Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity

Ln this investigation, we have examined the integrated relationship between IL-13, IL-4, and IL-5 for the development of airways hyperreactivity (AHR) in a model of asthma in BALB/c mite. Sensitization and aeroallergen challe nge of both wild-type (WT) and IL-13 gene-targeted (IL-13(-/-)) mice induce d allergic disease that was characterized by pulmonary eosinophilia and AHR to beta-methacholine. Although these responses in IL-13-/- mice were heigh tened compared with WT, they could be reduced to the level in nonallergic m ice by the concomitant neutralization of IL-4. Mice in which both IL-4 and IL-13 were depleted displayed a marked reduction in tissue eosinophils, des pite the development of a blood eosinophilia, Similar neutralization of IL- 4 in WT mice only partially reduced AHR with no effect on tissue eosinophil ia, In addition, neutralization of IL-5 in IL-13(-/-) mice, but not in WT m ice, inhibited AHR, suggesting that tissue eosinophilia is linked to the me chanism underlying AHR only in the absence of IL-13, Additionally, mucus hy persecretion was attenuated in IL-13(-/-) mice, despite the persistence of AHR. Taken together, our data suggest both a modulatory role for IL-13 duri ng sensitization and a proinflammatory role during aeroallergen challenge. The latter process appears redundant with respect to IL-4.