It is thought that release of cytokines from allergen-damaged epithelial cells induces production of an innate source of IL-4 and IL-13 that are important in initiating adaptive T-helper type II (Th2)-mediated allergic responses. However, detecting innate production of IL-4 or IL-13 in vivo is difficult due to high levels of adaptive production of IL-4 and IL-13 by Th2 cells. The IL-4 receptor (IL-4R) and the IL-4/13 co-receptor (IL-13R) share a common receptor subunit (IL-4Ra). Consequently, both IL-4 and IL-13 signal via the IL-4Ra-associated signaling molecule, signal transducer and activator of transcription factor 6 (STAT6). STAT6 signaling in T-cells, B-cells, and airway epithelial cells is essential for Th2 differentiation, isotype class switching to IgE, and mucus production, respectively. Therefore, Epi-STAT6 mice (STAT6-/- mice with airway epithelial-specific transgenic STAT6 expression) are defective in Th2 immune responses but can produce mucus in response to IL-4 and/or IL-13 in their airways. As compared to wildtype mice, allergen- challenged Epi-STAT6 mice were deficient in IgE production and the levels of IL-13 expressed were not above appropriate controls. However, significant levels of IL-4 and mucin gene expression were detected in their lungs. These observations support the existence of an allergen-responsive, non-Th2-derived source of IL-4 in the airways of mice.