The persistence of an otherwise normal inflammatory response results in a state of disease inclusive of autoimmune, chronic allergies and asthmatic diseases. Mechanisms regulating the expression of newly synthesized mediators of inflammation have been investigated. In the past year we have focused on the molecular events initiated by the interaction of an allergen with IgE, bound to the cell suface high affinity receptor for IgE expressed on mast cells, that result in cytokine gene expression. Three principal areas of investigation were developed: 1. Studies on molecular events, proximal to the activation of the high affinity receptor for IgE, that may influence cytokine gene expression. 2. Studies on the protein kinase C family of isozymes (effects on degranulation and cytokine gene expression). 3. Studies on the hematopoietic cell-specific protein Vav, its role in regulating cytokine expression in mast cells. We have found that high levels of IgE in the blood, induced by injection of IgE or by parasite infection of rats, result in the upregulation of the high affinity receptors for IgE on mast cells and an increase in the number of mast cells and progenitors localized to the sites of inflammation. These studies provide insights on the correlation of atopy and increased hypersensitivity in atopic individuals and may provide a model for in vivo study of mast cell cytokine responses. Studies on the regulation of the activity of the kinases associated with the high affinity receptor for IgE have revealed that protein kinase Cdelta plays a role in regulating the activity of Lyn kinase, a protein necessary for the activation of the high affinity receptor for IgE. This finding provides a novel area of investigation to define whether protein kinase Cdelta provides a therapeutic target for abrogating degranulation and cytokine responses in mast cells. We have also investigated the efficacy and molecular target of the acridone-related compound, ER-27319, as a mast cell selective inhibitor. These studies show that this compound targets the activation of Syk kinase, an activity required for mast cell degranulation and cytokine production, selectively in mast cells and not in B-cells or platelets which also express this kinase. These findings promote the therapeutic potential of ER-27319 in allergies. We also found that both protein kinase Cbeta and Vav, a hematopoietic cell-specific protein, regulate cytokine gene expression in mast cells. Overexpression of these proteins results in enhanced production of IL-2 and IL-6 and possibly other cytokines. Overexpression of other highly homologous proteins does not induce these responses. Thus these studies provide the framework to explore the molecular steps that initiate these responses in mast cells.
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