The biologic activities of interleukin (IL)-13 and IL-4 often overlap, and evidence supports their importance in atopic disease and airways hyperresponsiveness. Here, their capacity to release eosinophil-activating cytokines was examined in cultured human airway smooth muscle. IL-13 and IL-4 induced selective release of eotaxin with no effect on granulocyte-macrophage colony-stimulating factor, regulated upon activation, normal T-cell expressed and secreted (RANTES), or IL-8. A profound synergistic increase in eotaxin release occurred when IL-13 or IL-4 was combined with IL-1 β that was abrogated by a neutralizing antibody to the IL-4 receptor α (IL-4R α )-chain but not to the IL-2 receptor γ (IL-2R γ )-chain. Expression of cell surface IL-4 receptors and IL-4R α in lysates was constitutive and unchanged by treatment with IL-13 or IL-4 alone or in combination with IL-1 β . Activation of IL-4R α by IL-13 or IL-4 induced signal transducer and activation of transcription-6 (STAT6), p42/ p44 ERK, p38, and to a lesser extent, SAPK/JNK mitogen-activated protein kinase phosphorylation. STAT6 and MAP kinase activation by IL-13 or IL-4 was not further potentiated after combined stimulation with IL-1 β . However, eotaxin release induced by IL-13 or IL-4 alone, and in combination with IL-1 β , was prevented by the MEK inhibitor U 0126 and by the p38 inhibitor SB 202190. Collectively, the data suggest that selective eotaxin release induced either by IL-13 and IL-4 or when combined with IL-1 β is mediated by a constitutive cell surface IL-4R α and the activation of multiple intracellular pathways.