The cytokines IL-4 and IL-13 are produced by Type 2 (TH2) helper T cells in response to antigen receptor engagement, by mast cells and basophils upon cross-linkage of the high affinity receptor for immunoglobulin E (IgE), and by activated eosinophils. These two cytokines elicit similar responses in vitro, many of which are associated with allergy and asthma. These responses are elicited by binding to two types of high affinity receptor complexes (Type I and Type II) and initiating signal transduction pathways primarily dictated by the IL-4Ra chain. The regulation of TH2 development and mucus secretion by lung epithelial cells are key responses shown to be regulated by the IL-4Ra during allergic inflammation and are dependent upon STAT6 expression. In addition, we recently found that expression of the IL-4Ra on bone-marrow derived, non-lymphoid cells greatly enhances the eosinophilic inflammation in the lungs in an ovalbumin induced model of allergic inflammation. Preliminary phenotyping suggests a role for signaling by the IL-4Ra on MHC Class II+, CD11b+ mononuclear cells and on eosinophils. It is not known if these cells are primarily responding to IL-4 or IL-13. We have found a differential ability of IL-4 and IL-13 to induce the IRS2 signaling pathway that is recruited by a sequence motif in the IL-4Ra called the I4R-motif. Our broad goal of this application is to understand the molecular mechanisms of signaling through the IL-4Ra by IL-4 and IL-13 and its contribution to the pathogenesis of asthma. Based on our preliminary results, we propose that signaling by the Type I receptor preferentially activates the IRS2 signaling pathway, that signaling by the IL-4Ra expressed on macrophages and/or eosinophils substantially contributes to the severity of allergic inflammation, and that the critical signaling is mediated by IL-4 through the Type I receptor, rather than by IL-13.
The specific aims designed to test these hypotheses are 1) To characterize the differences in signaling responses between IL-4 and IL-13, 2) To elucidate differences in IL-4- and IL-13- induced biological responses in macrophages and eosinophils, and 3) To test the contribution of the IL-4Ra+ macrophages and eosinophils to the severity of allergic lung inflammation in vivo. Therapeutic strategies targeting the cytokines IL-4 and IL-13 or their receptors and signaling pathways are currently being developed to treat allergy and asthma. Our studies will provide a greater understanding of their mechanism of action and contribution to allergic inflammation. This new knowledge could help to develop better approaches to treat allergy and asthma. ? ? ?
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