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Integrated Signals Between IL-13, IL-4, and IL-5 Regulate Airways Hyperreactivity

Dianne C. Webb^*, Andrew N. J. McKenzie, Aulikki M. L. Koskinen^*, Ming Yang^*, Joërg Mattes^* and Paul S. Foster^1,*

^* Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra, Australia; and Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom

In 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 mice. Sensitization and aeroallergen challenge of both wild-type (WT) and IL-13 gene-targeted (IL-13^-/-) mice induced allergic disease that was characterized by pulmonary eosinophilia and AHR to ß-methacholine. Although these responses in IL-13^-/- mice were heightened compared with WT, they could be reduced to the level in nonallergic mice 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, despite the development of a blood eosinophilia. Similar neutralization of IL-4 in WT mice only partially reduced AHR with no effect on tissue eosinophilia. In addition, neutralization of IL-5 in IL-13^-/- mice, but not in WT mice, inhibited AHR, suggesting that tissue eosinophilia is linked to the mechanism underlying AHR only in the absence of IL-13. Additionally, mucus hypersecretion was attenuated in IL-13^-/- mice, despite the persistence of AHR. Taken together, our data suggest both a modulatory role for IL-13 during sensitization and a proinflammatory role during aeroallergen challenge. The latter process appears redundant with respect to IL-4.