 in the Inhibition of the Allergic Airway
Inflammation Caused by IL-12
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Abstract |
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Abstract
Introduction
Materials & Methods
Results
Discussion
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T-helper 2 (Th2)-like cells are thought to play a crucial role in the pathogenesis of the eosinophilic airway
inflammation observed in asthma. In a murine model of allergen-induced airway eosinophilia and bronchial hyperresponsiveness (BHR), we have shown that interleukin (IL)-12 can suppress antigen-induced
airway changes despite the presence of circulating specific IgE. In the present study, we investigated the
role of interferon-
(IFN-) in the inhibitory effects of IL-12 on allergic airway inflammation. Repeated
daily exposure of actively immunized mice to aerosolized ovalbumin (OVA), as compared with aerosolized saline (SAL), induced a significant increase in bronchoalveolar lavage fluid (BALF) eosinophilia
and OVA-specific serum IgE in both IFN--receptor-deficient (IFN-R KO) and wild-type mice. As compared with placebo (PLAC), administration of recombinant murine IL-12 (rmIL-12) during the daily aerosol
exposure (but not at the time of immunization) significantly inhibited BALF eosinophilia in both IFN-R
KO mice and wild-type controls, without influencing the production of specific IgE. In contrast, administration of rmIL-12 during the active immunization inhibited both BALF eosinophilia and specific IgE in
wild-type mice as compared with littermates given PLAC; however, treatment with rmIL-12 during immunization, in comparison with PLAC, caused a significant increase in BALF eosinophilia and specific IgE
in IFN-R KO mice. These results demonstrate that inhibition of the allergen-induced eosinophil influx in
murine airways by IL-12 is IFN--dependent during the initial sensitization, but becomes IFN--
independent during the secondary response.
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Introduction |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Interleukin (IL)-12 is a heterodimeric cytokine produced
by phagocytes (monocytes, macrophages) and antigen-presenting cells (B cells, dendritic cells) (1, 2). IL-12 activates natural killer (NK) cells, mast cells, and T lymphocytes, and seems particularly potent in its ability to induce
production of interferon- (IFN-). IL-12 sends a powerful signal to naive precursor cells of the T-helper (Th) lineage, directing differentiation into Th1 cells in vitro and in
vivo, and shifting an unfolding immune response toward
cell-mediated immunity (3, 4).
We have developed a murine in vivo model of allergic
airway inflammation (5). Repeated daily exposures of actively immunized mice to aerosolized ovalbumin (OVA)
induced production of OVA-specific IgE, airway hyperresponsiveness (AHR), a peribronchial inflammation, and
an increase in bronchoalveolar lavage fluid (BALF) eosinophilia (6). In this model, we have shown that IL-12 inhibits antigen-induced airway eosinophilia and hyperresponsiveness, even in the presence of circulating specific
IgE (7). However, to date, the mechanism of inhibition of
the antigen-induced influx of eosinophils into the airways
by IL-12 is not known. To examine whether the inhibition by IL-12 could be mediated by IFN-, we studied the effect of IL-12, administered during initial antigen presentation or during subsequent aerosolized antigen exposure, in
wild-type mice and in IFN--receptor-deficient (IFN-R
KO) mice (i.e., mice without functional IFN-R due to targeted disruption of this receptor) (8).
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Materials and Methods |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Animals
Specific pathogen-free homozygous IFN-R KO (129/Sv × C57BL/6) mice and wild-type littermates were a generous
gift from M. Aguet (Institute of Molecular Biology I, University of Zürich, Zürich, Switzerland) (8). All mice were
housed in the animal research facility of the University
Hospital (Ghent, Belgium).
Immunization and Exposure
On the first day of the experiment (day 0), all animals were actively immunized to ovalbumin (OVA; Sigma, St. Louis, MO) by intraperitoneal injection of 10 µg OVA adsorbed to 1 mg Al(OH)3. From days 14 to 20, awake animals were exposed daily to aerosolized OVA (1%) as described previously (5). Control mice were exposed to aerosolized sterile saline (SAL).
Study Protocol
Part 1. Two groups of 12 IFN-R KO mice each, and
two groups of 12 wild-type controls each were immunized
and exposed to either aerosolized OVA or SAL as described earlier. On day 21, at 24 h after the last aerosol exposure, BAL and measurement of specific serum IgE were
performed.
Part 2.
Groups of 10 animals each were given placebo
(PLAC) or treated with recombinant murine IL-12 (rmIL-12; kindly provided by M. Gately, Roche, Nutley, NJ), administered intraperitoneally at 1 µg/animal/day from days
0 to 5 (i.e., during active immunization) or from days 14 to
19 (i.e., during subsequent aerosol exposure). Assessment
of outcome variables was performed on day 21, as outlined in Part 1.
Bronchoalveolar Lavage
At 24 hours after the last aerosol exposure, bronchoalveolar lavage (BAL) was performed as described elsewhere (5). After the animals were anesthetized with an intraperitoneal injection of pentobarbital 60 mg/kg body weight (Abbott Laboratories, Louvain-la-Neuve, Belgium), the trachea was cannulated and the airways were lavaged twice with 1 ml of HBBS (Pasteur, Brussels, Belgium). The BALF was immediately centrifuged (10 min, 4°C, 700 × g). After removing the supernatant and washing the BAL cells, the cells were counted manually in a Bürcker chamber. Cytocentrifuged preparations (Cytospin 2; Cytospin, Shandon, UK) were stained with May-Grünwald-Giemsa for differential cell counts, based on standard morphologic criteria, on 300 cells.
Measurement of OVA-specific Serum IgE
At the end of the experiment, blood was drawn from the sinus cavernosus for measurement of OVA-specific IgE with an isotype-specific enzyme-linked immunosorbent assay (ELISA), as described elsewhere (5). After coating 96-well plates with OVA grade V (Sigma) serial dilutions of serum were applied, followed by biotin-conjugated rabbit antimouse IgE (S. Florquin, Faculty of Medicine, Université Libre de Brusselles, Brussels, Belgium) and horseradish peroxidase-streptavidin conjugate. A serum pool from OVA-sensitized animals was used as internal laboratory standard; a 1:100 dilution of this pool was chosen as arbitrary unit (in U/ml).
Statistical Analysis
All results are expressed as mean ± SEM. The cellular composition of BALF and serum IgE levels in the various groups were compared with a Mann-Whitney U test. Differences between two groups were considered significant at P < 0.05.
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Results |
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Abstract
Introduction
Materials & Methods
Results
Discussion
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Part 1: Allergen-induced Airway Changes in
Wild-type and IFN-R KO Mice
In actively sensitized wild-type mice, repeated exposure to
aerosolized OVA induced a significant increase in the number of lymphocytes and eosinophils in BALF as compared
with that of SAL-exposed animals (lymphocytes: 4.3 ± 1.1% versus 1.0 ± 0.6%, P < 0.05; eosinophils: 20.4 ± 5.1% versus 0.6 ± 0.4%, P < 0.001) (Table 1). In immunized IFN-R KO mice, daily exposure to aerosolized OVA also induced a significant increase in the number of
BALF lymphocytes and eosinophils (lymphocytes: 4.7 ± 1.4% versus 1.0 ± 0.5%, P < 0.05; eosinophils: 25.3 ± 5.3% versus 1.0 ± 0.4%, P < 0.001). Serum of both sensitized wild-type and IFN-R KO mice contained measurable amounts of OVA-specific IgE, which were significantly enhanced by repeated exposure to aerosolized OVA
(OVA-specific IgE [U/ml]: 2.7 ± 0.5 versus 22.2 ± 4.2 in
SAL- versus OVA-exposed wild-type mice, P < 0.001;
3.7 ± 1.2 versus 52.4 ± 14.0 in SAL- versus OVA-exposed
IFN-R KO mice, P < 0.001, respectively) (Figure 1). Although BALF eosinophilia and serum OVA-specific IgE
levels tended to be higher in OVA-treated IFN-R KO
mice than in OVA-treated wild-type littermates, this did
not reach statistical significance (Table ; Figure 1).
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Part 2: Treatment with rmIL-12 during Immunization
or During Subsequent Aerosol Exposure in Wild-type
and IFN-R KO Mice
In order to determine whether IFN- played a different
role in immunization than in later exposures, we studied
the effect of IL-12, administered during initial antigen presentation or during subsequent aerosolized antigen exposure, in wild-type and IFN-R KO mice. IL-12 treatment
of wild-type mice during aerosol exposure (days 14 to 19)
significantly reduced the allergen-induced influx of eosinophils in BALF, as compared with OVA-exposed animals given PLAC (2.8 ± 1.4% versus 22.1 ± 4.8%; P < 0.05) (Figure 2A). In OVA-exposed IFN-R KO mice,
treatment with IL-12 during aerosol exposure also significantly inhibited the allergen-induced BALF eosinophilia,
as compared with littermates given PLAC (8.9 ± 1.2% versus 31.3 ± 4.6%, P < 0.05). However, whereas IL-12
treatment during immunization (days 0 to 5) inhibited the
allergen-induced influx of eosinophils into BALF in wild-type animals (7.3 ± 1.6% versus 24.4 ± 6.1%, P < 0.05),
this treatment caused a significant increase in the number
of BALF eosinophils in OVA-exposed IFN-R KO mice
(61.2 ± 3.9% versus 32.0 ± 6.5%, P < 0.05) (Figure 2B).
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In order to determine the role of IFN- in the effects of
IL-12 on the synthesis of allergen-specific IgE, blood was
drawn at the end of each experiment for measurement of
OVA-specific IgE. As shown previously (5), IL-12 treatment during aerosol exposure did not affect OVA-specific
serum IgE levels in OVA-exposed wild-type animals as
compared with controls given PLAC (24.0 ± 4.1 U/ml versus 17.5 ± 6.6 U/ml, P > 0.05) (Figure 1). Similarly, treatment with IL-12 during aerosol exposure did not affect
OVA-specific IgE levels in serum of allergen-exposed IFN-R KO mice (19.9 ± 5.6 U/ml versus 36.2 ± 13.8 U/ml, P > 0.05). In contrast, whereas IL-12 treatment during immunization inhibited the allergen-induced increase in OVA-specific serum IgE in wild-type animals (5.9 ± 0.8 U/ml versus
27.2 ± 5.1 U/ml, P < 0.05), this treatment further augmented
the allergen-induced increase in specific IgE in IFN-R KO
mice (114.4 ± 25.1 U/ml versus 30.9 ± 11.6 U/ml, P < 0.05).
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Discussion |
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Abstract
Introduction
Materials & Methods
Results
Discussion
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Chronic eosinophilic airway inflammation is currently
considered to play a crucial role in the pathogenesis of
bronchial asthma and is thought to be orchestrated by the
preferential development and activation of T-helper 2 (Th2)-like lymphocytes (9). IL-12 plays an essential
role in directing Th1 development both in vitro and in vivo
(1). However, whether IL-12 exerts its effects directly
on the T-helper (precursor) cell or requires production of
other cytokines to mediate Th1 differentiation remains to
be fully determined. IL-12 is known to induce the production of an array of cytokines, including IL-10 but especially
IFN-. In a murine model of allergen-induced eosinophilic
airway inflammation, we have shown that administration of
rmIL-12 during active immunization prevented both antigen-induced airway eosinophilia and specific IgE production, whereas treatment with IL-12 during the subsequent aerosol exposure inhibited airway eosinophilia without influencing specific serum IgE levels (7). BALF obtained
from these animals contained increased levels of IFN-. In
order to examine whether the inhibition of allergen-induced
airway changes by IL-12 is a direct effect or is mediated
through IFN-, we administered IL-12 or PLAC, during active immunization or during subsequent aerosolized allergen exposure, to both wild-type and IFN-R KO mice.
Repeated daily exposure of immunized IFN-R KO
and wild-type mice to aerosolized OVA induced a significant increase of lymphocytes and eosinophils in BALF.
BALF eosinophilia, however, was not significantly different in OVA-exposed IFN-R KO mice than in wild-type
controls. This is in agreement with the finding in a study by
Anderson and coworkers, who demonstrated no difference in the acute recruitment of eosinophils into the lung
in wild-type and IFN-R KO mice, implying that endogenous production of IFN- does not play a critical role in
acute allergen-induced airway eosinophil recruitment in vivo (12). However, for up to 2 mo after a single antigen
challenge, eosinophils were still present in the lungs of
IFN-R KO but not those of wild-type mice indicating a
transition from a spontaneously resolving to a persisting
eosinophilic inflammation of the lungs in the absence of
IFN- (12). Whereas Lack and colleagues demonstrated that exogenous IFN- is unable to influence antigen-induced
eosinophil influx into the airways, except when given prior
to immunization, Li and coworkers in contrast showed
that mucosal IFN- gene transfer inhibited pulmonary eosinophilia even when done at the time of antigen challenge
(13, 14). Moreover, recombinant IFN-, given by intraperitoneal injection or by aerosol at the time of antigen challenge, prevented eosinophil recruitment into the mouse trachea by inhibiting the infiltration of CD4+ T cells (15, 16).
IL-12 administered during allergen exposure in our
study (days 14 to 19) caused a significant decrease in
BALF eosinophils in both wild-type and IFN-R KO mice
as compared with animals given PLAC. Thus, the inhibitory effect of IL-12 on antigen-induced airway eosinophilia appeared to be largely IFN--independent when IL-12 was given during secondary allergen exposure. In a
similar murine model of antigen-induced airway inflammation, treatment of intraperitoneally sensitized mice with
anti-IFN- mAb administered just before the secondary
intratracheal antigen (sheep red blood cells) challenge did
not significantly reverse the IL-12-induced decrease in antigen-induced BALF eosinophilia (17). Although the lack
of IFN- dependence of the IL-12-mediated inhibition of
allergen-induced eosinophil influx in the latter study may have been caused by incomplete anti-IFN- neutralization
of IL-12-induced IFN-, the use of IFN-R KO mice in
our study excludes this possibility. Similarly, in mice infected with the nematode parasite Nippostrongylus brasiliensis, IL-12 inhibited IgE, mucosal mast-cell, and blood and tissue eosinophil responses during primary infections,
but inhibited only eosinophil responses during secondary
infections (18). Interestingly, anti-IFN- mAb did not affect
IL-12 inhibition of eosinophilia during a second N. brasiliensis infection, again suggesting that IL-12 may directly
suppress IL-5 expression or eosinophil production, or stimulate the production of mediators other than IFN- that
have these effects.
Whereas IL-12 administered during active immunization in the present study (days 0 to 5) caused a significant
inhibition of BALF eosinophil influx and OVA-specific
serum IgE levels in wild-type animals, IL-12 exacerbated
BALF eosinophilia and antigen-specific IgE
two responses controlled by Th2 cytokinesin IFN-R KO mice as compared with littermates given PLAC. These data are
in agreement with the in vivo model of schistosome-egg-
induced granuloma formationa Th2 dominated immune
responsein which IL-12 exacerbates rather than suppresses Th2-dependent pathology in the absence of endogenous IFN- (19). Although in vitro studies using T cells
from T-cell-receptor (TCR)-transgenic mice have indicated that IL-12 acts directly in promoting Th1 development, IFN- appeared to be necessary for the inhibitory
effects of IL-12 on Th2 cytokine expression (20). Indeed,
analysis of cytokine expression in IFN- KO mice revealed an increase in IL-4 and IL-5 secretion as a result of
treatment with IL-12, indicating that in the complete absence of IFN-, IL-12 not only seems to fail to inhibit Th2
cytokine responses, but may actually partly enhance some
Th2 responses (19). Moreover, in vivo studies of the cytokine profile elicited by immunization with soluble antigen
and IL-12 revealed that during the primary response, IL-12 induced in spleen cells the capacity to express both IL-4
and IFN-, and that upon subsequent challenge with antigen, immunization with IL-12 not only induced a Th1 recall response but also supported the development of a Th2
recall response (21). Thus, since IL-4 production is not inhibited in the absence of IFN-R, even small amounts of
IL-4 are unimpeded in stimulating Th2 cell differentiation
and BALF eosinophilia in IFN-R KO mice.
Therefore, depending upon whether IL-12 is administered during sensitization or during subsequent allergen exposure, the inhibition of airway eosinophilia by IL-12 appears to be IFN--dependent or -independent, respectively.
Importantly, although IL-12 has enormous potential as an
adjuvant for the preferential development of Th1 cytokine
responses, our data suggest that in individuals with deficiencies in IFN- production, exogenously administered IL-12 might, in addition to promoting Th1 responses, also
exacerbate Th2-dependent pathology.
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Footnotes |
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Address correspondence to: Guy G. Brusselle, M.D., Department of Respiratory Diseases, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium.
(Received in original form October 28, 1996 and in revised form April 29, 1997).
Acknowledgments:
The authors acknowledge the excellent technical assistance
of E. Castrique, C. Snauwaert, T. Tuypens, G. Barbier, and A. Neesen. They
also gratefully thank M. Gately for kindly providing rmIL-12, and acknowledge
M. Aguet for providing the IFN-R KO mice. This work was supported by the
National Fund for Scientific Research, Belgium.
Abbreviations
BAL, bronchoalveolar lavage;
IFN-, interferon-;
IFN-R KO (mice), IFN--receptor-deficient;
IL-12, interleukin-12;
OVA, ovalbumin;
PLAC, placebo;
rmIL-12, recombinant murine IL-12;
SAL, saline;
Th, T helper.
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References |
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Abstract
Introduction
Materials & Methods
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Discussion
References
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E. Campbell, S. L. Kunkel, R. M. Strieter, and N. W. Lukacs Differential Roles of IL-18 in Allergic Airway Disease: Induction of Eotaxin by Resident Cell Populations Exacerbates Eosinophil Accumulation J. Immunol., January 15, 2000; 164(2): 1096 - 1102. [Abstract] [Full Text] [PDF]
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M. R. Stämpfli, G. Scott Neigh, R. E. Wiley, M. Cwiartka, S. A. Ritz, M. M. Hitt, Z. Xing, and M. Jordana Regulation of Allergic Mucosal Sensitization by Interleukin-12 Gene Transfer to the Airway Am. J. Respir. Cell Mol. Biol., September 1, 1999; 21(3): 317 - 326. [Abstract] [Full Text]
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 K F Chung and P J Barnes Cytokines in asthma Thorax, September 1, 1999; 54(9): 825 - 857. [Full Text]
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 P. J. Barnes, K. F. Chung, and C. P. Page Inflammatory Mediators of Asthma: An Update Pharmacol. Rev., December 1, 1998; 50(4): 515 - 596. [Abstract] [Full Text] [PDF]
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C. L. Hofstra, I. Van Ark, G. Hofman, M. Kool, F. P. Nijkamp, and A. J. M. Van Oosterhout Prevention of Th2-Like Cell Responses by Coadministration of IL-12 and IL-18 Is Associated with Inhibition of Antigen-Induced Airway Hyperresponsiveness, Eosinophilia, and Serum IgE Levels J. Immunol., November 1, 1998; 161(9): 5054 - 5060. [Abstract] [Full Text] [PDF]
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