EFFECT OF INTERLEUKIN 5 RECEPTOR ACTIVATION ON EOSINOPHIL SIGNAL TRANSDUCTION

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Allergic inflammation and asthma are characterized by eosinophilia and the increased production of interleukin 5 (Il-5) in blood and affected tissues. Eosinophils can promote both bronchial smooth muscle contraction and increased permeability of bronchial mucosa. Eosinophil- derived mediators [e.g., granule proteins, reactive oxygen species and leukotriene C4 (LTC4)], can evoke hyper-responsiveness, epithelial damage, inflammation and bronchoconstriction. IL-5 is known to regulate eosinophil function, which can contribute to the pathogenesis of asthma. For example, IL-5 stimulation of blood eosinophils can produce several functional changes that mirror the phenotypic characteristics of the airway eosinophil, and these IL-5-induced changes include the priming LTC4 release, the increased membrane expression of CD11b/CD18, the enhance adherence to endothelial cells, and prolonged survival. Because little is known about IL-5 signal transduction in eosinophils, the present project is designed to explore the mechanisms by which Il-5 mediates alterations in eosinophil function, thereby increasing its inflammatory potential. This proposal will test a model of IL-5 intracellular signaling processes that is based on studies by us and others on the IL-5 family of cytokines. Our overall goal is to assess the importance of various aspects of this model to the intracellular events in human eosinophils stimulated with IL-5, and to relate these signaling processes to eosinophil function. The studies will focus on functional changes, namely chemotaxis, adherence to endothelium, LTC4 generation and suppression of apoptotic cell death, that are of particular relevance to the inflammatory capacity and accumulation of eosinophils in the pathogenesis of asthma. The proposed research centers around our observation that IL-5 stimulates the tyrosine phosphorylation of several cellular proteins, including the phosphorylation and activation of a 45-kDa mitogen- activated protein kinase (MAP kinase). The central hypothesis is developed that multiple pathways are involved in the IL-5 mediated tyrosine phosphorylation and activation of MAP kinases in eosinophils. To test this hypothesis, we will analyze the events that link IL-5 receptor activation to MAP kinase stimulation, such as pathways encompassing tyrosine kinases, Ras, protein kinase C, and/or pertussis toxin-sensitive G-proteins. Secondly, we will also examine selected processes that may result from IL-5-stimulated MAP kinase activity, including the regulation of phospholipase A2, ribosomal S6 kinase II (Rsk) and the hematopoietic transcription factor GATA-2, since these proteins are established MAP kinase substrates. These investigations lead to the related hypothesis that MAP kinase activation is a key intracellular mechanism, that along with other signaling events, is associated with IL-5 mediated changes in eosinophil function, including the priming of LTC4 generation, increased adherence to endothelial cells, chemotaxis and suppression of apoptotic cell death. In sum, it is anticipated that these studies will lead to a greater understanding of the molecular processes associated with eosinophilic inflammation that is a major characteristic of the pathophysiology of asthma.