IL-4 is an essential cytokine in the immune response, regulating T cell differentiation, B cell immunoglobulin production, and the activation of macrophages. These activities give IL-4 a pivotal role in allergic disease. IL-4 acts through binding to the IL-4 receptor (IL-4R), composed of IL-4Ra and the common gamma chain, gc. The results of IL-4 signaling on target cells can be broadly characterized as growth or gene regulation, activities, which are predominantly controlled by two distinct domains of IL-4Ra. Many IL-4-induced gene expression events require the activation of STAT6, which is regulated by the IL-4Ra Gene Regulation Domain. Our work is focused on understanding how IL-4Ra activates STAT6 and the result of this activation on target cell signaling events. The first specific aim is to structurally characterize the IL-4Ra Gene Regulation Domain, through mapping of this domain's minimal STAT6 activation sequence, determining the mobility of this sequence, and ascertaining the essential nature of this sequence in IL-4-mediated gene expression. The second and third specific aims will determine the role of STAT6 in IL-4- mediated negative signaling of mast cells and macrophages using STAT6- deficient mice. These experiments will yield a greater understanding of the structure-function relationship if IL-4Ra and STAT6, and an understanding of these functions in cell signaling and allergic disease.
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