IL-18 deficiency selectively enhances allergen-induced eosinophilia in mice,☆☆,

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Abstract

Background: TH2 cytokines are associated with airway inflammation and hyperreactivity in bronchial asthma, and restoration of the TH1/TH2 imbalance is a potential avenue for novel therapies. IL-18 is a cytokine secreted by activated macrophages, and it shares some of its biologic activities with IL-12, a typical TH1-type cytokine. Although IL-18 and IL-12 act on T cells synergistically to induce IFN-γ production, the contribution of IL-18 TH1/TH2 imbalance and to subsequent asthmatic response has not been elucidated in vivo. Objective: We studied a model of allergic asthma in IL-18–deficient mice to investigate the modulatory role of IL-18 on induction and maintenance of TH2 mucosal immunity. We also have investigated the ability of intraperitoneal instilled IL-18 to reduce TH2 mucosal immunity in IL-18–deficient mice. Methods: IL-18–deficient mice immunized to ovalbumin by means of intraperitoneal injection were challenged 3 times with an aerosol of ovalbumin every second day for 8 days. Recombinant (r)IL-18 was intraperitoneally administered in mice before every first challenge. Mice were analyzed for effects on lung eosinophilia, cytokines, and serum IgE levels. Results: In IL-18–deficient mice, levels of eosinophilia and lung damage were significantly higher than in wild-type C57/BL6 litter mates. Intraperitoneal administration of rIL-18 in deficient mice reduced these antigen-induced changes to levels seen in wild-type mice in association with a decrease in IL-4 in bronchoalveolar lavage fluid and lung tissue. However, administration of rIL-18 did not affect the IFN-γ level and somewhat enhanced the production of IL-5. Notably, reconstitution with rIL-18 increased the numbers of cells staining for Fas ligand, as well as apoptotic cells stained by nick end-labeling in bronchial submucosa infiltrates. Conclusion: These findings indicate that in vivo IL-18 not only inhibited antigen-specific TH2 development but also affected apoptosis through Fas-Fas ligand interactions. These data support a role for IL-18 in the complex pathogenesis of allergic inflammation in which IL-18 limited the development of the local inflammatory response to antigen. (J Allergy Clin Immunol 2000;105:45-53.)

Section snippets

Animals

Specific pathogen-free male C57BL/6 mice 6 to 8 weeks old were purchased from Charles River Laboratories (Atsugi, Japan). Male homozygous IL-18–deficient mice of C57BL/6 lineage that had been produced and bred at the Institute for Advanced Medical Sciences, Hyogo College of Medicine (Nishinomiya, Japan),14 were studied at 6 to 10 weeks of age. A normal immune system develops in these mice, except that they display reduced production of IFN-γ, impaired NK-cell activity, and downregulated TH1

Antigen-induced pulmonary eosinophilia in IL-18–deficient mice

In actively immunized wild-type mice, inflammatory cells infiltrating lung tissues were increased dramatically after repeated exposure to OVA in comparison with mice exposed only to saline. Analysis of BALF cells also revealed marked elevation of the eosinophil population (37.8 ± 25.0 vs <0.1 × 105/mL) and slight increases in neutrophils (2.3 ± 0.8 vs <0.1 × 105/mL), lymphocytes (6.5 ± 1.6 vs 0.2 ± 0.1 × 105/mL), and macrophages (9.3 ± 4.8 vs 2.7 ± 0.8 × 105/mL). An increase in inflammatory

DISCUSSION

IL-18 originally was termed IFN-γ–inducing factor because it induces production of IFN-γ by T cells in vitro.13, 19 Recent reports have provided evidence that IL-18 shares its biologic functions with IL-12, which is known to have immunoregulatory activity, including induction of IFN-γ production,20 enhancement of NK-cell cytotoxicity,14, 21 and enhancement of activated T-cell proliferation. With respect to development of allergic inflammation, coadministration of IL-18 with IL-12 has been

Acknowledgements

We thank Ms Kyoko Obata and Ms Miho Fujisawa for assistance with the experiments and Dr Shigeru Miyata, Dr Shin-ichiro Kashiwamura, and Dr Haruyasu Ueda for helpful discussion.

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    Supported in part by grants from Hyogo College of Medicine Research and the Ministry of Education, Science and Culture, Japan.

    ☆☆

    Reprint requests: Tomohiro Matsuyama, MD, PhD, Fifth Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.

    0091-6749/2000/$12.00 + 0  1/1/103415

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