Atopic dermatitis (AD), a chronic relapsing inflammatory skin disease, is a major public health problem affecting 9-20% of the population of the United States. This disease results from complex interactions between host factors (genetic susceptibility, immunologic responses, and skin barrier dysfunction) and environmental factors such as allergens, irritants, and infectious agents. IL-13 is an immunoregulatory Th2 cytokine that has been implicated in the pathogenesis of AD by multiple studies. IL-13, but not IL-4, is expressed in the lesions from individuals with AD, and investigators have demonstrated 10-20 fold increases in a variety of IL-13 inducible genes in expression profiles from murine models of AD. Furthermore, recent studies have found that the percentage of peripheral blood CD4+IL-13+ T lymphocytes correlates with AD disease severity in children. IL-13 is a central mediator of allergic inflammation. Despite mounting evidence supporting the importance of IL-13 in atopic dermatitis, there is a lack of information regarding the regulation of IL-13 responses in skin cells. This gap in understanding has hindered the development of novel therapeutic interventions for this disease targeting IL-13 or its signaling pathways. Our preliminary data demonstrate that IL-13 receptors, specifically IL-13R 2, are regulated by allergic inflammation and/or Th2 cytokines in keratinocytes, in mouse models of AD, and in human AD lesions. Alterations in the absolute and relative expressions of these receptors will impact IL-13 responses. These and other findings led us to hypothesize that IL-13R 2 is an important regulator of cutaneous allergic inflammation and that alterations in IL-13R 2 expression and cellular distribution in keratinocytes contribute to AD pathogenesis. We propose 3 aims designed to understand the regulation of IL-13 receptors in keratinocytes, the role of IL-13R 2 in an animal model of AD, and the association of IL-13 receptors with AD phenotypes in human disease. The public health impact of this study will be significant. Through the results of this study, we will be able to provide information regarding the biology of IL-13 receptors in keratinocytes and how IL-13 responses are regulated in AD. Delineating the mechanisms responsible for modulating cutaneous IL-13 responses will provide novel insight into the pathogenesis of AD and identify targets for new therapeutic interventions. Furthermore, we may identify clinically useful IL-13 receptor biomarkers of atopic dermatitis phenotypes. ? ? ?
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