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

Background: T-H2 cytokines are associated with airway inflammation and hyperreactivity in bronchial asthma, and restoration of the T-H1/T-H2 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 T-H1-type cytokine. Although IL-18 and IL-12 act on T cells synergistically to induce IFN-gamma production, the contribution of IL-18 T-H1/T-H2 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 T-H2 mucosal immunity. We also have investigated the ability of intraperitoneal instilled IL-18 to reduce T-H2 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-gamma 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 T-H2 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.