Interleukin-13 mediates airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin

Interleukin (IL)-13 is a central mediator of the processes underlying the i nduction of airways hyperreactivity (AHR) in the allergic lung. However, th e mechanisms by which IL-13 induces AHR and the associated role of inflamma tory infiltrates as effector cells has not been fully elucidated. In this i nvestigation, we show that intratracheal administration of IL-13 induces AH R in the presence and absence of inflammation. The initial AHR response (pe ak, 6 to 24 h; preinflammatory phase [PIP]) was dissociated from inflammati on (eosinophilia) and mucus hypersecretion but was critically regulated by signaling through the IL-4 receptor a chain (IL-4R alpha) and signal transd ucers and activators of transcription (STAT)-6. The second response (> 24 h , inflammatory phase [IP]) was characterized by an amplified AHR, eosinophi l accumulation, and mucus hypersecretion. These features of the IP were not observed in IL-4R alpha- or STAT-6-deficient mice. To determine the role o f eosinophils in the induction of IP AHR and mucus hypersecretion, we admin istered IL-13 to IL-5-, eotaxin-, and IL-5/eotaxin-deficient mice. IL-13-me diated eosinophil accumulation was significantly attenuated (but not ablate d) in IL-5-, eotaxin-, or IL-5/eotaxin-deficient mice. However, IL-13-induc ed AHR and mucus secretion occurred independently of IL-5 and/or eotaxin. T hese findings demonstrate that IL-13 can induce AHR independently of these eosinophil regulatory cytokines and mucus hypersecretion. Furthermore, IL-1 3-induced AHR, eosinophilia, and mucus production are critically dependent on the IL-4R alpha chain and STAT-6.