Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells

Airway inflammation associated with asthma is characterized by massive infi ltration of eosinophils, mediated in part by specific chemoattractant facto rs produced in the lung. Allergen-specific Th2 cells appear to play a centr al role in asthma; for example, adoptively transferred Th2 cells induced lu ng eosinophilia associated with induction of specific chemokines. Interesti ngly, Th2 supernatant alone administered intranasally to naive mice induced eotaxin, RANTES, monocyte-chemotactic protein-1, and KC expression along w ith lung eosinophilia, We tested the major cytokines individually and found that IL-4 and IL-5 induced higher levels of macrophage-inflammatory protei n-1 alpha and KC; IL-4 also increased the production of monocyte-chemotacti c protein-1; IL-13 and IL-4 induced eotaxin, IL-13 was by far the most pote nt inducer of eotaxin; indeed, a neutralizing anti-IL-13 Ab removed most of the eotaxin-inducing activity from Th2 supernatants, although it did not e ntirely block the recruitment of eosinophils. While TNF-alpha did not stimu late eotaxin production by itself, it markedly augmented eotaxin induction by IL-13, IL-13 was able to induce eotaxin in the lung of JAK3-deficient mi ce, suggesting that JAK3 is not required for IL-13 signaling in airway epit helial cells; however, eosinophilia was not induced in this situation, sugg esting that JAK3 transduces other IL-13-mediated mechanisms critical for eo sinophil recruitment. Our study suggests that IL-13 is an important mediato r in the pathogenesis of asthma and therefore a potential target for asthma therapy.