Mast cells and basophils play a critical role in the pathogenesis of IgE- dependent immediate hypersensitivity reactions. These reactions are elicited within minutes of exposure to the antigens (such as pollen, mole spores, animal dander) and are characterized by anaphylaxis, bronchospasm, rhinorrhea and allergic urticaria. Activation of mast cells follows the cross-linking of IgE molecules on the mast cell surface by multivalent antigen which elicits the release of allergic mediators such as histamine, leukotrienes and prostaglandins. Mast cells can also participate in chronic inflammatory or immunological responses such as allergic asthma. These latter actions are associated with the recruitment of leukocytes to the affected area. Adenosine, a metabolite of ATP, can augment antigen- stimulated degranulation of mast cells by interacting with a novel adenosine receptor (AR) on a cell clone (RBL-2H3). This receptor subtype appears to be unique from the A/1, or A/2ARs because of its relative subsensitivity to methylxanthine antagonists. Its pharmacological profile suggests it to be similar, if not identical, to the A/3 adenosine receptor (A/3AR) cloned from rat brain. Activation of these A/3AR on RBL-2H3 cells increased the production of inositol 1,4,5-triphosphate (IP/3) and promoted the release of intracellular Ca2+ and histamine. Treatment of RBL-2H3 cells with the immunosuppressive agent, dexamethasone, attenuated the responses of these cells to antigens. In contrast, dexamethasone augmented the secretory response elicited by adenosine. Our current hypothesis is that the augmented response to adenosine involves amplification of the A/3AR signal transduction pathway. During the tenure of this study, the effect of dexamethasone on various components of the A/3AR signalling system will be tested using functional studies, Western and Northern blotting and radioligand binding experiments. Secondly, cDNA and genomic cloning of the A/3AR will be performed to determine the mechanism by which dexamethasone regulates the A/3AR gene expression. Overall, these studies will contribute greatly to our understanding of how the mast cell A/3AR is regulated by corticosteroids and provide a model for regulation of A/3AR expression in various tissues. Moreover, these studies might shed some light as to why certain asthmatic individuals are not responsive to dexamethasone.
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