Differential roles of IL-18 in allergic airway disease: Induction of eotaxin by resident cell populations exacerbates eosinophil accumulation

Cytokine regulation during an allergic response can dictate the severity of the inflammation and resulting injury. In the present study, we have exami ned the systemic and local effects of IL-18, a Th1-associated cytokine, on a cockroach allergen-induced airway response. In initial studies, temporal increases in IL-18 levels were observed within the lungs. When IL-18 was ne utralized systemically the allergen-associated eosinophil accumulation was significantly accelerated 5-fold by 8 h postchallenge, suggesting a regulat ory role for IL-18, Recombinant IL-18 (200 ng) was instilled into the airwa y at the time of allergen challenge to examine whether a direct impact on l ocal eosinophil accumulation could be induced. When IL-18 was instilled, a significant increase in peribronchial eosinophil accumulation was observed in allergic mice as well as in nonallergic mice, A possible mechanism was o bserved in a significant increase in eotaxin, but not other eosinophil chem otactic factors, in bronchoalveolar lavage fluid after IL-18 instillation. The role of eotaxin was confirmed using eotaxin -/- mice, which demonstrate d significantly less eosinophil accumulation compared with littermate contr ols. IL-18 was subsequently shown to induce eotaxin production from bronchi al epithelial cells and isolated macrophages in in vitro assays. The clinic al relevance of these findings was determined in treated mite and demonstra ted that neutralization of IL-18 exacerbated, whereas exogenous IL-18 had n o effect on airway hyperreactivity, Altogether, these data demonstrate that IL-18 may have multiple functions during an immune response that differ de pending upon the local or systemic effects.