by the processes of
desensitization and tolerization appears to occur in the absence of SAP.
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ACKNOWLEDGMENTS |
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We thank M. Botto and M. B. Pepys for providing the SAP0/0 mice and J. Vanden Berghe for technical assistance.
W.V.M. is a research assistant and P.B. is a research associate with the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen. T.H. is a fellow with the Vlaams Instituut voor de Bevordering van het Wetenschappelijk-technologisch Onderzoek in de Industrie. This research was supported by the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (grant G023698N) and the Interuniversitaire Attractiepolen.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Ghent, K. L. Ledeganckstraat 35, B-9000 Ghent, Belgium. Phone: 32-9-264-51-31. Fax: 32-9-264-53-48. E-mail: claude{at}dmb.rug.ac.be.
Editor: R. N. Moore
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