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-Dependent and -Independent Mechanisms in Adverse Effects Caused by Concomitant Administration of IL-18 and IL-12
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Fujisaki Cell Center and
Fujisaki Institute, Hayashibara Biochemical Laboratories, Inc., Okayama City, Okayama, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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level in the serum. Since
treatment with IL-18 alone did not have any apparent toxicity, and
treatment with IL-12 alone showed only limited toxicity in our system,
the synergy between the two cytokines was all the more remarkable. The
major symptoms of the toxicity were weight loss, diarrhea, hemorrhagic
colitis, splenomegaly, fatty liver, and atrophic thymus, most of which
are similarly found in endotoxin-induced septic shock. However, in
contrast to septic shock, TNF-
was not induced. The involvement of
IFN- in the toxicity was further studied in detail. Treatment of
athymic nude mice with anti-asialo-GM1 did not reduce the toxicity,
whereas anti-IFN- treatment of wild-type mice alleviated it.
When IFN--deficient mice were treated with IL-18/IL-12, the majority
of them showed mortality and toxicity with severe pulmonary edema.
These results indicate that IL-18/IL-12 treatment induces severe
adverse effects through not only IFN--dependent mechanisms but also
IFN--independent processes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and to
activate NK cells and T cells is comparable with or in some cases
greater than that of IL-12 (1, 5, 6, 7). The amino acid
sequence of IL-18 contains an IL-1 signature-like sequence and shows
15% homology at the amino acid level with the IL-1ß protein
(5, 8). Also, IL-18 requires caspase 1 (IL-1ß-converting
enzyme), as does IL-1ß, to produce mature protein
(9, 10, 11). Despite these similarities, IL-18 should be
distinguished from IL-12 or IL-1ß because its receptor, designated
IL-1Rrp, is specific for IL-18, but not for IL-12 or IL-1ß
(12). As a multifunctional cytokine, the roles of IL-18 have been described in both physiological and pathological processes. As an immunopotentiating factor, IL-18 is required for the development of both NK cells and Th1 cells, as shown in experiments with IL-18 gene knockout mice (13). Dao et al. (14) showed that IL-18 was also a potent factor for NK-T cell activation. The important role of endogenous IL-18 in the host defense mechanism was demonstrated in an anti-IL-18 Ab experiment for Salmonella infection (15). Also, exogenous IL-18 treatment was shown to be effective in antivirus (16, 17), antifungus (18), and antitumor (19) experimental systems. As for pathological aspects, the involvement of IL-18 was demonstrated in LPS-induced liver injury models (20), an autoimmune disease model (21, 22), and arthritis diseases (23).
One of several intriguing characteristics of IL-18 is its synergistic
function with IL-12, as demonstrated in a variety of experimental
systems. In in vitro systems, IL-18 and IL-12 synergistically activate
T cells (6, 7), B cells (24, 25), macrophages
(26), and NK cells (27) to produce IFN-.
Also, in in vivo experiments, synergistic antitumor activities of
IL-18/IL-12 have been demonstrated by the administration of proteins
(28) or by the inoculation of gene-transfected cells
(29). A preventive function was also shown in a mouse
model of allergic asthma with IL-18/IL-12 combination treatment
(30). However, in the course of analyzing the in vivo
effects of IL-18/IL-12, we found that severe and synergistic toxicity
of the cytokines accompanied marked induction of IFN-. In the
present study we investigated the toxicity of IL-18/IL-12 and the
possible involvement of IFN-.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Normal BALB/c and C57BL/6 mice and mutant
BALB/c-nu/nu mice were purchased from Charles River Japan
(Kanagawa, Japan) and were used at 7–10 wk of age. Mice lacking an
IFN- gene (strain C57BL/6-Ifng<tmjTs>, genotype
Ifg/Ifg) were purchased from The Jackson Laboratory (Bar
Harbor, ME) and were used at 7–9 wk of age. In all experiments except
that studying IFN- deficiency, female mice were used.
Cytokines
Recombinant murine IL-18, IL-12, and IFN-, were produced and
purified at Hayashibara Biochemical Laboratories (Okayama, Japan). For
in vivo administration, they were diluted in 0.9% NaCl solution
containing 0.1% mouse serum albumin
(MSA).2
IL-18/IL-12 treatment and toxicity monitoring
Mice were injected i.p. with vehicle (0.1% MSA in 0.9% NaCl solution) or with 1 µg of IL-18 and/or IL-12 once daily. Body weight changes were monitored as a symptom of toxicity. Relative body weight change, which was calculated as the ratio of the examination value to the pre-experiment value, was used to minimize individual variation. The serum glucose level was also monitored as a toxicity index. Glucose was measured with Dexter-Z (Bayer, Pittsburgh, PA) by partial bleeding from arteria infraorbitalis. Other toxicity symptoms, such as diarrhea and lethargy, were also recorded.
Serum cytokine measurement
Mouse sera were usually collected 6 h after injection of
cytokines and were used for determining the levels of various
cytokines. The concentrations of IFN-, IL-1, IL-1ß, IL-6,
IL-10, GM-CSF, and TNF- in the serum samples were measured by ELISA
using commercial kits for IFN- and IL-6 (Genzyme, Cambridge, MA);
IL-1, IL-1ß, GM-CSF, and TNF- (Endogen, Woburn, MA); and IL-10
(PerSeptive Diagnostics, Farmingham, MA) and following the protocols
recommended by the manufacturers.
Antiserum
Rabbit anti-mouse IFN- was prepared in our laboratories
and was used at the amount of activity neutralizing 5 x
104 U of mouse IFN-. Rabbit
anti-asialo-GM1 was purchased from Wako (Osaka, Japan) and was used
at a dose of 1 mg/mouse.
Treatment of athymic nude mice
BALB/c nude mice (nu/nu) were pretreated with rabbit
anti-asialo-GM1 or normal rabbit Ig fraction on day 0 to evaluate
the involvement of the NK cell population and were then administered
IL-18 and IL-12 (1 µg/mouse/day of each cytokine) daily from days
1–4. Weight change was monitored daily, and the serum IFN- level
was determined 6 h after the fourth injection.
Anti-IFN- treatment
BALB/c mice were administered rabbit anti-mouse IFN-
antiserum 1 h before IL-18/IL-12 treatment. Both antiserum
pretreatment and cytokine injection were performed on days 1 and 2. A
control mouse was injected with normal rabbit serum instead of the
antiserum.
Statistics
Results are expressed as the mean ± SD for the number of mice per group. Statistical data for comparison of groups were calculated by ANOVA, and paired data were compared using Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first observed adverse effects from the combination of IL-18
and IL-12 when tumor-bearing mice were treated with the two cytokines
(data not shown). Therefore, we examined the severity of the
combination toxicity by comparing it with single treatment toxicity
using non-tumor-bearing mice. A dose of 1 µg/mouse for both IL-18 and
IL-12 was used in this experiment and all others described below
because toxicity and mortality were reproducibly observed at this
dosage. Fig. 1
shows the body weight
changes in mice treated with IL-18 and/or IL-12 over a period of 15
days. Both BALB/c and C57BL/6 mice were used in these experiments.
MSA-treated (vehicle) or IL-18-treated mice showed slow or almost no
weight gain during the 15-day period in either BALB/c or C57BL/6 mice.
In the case of treatment with IL-12 alone, different degrees of
toxicity were observed between BALB/c and C57BL/6 mice. BALB/c mice
treated with IL-12 alone showed no apparent toxicity until day 14, and
only mild toxicity was indicated by a lower glucose level on day 15
(Fig. 2). On the other hand, in the group
of C57BL/6 mice treated only with IL-12, significant and continuous
body weight loss was observed from day 6, and two mice died by day 10.
Interestingly, thereafter four surviving mice in this group started to
gain weight even while they were still receiving IL-12 treatment.
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). IL-18/IL-12 treatment
was equally and severely toxic in both mouse strains. Since treatment
with IL-18 alone did not cause toxicity, and the toxicity of IL-12
alone was limited, the level of IL-18/IL-12 toxicity is synergistically
induced.
Synergistic induction of IFN- and other cytokines
We next analyzed the serum cytokine levels to look for a relevant
factor in the toxicity. Proinflammatory (IFN-, TNF-, IL-1,
IL-1ß, IL-6, GM-CSF) and anti-inflammatory (IL-10) cytokines in
the sera were measured after the third and fourth injections. The most
remarkable induction was detected for IFN- (Fig. 3). After three IL-18/IL-12 injections,
the IFN- level reached >2445 IU/ml, whereas vehicle-treated or
IL-18-treated mice showed undetectable levels (<1 pg/ml) of IFN-,
and mice treated with IL-12 alone showed 12 IU/ml. The combination of
IL-12/IL-18 and IL-12 alone induced equivalent levels of IFN- on
days 3 and 4, respectively, although significant synergy was apparent
with the costimulation.
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induction (detection level, 50
pg/ml) was observed in any group in these experiments (data not shown).
In all treatment groups, IL-1 was within the normal range (0–100
pg/ml), and IL-1ß was lower than the detection level (15 pg/ml). The
induction of IL-6, GM-CSF, and IL-10 was observed with treatment with
either IL-18 or IL-12 alone as well as with the IL-18/IL-12 combination
treatment (Fig. 3). Higher levels of GM-CSF and IL-10 were induced on
day 3 than on day 4, whereas higher levels of IL-6 were induced later.
Although the induction of GM-CSF by IL-18/IL-12 was synergistic
compared with the effect of IL-18 or IL-12 single treatment, IL-6 and
IL-10 inductions by IL-18/IL-12 seem to be no greater than an additive
effect.
Role of T and NK cells in toxicity and IFN- production
To investigate the cause of the IL-18/IL-12 toxicity, we focused
our attention on the strong induction of IFN-. Both IL-18 and IL-12
induce IFN- by stimulating NK and T cells. Therefore, we first
determined whether the removal of NK and/or T cells influences toxicity
as well as IFN- production. Athymic nude mice were used to examine
the effect of the thymus-dependent T cell population. As shown in Fig. 4, BALB/c nu/nu mice treated
with IL-18/IL-12 showed severe toxicity, as did wild-type mice. The
IFN- level of the nude mice was as high as that of the wild-type
mice, implying that the major source of IFN- was not the
thymus-dependent T cell population, but NK cells or the
thymus-independent T cell population. Therefore, we next pretreated
nude mice with anti-asialo-GM1 Ab to remove the NK cell population
(Fig. 5). Anti-asialo-GM1 treatment
reduced IFN- induction from 3226 to 785 IU/ml. However, the toxicity
caused by IL-18/IL-12 was not reduced, because no difference in body
weight change was observed between the two groups. The same results
were obtained using wild-type mice treated with anti-CD4,
anti-CD8, and anti-asialo-GM1 Abs (data not shown).
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treatment
We next investigated the effect of IFN- by neutralizing it with
Ab. One group of mice was pretreated with anti-IFN- antiserum,
and the other group was treated with control normal serum 1 h
before the injection of IL-18/IL-12 on days 1 and 2. We did not treat
the mice more than twice with anti-IFN- antiserum together with
IL-18/IL-12 to avoid artificial toxic effects resulting from a large
amount of IFN- immune complex. Toxicity was monitored from days
3–9. The results are shown in Fig. 6.
Both groups lost body weight after the second cytokine injection, but a
varying degree of toxicity was observed between the two groups. The
anti-IFN- treatment group showed less severe toxicity and
regained weight faster than the control group. On the other hand, the
control group had lost 15.5% relative body weight (compared with 6.4%
weight loss for the anti-IFN- treatment group) on day 4. Most
control group mice manifested diarrhea, but the anti-IFN-
treatment group did not.
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-deficient mice
The anti-IFN- Ab experiment suggested that IFN- may play
a substantial role in IL-18/IL-12-induced toxicity. However, the
anti-IFN- Ab could not completely abrogate the toxic effect of
IL-18/IL-12. Therefore, we further examined the involvement of IFN-
in toxicity using IFN--deficient mice. When wild-type C57BL/6 mice
were treated with IL-18/IL-12, a drastic weight loss was detected
starting on day 3, and half of the mice died by day 5 (Fig. 7). Curiously, IFN--deficient mice did
not show drastic weight loss even by day 4, but half of them died by
day 5, as did the wild-type mice. Pathological examination of the dead
IFN--deficient mice showed the major cause of death to be severe
pulmonary edema, which is not usual in wild-type mice treated with
IL-18/IL-12. Other symptoms of the IFN--deficient mice also differed
from those of their wild-type counterparts. Apparent symptoms of
illness, such as body weight loss and lethargy, were not evident in
IFN--deficient mice, while wild-type mice showed severe sickness
after the third injection of IL-18/IL-12. These results lead to the
tentative interpretation that IFN- is not involved in the toxicity
of IL-18/IL-12. Car et al. reported similar pathological results when
they investigated the role of IFN- in IL-12 single treatment
toxicity using IFN-R-deficient mice (31). Their
interpretation of the results was that endogenously induced IFN-
might have played a role in preventing fatal pulmonary disease in
IFN-R-deficient mice. Therefore, we further examined the effects of
exogenous IFN- on pulmonary edema.
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treatment in IFN--deficient mice
One group of IFN--deficient mice was treated with only
IL-18/IL-12 as in our previous experiments, and two other groups were
administered 1000 or 100 IU/mouse of IFN- daily in addition to
IL-18/IL-12. The results are shown in Fig. 8 with the individual values of body
weight change as the index of toxicity. Three of five mice in the group
injected with IL-18/IL-12 alone lost weight on day 4 and died by day 5.
Another mouse also lost weight on day 4, but recovered on day 7 even
while continuing IL-18/IL-12 treatment. The other mouse did not show
body weight loss until day 7 and lost weight drastically on day 8. In
the groups injected with IFN- together with IL-12/IL-18, the
toxicity was not reduced, but was actually enhanced, because all five
mice died by day 6 in the group receiving 100 IU/mouse of IFN-. In
the higher dose (1000 IU/mouse) IFN- group, all mice lost weight on
day 4, and two of them died by day 5. The remaining three mice
survived, but their weights were still lower than before the
experiment. All dead mice had pulmonary edema, and their lungs
contained pleural effusion. Therefore, IFN- treatment did not
prevent IFN--deficient mice from suffering from pulmonary edema and
ensuing death.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,
IFN-/ß, and TNF- as well as IL-12. Among them only IL-12 showed
significant synergistic effects in terms of antitumor activity and
toxicity. Although the adverse effects or immunosuppressive activity of
IL-12 have been reported (32, 33, 34), the severity of the
combination of IL-18 and IL-12 was unexpected, because no apparent
adverse effects of IL-18 single treatment had been observed by us or
other researchers. Therefore, we attempted to elucidate the cause of
these toxic effects using several experimental systems.
First, we investigated how severe the toxicity of the combination of
IL-18/IL-12 was by comparing IL-18 or IL-12 single treatment. Even
after 15 days of continuous administration, treatment of IL-18 only did
not cause any mortality or apparent body weight loss in either BALB/c
or C57BL/6 mice. Although the toxicity of treatment with IL-12 alone
varied from BALB/c to C57BL/6 mice, it did not result in total mouse
mortality. In sharp contrast, all IL-18/IL-12-treated mice of both
strains died in <7 days after dramatic weight loss, demonstrating the
severity of IL-18/IL-12 toxicity. The most remarkable observation was a
highly elevated level of IFN- in IL-18/IL-12-treated mice. The serum
level of IFN- in these mice was 1000 or 200 times higher than those
in mice treated with IL-18 or IL-12 alone, respectively. Because high
levels of IFN- have been known to cause adverse effects and even
mortality (35, 36), we focused our study on the role of
IFN- in IL-18/IL-12 toxicity.
The nude mouse experiments using anti-asialo-GM1 Ab showed that
removing most of the NK cell population together with the
thymus-dependent T cell population reduced IFN- induction but still
caused the same degree of toxicity, indicating that IFN- has only a
minor role in toxicity. On the other hand, the anti-IFN-
treatment experiment showed that neutralization of the induced IFN-
could reduce toxicity and indicated that IFN- may play an important
role in toxicity. The opposing results of the two experiments prompted
us to clarify the role of IFN- using IFN--deficient mice. The
experiments showed that even with the deficiency of the IFN- gene,
the majority of the mice treated with IL-18/IL-12 showed toxicity and
mortality. This clearly indicated that there were some
IFN--independent mechanisms in the toxicity. This conclusion
supports the interpretation of the anti-asialo-GM1 experiment, but
seems to conflict with the results of the anti-IFN- experiment.
However, we think that neither experiment conflicts with the other. Our
interpretation is that there are both IFN--dependent and
IFN--independent mechanisms in IL-18/IL-12 toxicity, and with one of
them missing, the toxic effects are incomplete. This would explain why
neutralization with anti-IFN- only partially alleviated the
toxicity and also explains why some of the IFN--deficient mice
recovered from the toxicity. Although we did not further investigate
the IFN--independent mechanisms in detail, our preliminary
experiments using nitric oxide inhibitors suggested that nitric oxide
did not play a major role in toxicity. Also, we tried to reduce
toxicity by administering glucose to the hypoglycemic mice, but it did
not have the desired effect. As described by other investigators
(31, 37, 38), one of the IFN--independent mechanisms
could be the direct effects of IL-12 on hemopoietic and other tissue
cells. Another possibility is the involvement of inflammatory cytokines
other than IFN-, as suggested by the synergistic induction of IL-6,
GM-CSF, and IL-10 by treatment with IL-18/IL-12. However, we could not
determine how much these cytokines contributed to the toxicity.
Because the symptoms of IL-18/IL-12 toxicity are very similar to those
of endotoxin shock syndrome (35), at first the mechanisms
causing both types of toxicity seemed to be similar. However, cytokine
induction profiles showed that there was no induction of TNF-, which
was a distinct phenomenon from endotoxin shock. Since TNF- is
usually induced at an early stage of treatment, we also examined the
possibility of TNF- induction 1–2 h after the first treatment.
However, we could not detect any TNF- in those cases (data not
shown). Originally, IL-18 was identified in the serum or liver Kupffer
cells in the endotoxin shock model mice (1), and both
IL-18 and IL-12 were shown to be involved in the pathology of this
liver injury (20). However, the lack of TNF- induction
indicated that exogenous IL-18/IL-12 may trigger a course of pathology
different from endotoxin shock.
Various synergistic effects of IL-18/IL-12 have been described both in
vitro and in vivo since the identification of IL-18 as a new cytokine.
An IL-12-dependent cell line (1), the murine Th1 clones
(7), and an enriched T cell population (6)
all produced IFN- synergistically with IL-18/IL-12 treatment. One of
the explanations of this synergy was the induction of the IL-18R by
IL-12, but there were also cases that could not be explained by this
receptor induction model (39). In vivo synergistic effects
have also been reported by some other researchers. Osaki et al. showed
in vivo IL-18/IL-12 synergy in terms of antitumor activity and IFN-
production by exogenous protein administration, and they also observed
severe toxicity (28). They did not further investigate the
mechanisms of the toxicity, but suggested that IFN- was not the sole
cause. Coughlin et al. demonstrated IL-18/IL-12 synergy for antitumor
protection by injecting gene-transfected cells into mice and concluded
that the inhibition of tumor angiogenesis was likely to account for the
effects (29). They did not describe the toxicity of
IL-18/IL-12, so it is possible that local secretion of IL-18/IL-12 is
less toxic than systemic administration. Moreover, Qureshi et al.
(40) reported that they could prevent cryptococcal
infection of mice using suboptimal doses of IL-18/IL-12 (2 and 0.005
µg/mouse/day, respectively) without observing any adverse effect.
They showed that the subtherapeutic doses of the two cytokines enhanced
the local production of IFN- by NK cells and 
T cells. This and
our present study deal with the synergy of exogenously administered
IL-18 and IL-12. Fantuzzi et al. (41) presented
interesting data showing that even sole administration of IL-12 induced
endogenous IL-18 secretion in a caspase-1-dependent manner. Therefore,
administration of IL-12 alone, especially when used at a high dose,
could result in synergy with endogenously induced IL-18. The mechanisms
of in vivo synergy have not been well elucidated, but some could be
explained by a receptor induction model, as in the in vitro case
(39).
One intriguing observation was pulmonary edema in the IFN--deficient
mice as a pathological condition distinct from those in wild-type mice,
such as fatty liver and hemorrhagic colitis. A similar observation was
reported by Car, et al. about IL-12 single treatment toxicity
(31). They used IFN-R-deficient mice instead of
IFN--deficient mice and administered IL-12 alone to them. As in our
experiments, they observed severe pulmonary edema with abundant pleural
effusion in their mice. One point in their interpretation was that the
severe pulmonary edema was a direct effect of IL-12 and could be
prevented by IFN-, because there was antagonistic interaction
between IL-12 and IFN-. They implied a protective role of IFN-,
but did not provide any data to prove it. Therefore, we examined this
possibility in our system and found that neither a higher nor a lower
dose of IFN- prevented the mortality and toxicity accompanying the
pulmonary edema, thus ruling out their interpretation.
Another interesting observation was that some of IFN--deficient mice
seem to become tolerant to IL-18/IL-12 toxicity as shown in Fig. 8. A
similar phenomenon was observed when C57BL/6 mice were treated with
IL-12 only, as shown in Fig. 1. Tolerance induction to IL-12 toxicity
has been reportedly induced by pretreating mice with a single injection
of IL-12 1 or 2 wk before subsequent treatment (33, 34).
Despite extensive studies, these studies could not show any definite
mechanisms for the tolerance induced, but down-regulation of IL-12R or
overproduction of IL-10 does not seem to be involved (33, 34). In the case of IL-18/IL-12 toxicity in IFN--deficient
mice, there could be similar tolerance mechanisms to IL-12 toxicity,
but further studies will be necessary to elucidate them.
In this study we analyzed the mechanisms of the toxicity caused by
IL-18/IL-12 and concluded that the induction of IFN- is indeed one
such mechanism, but there are others. Because in vivo IL-18/IL-12
treatment induces remarkable synergy in several aspects other than
toxicity, understanding the role of IFN- in this toxicity would help
in understanding the mechanisms of IL-18/IL-12 synergy in other
beneficial aspects.
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Acknowledgments |
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Footnotes |
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2 Abbreviation used in this paper: MSA, mouse serum albumin.
Received for publication May 25, 1999. Accepted for publication January 5, 2000.
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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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E. Esfandiari, I. B. McInnes, G. Lindop, F.-P. Huang, M. Field, M. Komai-Koma, X.-q. Wei, and F. Y. Liew A Proinflammatory Role of IL-18 in the Development of Spontaneous Autoimmune Disease J. Immunol., November 1, 2001; 167(9): 5338 - 5347. [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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 B. Siegmund, G. Fantuzzi, F. Rieder, F. Gamboni-Robertson, H.-A. Lehr, G. Hartmann, C. A. Dinarello, S. Endres, and A. Eigler Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2001; 281(4): R1264 - R1273. [Abstract] [Full Text] [PDF]
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 T. K. Varma, T. E. Toliver-Kinsky, C. Y. Lin, A. P. Koutrouvelis, J. E. Nichols, and E. R. Sherwood Cellular Mechanisms That Cause Suppressed Gamma Interferon Secretion in Endotoxin-Tolerant Mice Infect. Immun., September 1, 2001; 69(9): 5249 - 5263. [Abstract] [Full Text] [PDF]
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L. Del Rio, A. J. Buendia, J. Sanchez, M. C. Gallego, M. R. Caro, N. Ortega, J. Seva, F. J. Pallares, F. Cuello, and J. Salinas Endogenous Interleukin-12 Is Not Required for Resolution of Chlamydophila abortus (Chlamydia psittaci Serotype 1) Infection in Mice Infect. Immun., August 1, 2001; 69(8): 4808 - 4815. [Abstract] [Full Text] [PDF]
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D. W. Ju, Q. Tao, G. Lou, M. Bai, L. He, Y. Yang, and X. Cao Interleukin 18 Transfection Enhances Antitumor Immunity Induced by Dendritic Cell-Tumor Cell Conjugates Cancer Res., May 1, 2001; 61(9): 3735 - 3740. [Abstract] [Full Text]
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N. J. Horwood, J. Elliott, T. J. Martin, and M. T. Gillespie IL-12 Alone and in Synergy with IL-18 Inhibits Osteoclast Formation In Vitro J. Immunol., April 15, 2001; 166(8): 4915 - 4921. [Abstract] [Full Text] [PDF]
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Y.-I. Son, R. M. Dallal, R. B. Mailliard, S. Egawa, Z. L. Jonak, and M. T. Lotze Interleukin-18 (IL-18) Synergizes with IL-2 to Enhance Cytotoxicity, Interferon-{{gamma}} Production, and Expansion of Natural Killer Cells Cancer Res., February 1, 2001; 61(3): 884 - 888. [Abstract] [Full Text]
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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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) or fourth injection
(
). Values are the mean ± SD.
) or IL-18/IL-12 (1 µg
each/mouse/day; 