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Departments of
*
Medicine and
Surgery, University of Colorado Health Sciences Center, Denver, CO 80262; and Departments of
Medicine and
§
Rheumatology, University Hospital, Nijmegen, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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synthesis, IL-18 also possesses
inflammatory effects by inducing synthesis of the proinflammatory
cytokines TNF and IL-1ß and the chemokines IL-8 and macrophage
inflammatory protein-1
. We hypothesized that neutralization of IL-18
would have a beneficial effect in lethal endotoxemia in mice. IL-1ß
converting enzyme (ICE)-deficient mice, lacking the ability to process
mature IL-18 and IL-1ß, were completely resistant to lethal
endotoxemia induced by LPS derived from either Escherichia
coli or Salmonella typhimurium. In contrast,
both wild-type and IL-1ß-/- mice were equally
susceptible to the lethal effects of LPS, implicating that absence of
mature IL-18 or IFN- but not IL-1ß in ICE-/- mice is
responsible for this resistance. However, IFN--deficient mice were
not resistant to S. typhimurium LPS, suggesting an
IFN--independent role for IL-18. Anti-IL-18 Abs protected mice
against a lethal injection of either LPS. Anti-IL-18 treatment also
reduced neutrophil accumulation in liver and lungs. The increased
survival was accompanied by decreased levels of IFN- and macrophage
inflammatory protein-2 in anti-IL-18-treated animals challenged
with E. coli LPS, whereas IFN- and TNF concentrations
were decreased in treated mice challenged with S.
typhimurium. In conclusion, neutralization of IL-18 during
lethal endotoxemia protects mice against lethal effects of LPS. This
protection is partly mediated through inhibition of IFN- production,
but mechanisms involving decreased neutrophil-mediated tissue damage
due to the reduction of either chemokines (E. coli LPS)
or TNF (S. typhimurium LPS) synthesis by anti-IL-18
treatment may also be involved. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and IL-1ß and the chemokines IL-8, macrophage inflammatory
protein-1
(MIP-1),3 and MIP-2
(2, 3). Stimulation of cytokines and chemokines is of
pivotal importance in the pathogenesis of sepsis because they are
believed to be the main endogenous mediators of organ injury in
endotoxic shock (1, 2). IL-18 (initially described as
IFN--inducing factor) is a newly discovered proinflammatory cytokine
that serves as a costimulus for IFN- production in the context of
microbial stimulation of macrophage cytokines such as IL-12
(4). IL-18 is synthesized as an inactive precursor that
requires cleavage by IL-1ß converting enzyme (ICE, caspase-1) to
release the mature active form (5, 6). ICE-deficient
(ICE-/-) mice lacking both mature IL-18 and
IL-1ß are protected against lethal endotoxemia. The fact that
IL-1ß-/- mice are susceptible to lethal
endotoxemia (7) suggests that the protection of
ICE-deficient animals is mediated by the lack of mature IL-18 or
IFN-. However, controversial data exist regarding the susceptibility
of IFN--R-/- mice to LPS (8, 9), suggesting that IFN--independent mechanisms also may be
involved in the modulatory activity of IL-18.
Although IL-18 exerts some of its proinflammatory effects through
induction of IFN-, recent data suggest that IL-18 has direct
proinflammatory properties. In this respect, IL-18 stimulates
activation of NF-
B (10), induces production of
proinflammatory cytokines such as TNF and IL-1ß and chemokines such
as IL-8 and MIP-1 (11), and up-regulates expression of
adhesion molecules such as ICAM-1 (12). The hypothesis
that these direct inflammatory effects may contribute to disease
prompted us to investigate the role of IL-18 in lethal endotoxemia. We
have assessed the effect of IL-18 neutralization in endotoxic shock
using two methods: the use of ICE-/- mice known
to be deficient in mature active IL-18 (5, 6) and
neutralization of IL-18 by treatment with anti-IL-18 Abs. Because
the precise effects of Escherichia coli and Salmonella
typhimurium LPS in various types of knock-out mice are divergent
(8, 9), suggesting differential pathogenic mechanisms
involved in mortality induced by these two species of LPS, we have
assessed the effect of IL-18 blockade in mice challenged with either
E. coli or S. typhimurium LPS. We have
investigated the mechanisms through which anti-IL-18 strategies may
beneficially influence the course of lethal endotoxemia.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LPS (E. coli serotype O55:B5, catalog no. L4005; and
S. typhimurium, catalog no. L1519) was obtained from Sigma
(St. Louis, MO). The anti-IL-18 antiserum was obtained from a New
Zealand rabbit immunized by intradermal injection of murine IL-18
(PeproTech, Princeton, NJ) in the presence of Hunter’s Titermax
adjuvant. This Ab has been shown to inhibit LPS-induced IFN-
production in vivo (13).
Animals
The in vivo experimental studies were approved by the Animal Use
and Care Committee at the University of Colorado Health Sciences
Center. The generation and background of ICE-/-
and IL-1ß-/- mice were previously described
(14, 15). The wild-type mice used as controls were of the
same genetic background, sex, and age as the knock-out mice.
IFN--/- mice and their wild-type littermates
were a kind gift from Organon (Oss, The Netherlands). C57BL/6J mice
were obtained from Taconic Laboratory (Germantown, NY). For the
experiments, 6- to 8-wk-old mice weighing 20–25 g were used. The
animals were fed standard laboratory food and were housed under
specific pathogen-free conditions.
Lethal endotoxemia model
Knock-out and control mice were injected i.p. with LPS suspended
in PBS (40 mg/kg unless otherwise indicated). In separate experiments,
C57BL/6J mice were treated i.p. with 200 µl of either normal rabbit
serum (NRS) as control or anti-IL-18 antiserum 30 min before the
LPS administration. The neutralizing characteristics of the
anti-IL-18 antiserum were previously reported for in vitro
(13) and in vivo (16) experiments. Ninety
minutes after challenge with LPS, five animals from each group were
anesthetized with ether and were bled from the retroorbital plexus for
measurement of TNF- and MIP-2 circulating concentrations. Another
five animals per group were bled 6 h after LPS challenge for the
measurement of IFN- circulating concentrations. In addition, lungs
and livers from the sacrificed mice were aseptically removed, placed
into liquid nitrogen, and stored at -70°C. Half of the tissue
material was used for myeloperoxidase (MPO) measurements, and the rest
was used for tissue cytokine determinations. For cytokine measurements,
the tissue was suspended and homogenized 1:4 (w:v) in sterile PBS
containing 0.1% Tween 20 and centrifuged at 20,000 x
g for 15 min, and the supernatant was collected and stored
at -70°C until assay. In the remaining mice (5–7 animals/group),
survival was assessed daily for 7 days.
Cytokine measurements
Murine IL-18 was measured by electrochemiluminescence as
previously described (45). Murine TNF concentrations were assessed by
electrochemiluminescence (17). The detection limits were
160 pg/ml (IL-18) and 62 pg/ml (TNF). IFN- measurements were
performed with an ELISA kit (Endogen, Woburn, MA) (detection limit 20
pg/ml). MIP-2 concentrations were measured using a commercial ELISA kit
(Quantikine, R&D Systems, Minneapolis, MN) with a detection limit of 7
pg/ml.
MPO assay
The content of MPO in the tissues was measured as previously described (18). Briefly, organs were weighed and then either both lungs or a segment of the liver (150–200 mg of tissue) was homogenized by a Virtishear homogenizer (Virtis, Gardner, NY) for 30 s in 4 ml of 20 mM potassium phosphate buffer (pH 7.4) and then centrifuged for 30 min at 40,000 x g at 4°C in a Beckman L-80 Ultracentrifuge (Beckman Instruments, Palo Alto, CA). The pellet was resuspended in 4 ml of 50 mM potassium phosphate buffer (pH 6.0) containing 0.5g/dl cetrimonium bromide. The samples were sonicated for 90 s at full power with an Ultrasonic homogenizer (Cole-Parmer Instrument, Chicago, IL), incubated in a 60°C water bath for 2 h, and centrifuged for 10 min at 20,000 x g. The supernatant (25 µl) was added to 725 µl of 50 mM phosphate buffer (pH 6.0) containing 0.167 mg/ml o-dianisidine (Sigma) and 5 x 10-4% hydrogen peroxide. Absorbance of 460 nm visible light was measured between 1 and 3 min with a Beckman DU7 spectrophotometer (Beckman Instruments, Irvine, CA). MPO activity per gram of wet tissue was calculated as: MPO activity (U/g wet tissue) = (A460)(13.5)/tissue weight (g), where A460 is the change in the absorbance of 460 nm light from 1 to 3 min after the initiation of the reaction. The coefficient 13.5 was empirically determined such that 1 U MPO activity is the amount of enzyme that will reduce 1 µmol peroxide/min.
Statistical analysis
The differences between groups were analyzed by Mann-Whitney U test and, if appropriate, by Kruskal-Wallis ANOVA test. Survival curves were analyzed by the Kaplan-Meyer log-rank test. Experiments were performed twice on two separate occasions, and the data are presented as cumulative results of both experiments.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All wild-type and IL-1ß-/- mice injected
with 40 mg/kg LPS died within 5 days after the endotoxin challenge
(Fig. 1
, A and B).
In contrast, ICE-/- mice were completely
protected against the lethal effects of LPS derived either from
E. coli or from S. typhimurium LPS (Fig. 1, A and B). None of the wild-type or knockout mice
died when they were injected with 20 mg/kg LPS (n = 4
wild-type mice and n = 5 each for
IL-1ß-/- and ICE-/-
mice). These data suggest that the protection of
ICE-/- mice to the lethal effects of LPS is
mediated through the lack of mature IL-18, presumably resulting in the
reduced production of IFN-. However, the hypothesis that the
ICE-/- mice are protected due to the lack of
IFN- is not supported by the observation that
IFN--/- mice were only partially protected
against lethal endotoxemia induced by E. coli LPS (Fig. 1C) and were totally susceptible to S.
typhimurium LPS (Fig. 1D).
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production. C57BL/6J mice were injected
with E. coli LPS after pretreatment with a neutralizing
rabbit anti-mouse IL-18 Ab. Treatment of C57BL/6J mice with
anti-IL-18 antiserum completely prevented the mortality induced by
40 mg/kg E. coli LPS (100% survival after anti-IL-18
treatment vs 10% survival in NRS-treated mice; p <
0.05; Fig. 2A). It is of
considerabe importance that anti-IL-18-treated mice were also
protected against S. typhimurium lethal effects (50% vs 0%
survival; p < 0.05; Fig. 2B).
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In healthy mice, circulating concentrations of IL-18 were under the detection limit of the assay (160 pg/ml). In contrast, constitutive expression of IL-18 was measured in the lungs (6020 ± 456 pg/g) and liver (9928 ± 1204 pg/g) of healthy mice. LPS challenge induced circulating IL-18 in the bloodstream of septic mice 90 min after endotoxin administration (273 ± 41 pg/ml after E. coli LPS and 279 ± 54 pg/ml after S. typhimurium LPS). At all other time points (30 min–24h), circulating IL-18 concentrations were below the detection limit of the assay. Ninety minutes after Salmonella LPS, there was an increase in the IL-18 content of the lung and liver (14,326 ± 1,737 and 13,111 ± 993 pg/g, respectively; p < 0.05), whereas E. coli LPS stimulation led to an increase in IL-18 levels only in the lungs (9,757 ± 1,028 pg/g; p = 0.06) and led to a significant decrease in IL-18 levels in the liver (5,027 ± 260 pg/g; p < 0.05).
The effect of anti-IL-18 treatment on the in vivo proinflammatory cytokine production
C57BL/6J mice were injected i.p. with 40 mg/kg LPS, and blood was
drawn 90 min and 6 h later for cytokine measurements.
Administration of the anti-IL-18 Abs did not influence TNF serum
concentrations measured 90 min after E. coli LPS
administration (Fig. 3A). In
contrast, TNF concentrations 90 min after S. typhimurium
injection were higher compared with the levels obtained after E.
coli LPS, and they were significantly diminished by the
anti-IL-18 treatment (Fig. 3A). IFN- circulating
concentrations measured 6 h after the injection of both LPS
species were significantly decreased by treatment of mice with
anti-IL-18 antiserum compared with the levels in NRS-treated
animals (Fig. 3B). It is important to note that the
anti-IL-18 Ab was more effective in reducing IFN- activation
after E. coli LPS (92% inhibition; p <
0.01) than it was after S. typhimurium LPS (48% inhibition;
p < 0.05).
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To assess the effect of anti-IL-18 treatment on LPS-induced
lung and liver neutrophil accumulation, we assessed the MPO content in
these two organs 6 h after LPS challenge. As shown in Fig. 4, LPS injection dramatically increased
MPO content in the lungs and liver. However, whereas E. coli
LPS was more effective than S. typhimurium LPS in increasing
MPO content of the lung, the latter induced more MPO in the liver.
Compared with NRS, treatment of mice with anti-IL-18 Abs
significantly reduced the MPO levels in the lungs of mice challenged
with E. coli but not of those challenged with S.
typhimurium LPS (Fig. 4A). In contrast, anti-IL-18
significantly reduced hepatic MPO after E. coli LPS (79%;
p < 0.05) and S. typhimurium LPS (61%;
p < 0.05) (Fig. 4B).
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Because neutrophil accumulation in the organs is largely dependent
on chemokines such as MIP-2, we investigated the content of this
chemokine in the lungs and liver of mice treated with anti-IL-18
and challenged with LPS. In mice injected with E. coli LPS,
anti-IL-18 treatment reduced MIP-2 expression in the lungs (52%
decrease; p < 0.05) and liver (49% decrease;
p < 0.05) (Fig. 5). In
contrast, no effects of anti-IL-18 Ab on MIP-2 synthesis after
S. typhimurium LPS injection were apparent (Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production,
particularly after E. coli LPS (13), which is
consistent with IFN--/- mice being partially
resistant to lethal E. coli LPS, 2) inhibition of MIP-2
production in tissues of mice challenged with E. coli LPS
probably resulted in decreased neutrophil infiltration, 3) the
beneficial effects of anti-IL-18 administration during S.
typhimurium endotoxemia may be mediated through decreased
production of TNF, leading to protection against liver injury, 4)
anti-IL-18 treatment likely reduces ICAM-1 expression
(12), and 5) because IL-18 induces Fas ligand expression
which plays an important role in hepatic toxicity (20),
inhibition of IL-18 may decrease liver toxicity through inhibition of
Fas ligand expression.
The requirement for IL-18 in IFN- production induced by bacterial
components has been shown in studies reporting the absence of processed
mature IL-18 (5, 6), administration of neutralizing
anti-IL-18 Abs (13, 21), or IL-18 binding protein
(22) in experimental animals. In most of these reports,
absence of IFN- was observed despite the presence of IL-12. The
essential role for IL-18 in IFN- production induced by LPS has been
confirmed in IL-18-deficient mice (23).
The importance of IL-18 as a proinflammatory cytokine is suggested by
experiments in which pretreatment with an anti-IL-18 Ab protected
against LPS-induced liver injury (21). A similar
protection was reported in IL-18-/- mice
(24). Although ICE-/- mice lacking
mature forms of IL-18 and IL-1ß are completely resistant to lethal
endotoxemia as shown in the present study and by others (5, 6), IL-1ß-/- mice are not
(7). Therefore, it has been proposed that the absence of
mature, active IL-18 determines the resistance of
ICE-/- mice via reduced IFN- production.
However, in the case of S. typhimurium LPS, we have found
that IFN--/- mice are not protected against
endotoxemia in that others have reported that absence of IFN--R does
not afford protection (9). One disadvantage of experiments
performed in knock-out mice may be the modified homeostasis due to the
absence of some genes, which may lead to multiple abnormalities.
Indeed, ICE-/- and
IFN--/- mice lack not only mature IL-1ß,
but also lack mature IL-18 and IFN-; in addition, production of
other cytokines such as , IL-1, TNF, and IL-6 is also impaired
compared with their wild-type counterparts (14, 25). In
contrast, this is not the case for the
IL-1ß-/- mice (26). Therefore,
our experiments with anti-IL-18 Abs are crucial, and these
experiments suggest that our conclusions regarding the role of IL-18 in
lethal endotoxemia are valid. Indeed, administration of an
anti-IL-18 polyclonal Ab protected mice against the deleterious
effects of both LPS species tested, supporting the concept that IL-18
has an important pathogenic role in both species of lethal
endotoxemia.
The beneficial effect of the anti-IL-18 Ab is consistent with the study of Xu et al. (27), showing protection against lethality induced by Salmonella LPS using an anti-IL-18 receptor Ab. Interestingly, this contrasts with the observation of Sakao et al. (24), who reported an increased mortality of IL-18-/- mice in the Propionibacterium acnes-sensitization LPS model, despite protection of animals against liver injury. However, this model is different from the model of high-dose LPS used by Xu et al. (27) and by us in the present study. The use of IL-18 knock-out mice adds a new variable to the experimental outcome because deficient animals probably up-regulate other cytokines and cytokine receptors, with subsequent hyperreactivity to inflammatory stimuli as has been shown for other proinflammatory cytokine knock-out mouse strains (28).
In contrast to E. coli LPS, it is unlikely that IFN-
plays an important role in the protection afforded by anti-IL-18
Abs after S. typhimurium LPS. After S.
typhimurium, we observed only a moderate inhibition of IFN-
synthesis by the anti-IL-18 and a lack of resistance in
IFN--/- mice. Other studies support our
observation because mice deficient in IFN--R are also susceptible to
lethal S. typhimurium LPS injection (9).
Whereas anti-IL-18 had no effect on circulating TNF levels induced
by E. coli LPS, the Ab significantly decreased levels of TNF
(55%; p < 0.02) after challenge of mice with S.
typhimurium LPS. This suggests that the effect of anti-IL-18
during S. typhimurium endotoxemia may be at least in part
due to inhibition of TNF.
Lung and liver injury during endotoxemia is largely mediated through
neutrophil accumulation (29, 30), which can be assessed by
the MPO content in the respective tissues (19).
Interestingly, E. coli LPS induced more neutrophil
infiltration in the lungs compared with S. typhimurium LPS,
whereas the latter was more effective in promoting neutrophil
accumulation in the liver. Treatment of mice with anti-IL-18 Abs
before challenge with E. coli LPS was accompanied by a
significant decrease in the lung and liver MPO content compared with
that of mice challenged with LPS that did not receive anti-IL-18.
The anti-IL-18-associated decrease in MPO content may have been
mediated through diminished chemokine production in these animals.
Indeed, the reduction in the neutrophil infiltration of lung and liver
in the anti-IL-18-treated mice after E. coli LPS
challenge was accompanied by a decrease in MIP-2 levels in the organs
of IL-18-treated animals compared with those of controls. Therefore, it
is conceivable that part of the effects of anti-IL-18 treatment
during E. coli endotoxemia is IFN--independent and
mediated through decreased MIP-2 expression. In contrast, we suggest
that the beneficial effect of anti-IL-18 treatment in S.
typhimurium endotoxemia is mediated by the reduction in
circulating TNF concentrations, which is supported by the observed
effect of anti-IL-18 on MPO. Although anti-IL-18 treatment
significantly decreased the MPO content of the liver after S.
typhimurium challenge, it had no influence on the MPO content of
the lungs. This pattern is consistent with the decreased TNF
concentration after anti-IL-18 Ab treatment during S.
typhimurium endotoxemia in that TNF has been shown to be involved
in LPS-mediated liver damage (31) but not lung injury
(32).
The present observations of differential responses to these two LPS species may have important theoretical consequences. The two species differ not only at the level of the polysaccharide chains but also at the level of lipid A. Compared with E. coli lipid A, lipid A from Salmonella contains an additional fatty acid (33) and different phosphate groups (34). Because lipid A binding to LPS binding protein (LBP) and CD14 results in cytokine production (35), it is not surprising that differences in the structure of lipid A may stimulate a different combination of cytokines. An additional argument is provided by studies performed in LBP-deficient (LBP-/-) mice. These mice responded with reduced cytokine production after stimulation with S. abortus equi LPS (36) compared with that after E. coli LPS (37). This differential cytokine response of LBP-/- mice to E. coli or Salmonella LPS raises the interesting possibility that these two LPS species may interact differently with the various Toll-like receptors (TLRs) known to be involved in the intracellular signaling induced by LPS (38, 39). In support of this hypothesis are the data of Yang et al. (38), which show that Salmonella-derived LPS is much more potent in inducing cytokines through TLR2 compared with E. coli LPS, whereas the two types of LPS are equally potent in inducing cytokines through TLR4 (40). Alternatively, differences between the two LPS preparations may be due to quantitative and/or qualitative differences in the "endotoxin-associated proteins." In our experiments, we have used commercial LPS chromatographically purified by gel filtration with a protein content less than 1%. However, even very small amounts of endotoxin-associated proteins may influence cytokine induction by LPS, as previously suggested by some (41) although not all (42) authors. Despite the fact that we used E. coli and S. typhimurium LPS isolated and purified by identical methods, suggesting that protein contamination is similar for both preparations, we cannot exclude a role of these endotoxin-associated proteins in the biological activities of the various LPS used. However, the importance of our data remains valid regardless of the exact source of differences between the two LPS used (differences in either the lipid A structure or the endotoxin-associated proteins) because these preparations have been used in all models of lethal endotoxemia reported in the literature. Therefore, our data on the differences in the cytokine network and pathogenic mechanisms between these two types of LPS are likely to explain some of the contradictory data in the literature such as resistance of TNF-/- mice to E. coli but not to Salmonella LPS (43, 44). The capacity of anti-IL-18 treatment to induce resistance against both of these two species of LPS underscores the importance of IL-18 as a regulator of pathological mechanisms in lethal endotoxemia.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Charles A. Dinarello, Division of Infectious Diseases, B168, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262.
3 Abbreviations used in this paper: MIP, macrophage inflammatory protein; ICE, IL-1ß converting enzyme; MPO, myeloperoxidase; NRS, normal rabbit serum; LBP, LPS binding protein; TLR, Toll-like receptor.
Received for publication August 11, 1999. Accepted for publication December 20, 1999.
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J. R. Maxwell, R. Yadav, R. J. Rossi, C. E. Ruby, A. D. Weinberg, H. L. Aguila, and A. T. Vella IL-18 Bridges Innate and Adaptive Immunity through IFN-{gamma} and the CD134 Pathway J. Immunol., July 1, 2006; 177(1): 234 - 245. [Abstract] [Full Text] [PDF]
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 C. A Dinarello Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process Am. J. Clinical Nutrition, February 1, 2006; 83(2): 447S - 455S. [Abstract] [Full Text] [PDF]
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R. W. DePaolo, R. Lathan, B. J. Rollins, and W. J. Karpus The Chemokine CCL2 Is Required for Control of Murine Gastric Salmonella enterica Infection Infect. Immun., October 1, 2005; 73(10): 6514 - 6522. [Abstract] [Full Text] [PDF]
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 A. R. Kitching, A. L. Turner, G. R.A. Wilson, T. Semple, D. Odobasic, J. R. Timoshanko, K. M. O'Sullivan, P. G. Tipping, K. Takeda, S. Akira, et al. IL-12p40 and IL-18 in Crescentic Glomerulonephritis: IL-12p40 is the Key Th1-Defining Cytokine Chain, Whereas IL-18 Promotes Local Inflammation and Leukocyte Recruitment J. Am. Soc. Nephrol., July 1, 2005; 16(7): 2023 - 2033. [Abstract] [Full Text] [PDF]
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S. M. Zughaier, S. M. Zimmer, A. Datta, R. W. Carlson, and D. S. Stephens Differential Induction of the Toll-Like Receptor 4-MyD88-Dependent and -Independent Signaling Pathways by Endotoxins Infect. Immun., May 1, 2005; 73(5): 2940 - 2950. [Abstract] [Full Text] [PDF]
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S. N. Rana, X. Li, I. H. Chaudry, K. I. Bland, and M. A. Choudhry Inhibition of IL-18 reduces myeloperoxidase activity and prevents edema in intestine following alcohol and burn injury J. Leukoc. Biol., May 1, 2005; 77(5): 719 - 728. [Abstract] [Full Text] [PDF]
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 W. Wang, S. Faubel, D. Ljubanovic, A. Mitra, S. A. Falk, J. Kim, Y. Tao, A. Soloviev, L. L. Reznikov, C. A. Dinarello, et al. Endotoxemic acute renal failure is attenuated in caspase-1-deficient mice Am J Physiol Renal Physiol, May 1, 2005; 288(5): F997 - F1004. [Abstract] [Full Text] [PDF]
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H. Shirota, I. Gursel, M. Gursel, and D. M. Klinman Suppressive Oligodeoxynucleotides Protect Mice from Lethal Endotoxic Shock J. Immunol., April 15, 2005; 174(8): 4579 - 4583. [Abstract] [Full Text] [PDF]
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 M. Lamkanfi, G. Denecker, M. Kalai, K. D'hondt, A. Meeus, W. Declercq, X. Saelens, and P. Vandenabeele INCA, a Novel Human Caspase Recruitment Domain Protein That Inhibits Interleukin-1{beta} Generation J. Biol. Chem., December 10, 2004; 279(50): 51729 - 51738. [Abstract] [Full Text] [PDF]
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C. Nakasone, K. Kawakami, T. Hoshino, Y. Kawase, K. Yokota, K. Yoshino, K. Takeda, S. Akira, and A. Saito Limited Role for Interleukin-18 in the Host Protection Response to Pulmonary Infection with Pseudomonas aeruginosa in Mice Infect. Immun., October 1, 2004; 72(10): 6176 - 6180. [Abstract] [Full Text] [PDF]
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 B. Liu, I. Mori, M. J. Hossain, L. Dong, K. Takeda, and Y. Kimura Interleukin-18 improves the early defence system against influenza virus infection by augmenting natural killer cell-mediated cytotoxicity J. Gen. Virol., February 1, 2004; 85(2): 423 - 428. [Abstract] [Full Text] [PDF]
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M. P. Gould, J. A. Greene, V. Bhoj, J. L. DeVecchio, and F. P. Heinzel Distinct Modulatory Effects of LPS and CpG on IL-18-Dependent IFN-{gamma} Synthesis J. Immunol., February 1, 2004; 172(3): 1754 - 1762. [Abstract] [Full Text] [PDF]
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V. Cusumano, A. Midiri, V. V. Cusumano, A. Bellantoni, G. De Sossi, G. Teti, C. Beninati, and G. Mancuso Interleukin-18 Is an Essential Element in Host Resistance to Experimental Group B Streptococcal Disease in Neonates Infect. Immun., January 1, 2004; 72(1): 295 - 300. [Abstract] [Full Text] [PDF]
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A. W. M. van der Velden, M. Velasquez, and M. N. Starnbach Salmonella Rapidly Kill Dendritic Cells via a Caspase-1- Dependent Mechanism J. Immunol., December 15, 2003; 171(12): 6742 - 6749. [Abstract] [Full Text] [PDF]
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G. Fantuzzi, N. K. Banda, C. Guthridge, A. Vondracek, S.-H. Kim, B. Siegmund, T. Azam, J. A. Sennello, C. A. Dinarello, and W. P. Arend Generation and characterization of mice transgenic for human IL-18-binding protein isoform a J. Leukoc. Biol., November 1, 2003; 74(5): 889 - 896. [Abstract] [Full Text] [PDF]
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 T. Hoshino, H. Nakamura, M. Okamoto, S. Kato, S. Araya, K. Nomiyama, K. Oizumi, H. A. Young, H. Aizawa, and J. Yodoi Redox-active Protein Thioredoxin Prevents Proinflammatory Cytokine- or Bleomycin-induced Lung Injury Am. J. Respir. Crit. Care Med., November 1, 2003; 168(9): 1075 - 1083. [Abstract] [Full Text] [PDF]
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S. Weijer, M. E. Sewnath, A. F. de Vos, S. Florquin, K. van der Sluis, D. J. Gouma, K. Takeda, S. Akira, and T. van der Poll Interleukin-18 Facilitates the Early Antimicrobial Host Response to Escherichia coli Peritonitis Infect. Immun., October 1, 2003; 71(10): 5488 - 5497. [Abstract] [Full Text] [PDF]
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M. J. Schultz, S. Knapp, S. Florquin, J. Pater, K. Takeda, S. Akira, and T. van der Poll Interleukin-18 Impairs the Pulmonary Host Response to Pseudomonas aeruginosa Infect. Immun., April 1, 2003; 71(4): 1630 - 1634. [Abstract] [Full Text]
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V. D. Joshi, D. V. Kalvakolanu, J. R. Hebel, J. D. Hasday, and A. S. Cross Role of Caspase 1 in Murine Antibacterial Host Defenses and Lethal Endotoxemia Infect. Immun., December 1, 2002; 70(12): 6896 - 6903. [Abstract] [Full Text] [PDF]
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S. J. Rowe, L. Allen, V. C. Ridger, P. G. Hellewell, and M. K. B. Whyte Caspase-1-Deficient Mice Have Delayed Neutrophil Apoptosis and a Prolonged Inflammatory Response to Lipopolysaccharide-Induced Acute Lung Injury J. Immunol., December 1, 2002; 169(11): 6401 - 6407. [Abstract] [Full Text] [PDF]
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V. D. Joshi, D. V. Kalvakolanu, J. D. Hasday, R. J. Hebel, and A. S. Cross IL-18 Levels and the Outcome of Innate Immune Response to Lipopolysaccharide: Importance of a Positive Feedback Loop with Caspase-1 in IL-18 Expression J. Immunol., September 1, 2002; 169(5): 2536 - 2544. [Abstract] [Full Text] [PDF]
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T. H. Wyman, C. A. Dinarello, A. Banerjee, F. Gamboni-Robertson, A. A. Hiester, K. M. England, M. Kelher, and C. C. Silliman Physiological levels of interleukin-18 stimulate multiple neutrophil functions through p38 MAP kinase activation J. Leukoc. Biol., August 1, 2002; 72(2): 401 - 409. [Abstract] [Full Text] [PDF]
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 C. D. Raeburn, C. A. Dinarello, M. A. Zimmerman, C. M. Calkins, B. J. Pomerantz, R. C. McIntyre Jr., A. H. Harken, and X. Meng Neutralization of IL-18 attenuates lipopolysaccharide-induced myocardial dysfunction Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H650 - H657. [Abstract] [Full Text] [PDF]
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J. Fierer, M. A. Swancutt, D. Heumann, and D. Golenbock The Role of Lipopolysaccharide Binding Protein in Resistance to Salmonella Infections in Mice J. Immunol., June 15, 2002; 168(12): 6396 - 6403. [Abstract] [Full Text] [PDF]
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R. J. L. Stuyt, M. G. Netea, I. Verschueren, G. Fantuzzi, C. A. Dinarello, J. W. M. Van der Meer, and B. J. Kullberg Role of Interleukin-18 in Host Defense against Disseminated Candida albicans Infection Infect. Immun., June 1, 2002; 70(6): 3284 - 3286. [Abstract] [Full Text] [PDF]
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X. Huang, S. A. McClellan, R. P. Barrett, and L. D. Hazlett IL-18 Contributes to Host Resistance Against Infection with Pseudomonas aeruginosa Through Induction of IFN-{gamma} Production J. Immunol., June 1, 2002; 168(11): 5756 - 5763. [Abstract] [Full Text] [PDF]
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 H. Tanaka, M. Narita, S. Teramoto, T. Saikai, K. Oashi, T. Igarashi, and S. Abe Role of Interleukin-18 and T-helper Type 1 Cytokines in the Development of Mycoplasma pneumoniae Pneumonia in Adults* Chest, May 1, 2002; 121(5): 1493 - 1497. [Abstract] [Full Text] [PDF]
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B. Wang, C. Feliciani, B. G. Howell, I. Freed, Q. Cai, H. Watanabe, and D. N. Sauder Contribution of Langerhans Cell-Derived IL-18 to Contact Hypersensitivity J. Immunol., April 1, 2002; 168(7): 3303 - 3308. [Abstract] [Full Text] [PDF]
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 R. L. Santos, S. Zhang, R. M. Tsolis, A. J. Baumler, and L. G. Adams Morphologic and Molecular Characterization of Salmonella typhimurium Infection in Neonatal Calves Vet. Pathol., March 1, 2002; 39(2): 200 - 215. [Abstract] [Full Text] [PDF]
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 M. Okamoto, S. Kato, K. Oizumi, M. Kinoshita, Y. Inoue, K. Hoshino, S. Akira, A. N. J. Mckenzie, H. A. Young, and T. Hoshino Interleukin 18 (IL-18) in synergy with IL-2 induces lethal lung injury in mice: a potential role for cytokines, chemokines, and natural killer cells in the pathogenesis of interstitial pneumonia Blood, February 15, 2002; 99(4): 1289 - 1298. [Abstract] [Full Text] [PDF]
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F. N. Lauw, J. Branger, S. Florquin, P. Speelman, S. J. H. van Deventer, S. Akira, and T. van der Poll IL-18 Improves the Early Antimicrobial Host Response to Pneumococcal Pneumonia J. Immunol., January 1, 2002; 168(1): 372 - 378. [Abstract] [Full Text] [PDF]
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R. Faggioni, R. C. Cattley, J. Guo, S. Flores, H. Brown, M. Qi, S. Yin, D. Hill, S. Scully, C. Chen, et al. IL-18-Binding Protein Protects Against Lipopolysaccharide- Induced Lethality and Prevents the Development of Fas/Fas Ligand-Mediated Models of Liver Disease in Mice J. Immunol., November 15, 2001; 167(10): 5913 - 5920. [Abstract] [Full Text] [PDF]
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 C A Dinarello Novel targets for interleukin 18 binding protein Ann Rheum Dis, November 1, 2001; 60(90003): iii18 - 24. [Abstract] [Full Text] [PDF]
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D. G. Mordue, F. Monroy, M. La Regina, C. A. Dinarello, and L. D. Sibley Acute Toxoplasmosis Leads to Lethal Overproduction of Th1 Cytokines J. Immunol., October 15, 2001; 167(8): 4574 - 4584. [Abstract] [Full Text] [PDF]
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F. N. Lauw, S. Florquin, P. Speelman, S. J. H. van Deventer, and T. van der Poll Role of Endogenous Interleukin-12 in Immune Response to Staphylococcal Enterotoxin B in Mice Infect. Immun., September 1, 2001; 69(9): 5949 - 5952. [Abstract] [Full Text] [PDF]
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B. P. Leung, S. Culshaw, J. A. Gracie, D. Hunter, C. A. Canetti, C. Campbell, F. Cunha, F. Y. Liew, and I. B. McInnes A Role for IL-18 in Neutrophil Activation J. Immunol., September 1, 2001; 167(5): 2879 - 2886. [Abstract] [Full Text] [PDF]
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L. A. B. Joosten, F. A. J. van de Loo, E. Lubberts, M. M. A. Helsen, M. G. Netea, J. W. M. van der Meer, C. A. Dinarello, and W. B. van den Berg An IFN-{gamma}-Independent Proinflammatory Role of IL-18 in Murine Streptococcal Cell Wall Arthritis J. Immunol., December 1, 2000; 165(11): 6553 - 6558. [Abstract] [Full Text] [PDF]
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 M. Narita, H. Tanaka, S. Abe, S. Yamada, M. Kubota, and T. Togashi Close Association between Pulmonary Disease Manifestation in Mycoplasma pneumoniae Infection and Enhanced Local Production of Interleukin-18 in the Lung, Independent of Gamma Interferon Clin. Vaccine Immunol., November 1, 2000; 7(6): 909 - 914. [Abstract] [Full Text] [PDF]
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C. A Dinarello Targeting interleukin 18 with interleukin 18 binding protein Ann Rheum Dis, November 1, 2000; 59(90001): i17 - 20. [Abstract] [Full Text] [PDF]
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) or anti-IL-18
antiserum (
) 30 min before LPS administration (40 mg/kg i.p.).
A, Circulating TNF at 90 min. B,
Circulating IFN-
