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Departments of
*
Pathology and
Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI 48109
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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as well as IL-12 (a potent inducer of
IFN-) have been demonstrated to inhibit airway eosinophilia and
associated bronchial hyperreactivity in murine models of allergic
airway disease (12, 13).
A recently identified cytokine, IL-18, has been described as a mediator
inducing IFN- release from Th1 cells, CD8+ T
cells, and NK cells, synergizing with IL-12 (14, 15, 16, 17, 18, 19, 20). The
IL-18 receptor complex is proposed to include a low-affinity chain,
IL-18R 
, identified as the IL-1 receptor family member, IL-1R
protein (IL-1Rrp) and a second chain, IL-18R 
, that does not bind
IL-18 directly, but is recruited once -chain binding occurs
(21, 22, 23, 24, 25). This has lead to suggestions that IL-18 is
related to the IL-1 family (14, 26, 27). In addition,
recent evidence suggests that IL-18 augments IFN- production in a
similar manner as IL-1. IL-1, as well as TNF, has been identified as a
cytokine released early in the inflammatory response initiating
cytokine cascades. These results are consistent with its ability to
recruit IL-1 receptor-activating kinase, leading to the translocation
of NF-
B (17, 18). The results from the present studies
indicate a more complicated pleiotrophic role for IL-18 than simply
induction of IFN- production, and may indicate a role in a broad
spectrum of inflammatory events. Systemically, neutralization of IL-18
demonstrated a predicted function of altered immune regulation with
exacerbated airway eosinophil accumulation and airway hyperreactivity.
In contrast, local IL-18 production appears to also exacerbate
eosinophil accumulation through the activation of eotaxin from local
cell populations, thus demonstrating the complexity of IL-18
biology.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female CBA/J mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and were maintained under standard pathogen-free conditions. Eotaxin knockout mice and their littermate controls (F2 generation) were a gift from Dr. Rodrigo Bravo of Bristol-Myers Squibb (New York, NY) as described previously (28).
Sensitization and induction of the airway response
To induce a Th2-type response, normal mice were sensitized and challenged with cockroach allergen as described previously (29). Briefly, mice were immunized with 10 µg of cockroach allergen (Bayer, Elkhart, IN) in incomplete Freund’s adjuvant on day 0. To localize the response to the lung, the mice were given an intranasal administration of 10 µg of cockroach allergen in 10 µl of diluent on day 14. This initial intranasal challenge with Ag induced little cellular infiltrate. Mice were then challenged 6 days later by intratracheal administration of 10 µg of cockroach allergen in 50 µl of sterile. In depletion studies, mice were pretreated with polyclonal rabbit anti-murine IL-18 Abs (0.5 ml, titers of 107/ml) given i.p. at 1 h before intratracheal Ag challenge. Control animals received 0.5 ml of normal rabbit serum.
Effect of recombinant murine IL-18 protein on airway inflammation in normal and sensitized mice
Normal CBA/J mice were anesthetized with ketamine (Bayer), and the trachea was exposed and preholed using a 24-gauge needle before direct instillation of 200 ng of endotoxin-free recombinant murine IL-18 in 50 µl. To assess inflammatory responses in sensitized animals, mice were immunized with cockroach allergen as described above, but coadministered IL-18 (or saline/BSA vehicle as a control) with cockroach allergen during the challenge phase (60-µl volume instilled). Airway inflammation was analyzed at varying time points after instillation.
Morphometric analysis of airway and peribronchial eosinophil accumulation
To assess migration of eosinophils into the airway, we subjected the mice to a 1-ml bronchoalveolar lavage (BAL)3 with PBS containing 25 mM EDTA at various time points after challenge. The cells were then dispersed using a cytospin (Shandon, Runcorn, U.K.) and differentially stained with Wright-Giemsa stain. The cell types (mononuclear phagocytes, lymphocytes, neutrophils, and eosinophils) were expressed as a percentage based on 200 total cells counted/sample. Lung tissue was preserved with 4% paraformaldehyde at various time points after challenge. The fixed lungs were embedded in paraffin and multiple 50-µm sections were differentially stained with Wright-Giemsa for the identification of eosinophils and viewed at x1000. The individual eosinophils were counted from 100 high-powered fields per lung at each time point using multiple step sections of lung. The eosinophils counted were only in the peribronchial region; this assured the enumeration of only those eosinophils within or immediately adjacent to an airway. The inflammation observed in this model was completely associated with the airway with little or no alveolitis.
Isolation of leukocytes to characterize the activity/expression of IL-18
Eosinophils were obtained from the peritoneum of Schistosoma mansoni-infected mice as described previously (30). Eosinophils were further purified using a two-step procedure including plastic plate adherence for 60 min, followed by magnetic cell separation system magnetic bead-negative selection with Abs specific for CD4, CD8, and class II-positive cell populations. The purity of the cells was >95% after the final step. Macrophages were isolated from peritoneum of normal mice using 10 1-ml washes of PBS containing 5 mM EDTA.
Production of anti-IL-18 Abs
Rabbit anti-murine IL-18 Abs were prepared by multiple-site
immunization of New Zealand White rabbits with recombinant murine IL-18
(R&D Systems, Rochester, MN) in CFA. Polyclonal Abs were titered by
direct ELISA and specifically verified by the failure to cross-react to
mIL-1, hIL-18, TNF, mIL-3, mIL-1, mTNF, murine
macrophage-inflammatory protein-1 (mMIP-1), IL-6, murine monocyte
chemoattractant protein-1 (mMCP-1), mMIP-1, human monocyte
chemoattractant protein-1, hIL-8, hRANTES, hMIP-1, hTNF, and
hMIP-1. The IgG portion of the serum was purified over a protein A
column and used in a sandwich ELISA and for in vivo neutralization. The
quality of the Ab was assessed using a Con A-stimulated lymphocyte
assay and measuring IFN production. A 1:200 dilution of Ab was
sufficient to inhibit the effects of 30 ng/ml of rIL-18 in in vitro
assays.
Quantitation of inflammatory mediators by specific ELISA
The levels of cytokine and chemokine proteins in whole-lung homogenate and from cell-free supernatants were measured by specific ELISA using a modification of a double-ligand method as described previously (31, 32). Briefly, lung tissue was homogenized on ice using a tissue-tearor (Biospec Products, Racine, WI) for 30 s in 1 ml of PBS containing 0.05% Triton X-100. The resulting supernatant was isolated following centrifugation (10,000 x g). Flat-bottom 96-well microtiter plates (Nunc Immunoplate I 96-F; Nunc, Roskilde, Denmark) were coated with 50 µl/well of rabbit polyclonal Abs, specific for the cytokine/chemokine in question, for 16 h at 4°C and then washed with PBS and 0.05% Tween 20. Nonspecific binding sites were blocked with 2% BSA in PBS and incubated for 90 min at 37°C. Plates were rinsed four times with wash buffer and cell-free supernatants were added (undiluted and 1/10) followed by incubation for 1 h at 37°C. Plates were washed four times, streptavidin-peroxidase conjugate (Bio-Rad, Richmond, CA) was added, and the plates were incubated for 30 min at 37°C. Plates were washed again and chromogen substrate (Bio-Rad) was added and incubated at room temperature to the desired extinction. The reaction was terminated with 50 µl/well of 3 M H2SO4 solution, and the plates were read at 490 nm in an ELISA reader. Standards were 0.5 logarithm dilutions of recombinant protein from 1 pg/ml to 100 ng/ml.
Measurement of airway hyperreactivity
Airway hyperreactivity was measured using a Buxco mouse
plethysmograph which is specifically designed for the low tidal volumes
(Buxco, Troy, NY) as described previously (29). Briefly,
the mouse to be tested was anesthetized with sodium pentobarbital and
intubated via cannulation of the trachea with an 18-gauge metal tube.
The mouse was subsequently ventilated with a Harvard pump ventilator
(tidal volume, 0.4 ml; frequency, 120 breaths/min; positive
end-expiratory pressure, 2.5–3.0 cm H2O; Harvard
Apparatus, Holliston, MA), and the tail vein was cannulated with a
27-gauge needle for injection of the methacholine challenge. The
plethysmograph was sealed and readings were monitored by computer.
Since the box was a closed system, a change in lung volume was
represented by a change in box pressure (Pbox)
which was measured by a differential transducer. The system was
calibrated with a syringe that delivered a known volume of 2 ml. A
second transducer was used to measure the pressure swings at the
opening of the trachea tube (Paw), referenced to
the body box (i.e., pleural pressure) and to provide a measure of
transpulmonary pressure (Ptp =
Paw - Pbox). The trachea
transducer was calibrated at a constant pressure of 20 cm of
H2O. Resistance was calculated by Buxco (Groton,
CT) software by dividing the change in pressure
(Ptp) by the change in flow (F)
(
Ptp/F; units = cm
H2O/ml/s) at two time points from the volume
curve based on a percentage of the inspiratory volume. The mouse was
attached to the box and ventilated for 5 min before acquiring readings.
Once baseline levels were stabilized and initial readings were taken, a
methacholine challenge was given via the cannulated tail vein. After
determining a dose-response curve (10–500 µg/kg), an optimal dose
was chosen, 50 µg/kg of methacholine. This dose was used throughout
the rest of the experiments in this study and induced little change in
resistance in normal nonallergic mice. After the methacholine
challenge, the response was monitored and the peak airway resistance
was recorded as a measure of airway hyperreactivity.
Statistics
Statistical significance was determined using ANOVA with p values <0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because IL-18 has been identified as a Th1-associated cytokine
with the ability to alter immune function, we were interested in
examining the systemic and local effects on Th2-type allergic
responses. To determine whether significant levels of IL-18 could be
detected in lungs of normal and allergic animals, whole-lung
homogenates were assayed for IL-18 by ELISA. IL-18 was detectable in
whole-lung homogenates of nonsensitized, nonchallenged CBA/J mice
(8.2 ± 2.3 ng/lung). Interestingly, baseline levels of IL-18 were
significantly higher in allergic compared with nonallergic mice at time
0 and continued to be significantly increased over control mice
throughout the response (Fig. 1
). The
IL-18 within the lung is likely composed of both the pro-IL-18 form and
the mature IL-18 species. In comparison, very low levels of IL-12
(<0.2 ng/lung) were detected in whole-lung homogenates during the
response, consistent with a strong Th2-type response. Thus, increased
levels of IL-18 could be detected locally within the lung during this
IL-4-dependent, Th2-type response.
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The sensitization and challenge of animals with cockroach allergen
is associated with an increase in peribronchial accumulation of
eosinophils (29). To determine whether IL-18 had a
regulating role during the response, we treated animals with Abs
specific for IL-18 and examined the inflammation that followed.
Pretreating sensitized mice with Abs to IL-18 at 1 h before
challenge greatly accelerated eosinophil accumulation at 8 h after
challenge compared with normal rabbit serum controls (Fig. 2). By 72 h, there was little
difference observed between control Ab and anti-IL-18 Ab-treated
groups. Altogether, these data follow previous work with IL-18
indicating that it is a Th1-associated cytokine that is antagonistic to
a Th2-type allergic airway response.
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Since our studies with Abs against IL-18 suggested that this
cytokine might confer a protective effect against inflammation during
allergy, we were interested in whether recombinant IL-18 given locally
within the airway would be beneficial. Sensitized mice were
intratracheally cochallenged with Ag plus either IL-18 (200 ng/ml) or
vehicle, and the inflammatory response was analyzed at various time
points thereafter. The administration of rIL-18 had a surprising effect
on the allergic airway inflammation (Fig. 3A). Examination of the
peribronchial accumulation indicated no significant effect on the
response at 8 h; however, a significant increase in eosinophils by
24 h after allergen challenge in the IL-18 to the control-treated
group. Likewise, when eosinophils were examined in the BAL fluid a
>4-fold increase in the number of eosinophils was detected in IL-18
compared with control-treated animals (Fig. 3B).
Interestingly, the addition of exogenous IL-18 (200 ng) into the airway
induced the production of IFN- (70 ± 8 pg/ml BAL), whereas
allergen-only-treated animals had no detectable IFN- (<10 pg/ml).
Lower doses of IL-18 (10 ng) had no effect on eosinophil accumulation
or IFN- production (data not shown). Overall, the local role of
IL-18 may be different from that of the systemic function elucidated by
neutralization of IL-18 and by other investigators when IL-18 was given
exogenously during sensitization in a systemic manner
(33).
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A). Because there was delay
in eosinophil accumulation in both allergic and naive mice, we
hypothesized that intermediary eosinophil chemoattractants might be
induced by IL-18. Evaluation of BAL samples from naive animal studies
demonstrated elevated eotaxin levels in IL-18 compared with
vehicle-instilled animals at 24 h (Fig. 4B). No
difference in eotaxin was observed at 8 h after instillation.
Other eosinophil chemoattracts were also examined, including MIP-1,
RANTES, monocyte chemoattractant protein-3, leukotriene
B4, as well as histamine levels, and no
significant differences were detected in IL-18 compared with
vehicle-instilled animals. Importantly, to determine whether IL-18 had
any direct effect on eosinophil migration, we examined this cytokine
using a modified Boyden chamber with isolated eosinophils (>95%
purity). IL-18 did not directly induce eosinophil migration and had no
significant effect on the migration induced by eotaxin or other
chemotactic factors (data not shown). These unexpected observations of
IL-18-induced eosinophilia demonstrated that although IL-18 may have
the ability to participate in a Th1-type response, it also appears to
be able to induce eotaxin production and increase eosinophilia in both
allergic and naive mice.
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), confirming our previous results. No
eosinophils were found in vehicle control-instilled mice. However,
because there were some eosinophils that accumulated around the airways
of eotaxin -/- mice when IL-18 was instilled, eotaxin appears not to
be the only factor involved. In additional experiments when we
attempted to instill eotaxin directly into the airways of normal and
allergic mice, few eosinophils could be found (data not
shown). Thus, other events related to chemotaxis must also be
controlled by IL-18. We also examined changes in eotaxin levels in
systemically delivered anti-IL-18 experiments and found no
significant difference in eotaxin levels in the local environment of
the lung (data not shown), suggesting only an extrapulmonary effect
during Ab administration.
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We were next interested in the possible source of the
IL-18-induced eotaxin production. Since epithelial cells and
macrophages have been identified as a source of eotaxin in the lung, we
examined the direct effect of IL-18 on cultures of isolated primary
macrophages and on a murine bronchial epithelial cell line, LA4. IL-18
induced eotaxin release from both cell populations after 24 h of
culture (Fig. 6). Although both the
macrophages and epithelial cells produced constitutive levels of other
chemokines, IL-18 only increased the production of eotaxin, consistent
with the above in vivo data. These data indicate that IL-18
can act as a potent activating factor with specific effects on a broad
range of cell populations.
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To determine whether the increased eosinophil accumulation had an
effect on the physiological function of the response, treated mice were
subjected to analysis of airway hyperreactivity. Using a mouse
plethysmograph, mice treated with either anti-IL-18 or rIL-18 as
above were ventilated, challenged with methacholine (50 µg/kg) i.v.,
and the airway hyperreactivity evaluated 24 h after allergen
challenge (peak hyperreactive response). The data in Fig. 7 demonstrate that neutralization of
IL-18 with specific Abs significantly exacerbated the airway
hyperreactive response. In contrast, the introduction of exogenous
IL-18 (100 ng/mouse) had no effect on the airway hyperreactivity, even
though an increase in eosinophil accumulation was observed.
Histological examination of the allergic mice treated with either
anti-IL-18 or rIL-18 demonstrated differences in the intensity and
the total number of eosinophils as well as mononuclear cell populations
by 24 h after stimulation (Fig. 8).
Altogether, these data demonstrate the importance of endogenous IL-18
for regulation of eosinophilia and airway hyperreactivity, whereas
exogenous IL-18 treatment increased only the inflammatory component
(especially eosinophils).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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has previously been demonstrated
to attenuate eosinophilia associated with a murine model of allergic
airway inflammation, as has IL-12, a potent inducer of IFN-
(12, 13, 37, 38). Therefore, in our studies using a murine
model of cockroach Ag-induced allergy, we were not surprised that
neutralization of endogenous IL-18, a recently identified inducer of
IFN- production (14, 15, 39), exacerbated eosinophilic
airway inflammation and airway hyperreactivity. In these experiments,
Abs were administered systemically before allergen challenge, and our
results indicate that the presence of IL-18 during the induction of the
allergic response might have a modulating effect on the subsequent
airway inflammation. Interestingly, recent studies indicate that IL-18
receptor expression was selective for naive and Th1-type lymphocytes,
but not Th2-type lymphocytes (22). In the present studies,
it was surprising that exogenous recombinant murine IL-18 protein
administered intratracheally to both normal and sensitized mice (at the
time of allergen challenge) exacerbated the eosinophil response around
the airways. Only a relatively high (pharmalogic), but not a lower
(physiologic), dose of IL-18 induced the observed changes. A logical
hypothesis is that IL-18 might generate an intermediary factor with
eosinophil chemoattractant activity. A number of CC chemokines have
been implicated in the pathogenesis of allergic airway inflammation by
virtue of their ability to induce the selective migration of
eosinophils as well as the fact that their production is up-regulated
during human asthma (29, 40, 41, 42, 43, 44, 45, 46, 47). We observed that the
localized administration of IL-18 to the lung was associated with
increased eotaxin levels in the airway. The proinflammatory and
eosinophil accumulation effects of IL-18 in naive mice could be
attenuated in eotaxin knockout mice compared with their littermate
controls. Eotaxin was originally isolated from the BAL fluid of
sensitized guinea pigs after allergen challenge and subsequently
characterized as being a potent chemoattractant/activating factor for
not only eosinophils, but also basophils and Th2
lymphocytes (48, 49, 50, 51). Additional in vitro experiments
revealed that IL-18 induced the release of eotaxin from isolated
macrophages and cultures of a bronchial epithelial cell line. Thus,
local IL-18 appears to increase eosinophil accumulation via eotaxin
production from multiple cell populations.
Although the treatment of allergic mice with either anti-IL-18 or
rIL-18 induced similar increases in eosinophil accumulation, the airway
hyperreactivity responses demonstrated significant differences. The
systemic neutralization of IL-18 drastically exacerbated airway
hyperreactivity correlating with the increase in eosinophil
accumulation, whereas local IL-18 administration had no significant
effect on airway hyperreactivity. These studies suggest that the
presence of eosinophils alone may not be enough to alter the response.
Although we were not able to detect changes in IFN-, the
neutralization of IL-18 may significantly alter the regulation of Th1-
vs Th2-type responses. Previous studies have clearly indicated that
IFN- has a regulatory effect on airway hyperreactivity responses.
Furthermore, even though the eosinophil recruitment was augmented in
the animals treated with IL-18, the physiological response was possibly
kept in control by the presence of additional IFN-. Interestingly,
examination of the histological section demonstrated an increase in
eosinophil and mononuclear cell infiltration in both the
anti-IL-18- and rIL-18-treated animals. The further dissection of
these subpopulations may help to elucidate the differences in these two
groups.
The ability for IL-18 to enhance inflammation locally during allergic airway responses differs from a previous study demonstrating that IL-18 can attenuate the eosinophil accumulation and airway responses (33). However, these previous studies administered the cytokine i.p. before allergen challenge during the sensitization phase and found an effect only in the presence of IL-12. In a systemic setting, IL-18 may impact the response primarily at the regional lymph nodes, altering the evolution of the response during the active immunization process. Our data would concur with these observations because the systemic neutralization of IL-18 up-regulated the eosinophil-associated responses. In contrast, when exogenous IL-18 was administered locally to the lung at the time of allergen challenge in the present studies, the effect was on increased eotaxin in the airway leading to enhancement of the chemotactic gradients and eosinophil accumulation. In addition, IL-18 has recently been shown to increase ICAM-1 expression in epithelial cell populations (52), possibly further explaining how rIL-18 could directly induce eosinophil accumulation around the airways of naive mice. These results are especially intriguing when considering recent studies that demonstrate that Th1-type cells have no apparent regulatory effect on an allergen-specific response and possibly intensify the inflammation and local damage in the lung (53, 54). Since levels of IL-18 in the lung increase during allergy, the local release of IL-18 may be physiologically relevant during the inflammatory response and enhance the increase of eosinophil accumulation. IL-18 has been reported to behave in a manner similar to IL-1, and it would, therefore, not be surprising to find that the two had similar pleiotropic functions. This may help explain why IL-18 cannot only induce eotaxin but also induce an "inflamed" environment in normal mice sufficient for eosinophil recruitment. Interestingly, preliminary experiments in our laboratory have demonstrated that a number of cell populations isolated from the lung can produce IL-18, including fibroblasts and smooth muscle cells (our unpublished data). Thus, locally generated IL-18 from multiple cell populations may alter the response in the airway without impacting on the overall Th cell phenotype generated in the draining lymph nodes. Overall, these studies suggest an ability of IL-18 to differentially effect an allergic response and further emphasize the importance of fully investigating and understanding the biology of immune mediators.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nicholas Lukacs, Department of Pathology, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI 48109-0602. E-mail address:
3 Abbreviations used in this paper: BAL, bronchoalveolar lavage; MIP-1, macrophage-inflammatory protein-1; m, murine; h, human.
Received for publication June 18, 1999. Accepted for publication November 4, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 L.-P. Ho, M. Davis, A. Denison, F. T. Wood, and A. P. Greening Reduced Interleukin-18 Levels in BAL Specimens From Patients With Asthma Compared to Patients With Sarcoidosis and Healthy Control Subjects* Chest, May 1, 2002; 121(5): 1421 - 1426. [Abstract] [Full Text] [PDF]
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 N. W. Lukacs, A. Berlin, D. Schols, R. T. Skerlj, and G. J. Bridger AMD3100, a CxCR4 Antagonist, Attenuates Allergic Lung Inflammation and Airway Hyperreactivity Am. J. Pathol., April 1, 2002; 160(4): 1353 - 1360. [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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N. W. Lukacs, K. K. Tekkanat, A. Berlin, C. M. Hogaboam, A. Miller, H. Evanoff, P. Lincoln, and H. Maassab Respiratory Syncytial Virus Predisposes Mice to Augmented Allergic Airway Responses Via IL-13-Mediated Mechanisms J. Immunol., July 15, 2001; 167(2): 1060 - 1065. [Abstract] [Full Text] [PDF]
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D. M. Walter, C. P. Wong, R. H. DeKruyff, G. J. Berry, S. Levy, and D. T. Umetsu IL-18 Gene Transfer by Adenovirus Prevents the Development of and Reverses Established Allergen-Induced Airway Hyperreactivity J. Immunol., May 15, 2001; 166(10): 6392 - 6398. [Abstract] [Full Text] [PDF]
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 N. W. Lukacs, M. M. Glovsky, and P. A. Ward Complement-dependent immune complex-induced bronchial inflammation and hyperreactivity Am J Physiol Lung Cell Mol Physiol, March 1, 2001; 280(3): L512 - L518. [Abstract] [Full Text] [PDF]
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, nonallergic. *, p <
0.05.
