Altered cAMP Regulation of CD40L in Asthma

DESCRIPTION (provided by applicant): Asthma, a common debilitating disease of the airways, has dramatically increased in prevalence over the past two decades. Of particular concern, morbidity and mortality are increasing despite the use of progressively more potent and effective bronchodilators. Beta-adrenoceptor agonists, a class of cAMP-inducing bronchodilators, are commonly used despite safety concerns that have persisted for over 20 years. Recently, the FDA halted a safety study of the beta-agonist Serevent because of increased risk of potentially serious and life-threatening episodes of asthma in patient subpopulations. Although mechanisms underlying adverse drug effects have not been identified, actions that increase T cell response may be involved. The role of T cells in asthma pathogenesis is well established. The T cell ligand, CD40L, is recognized as a contributing factor via its central role in IgE production and activation of B cells and antigen presenting cells. Importantly, expression of CD40L is recognized as a critical and rate limiting control point in the regulation of immune response. As such, our findings that 1) cAMP and p-agonists inhibit CD40L expression in control subjects yet enhance expression in asthmatics and 2) that an asthma-associated NK subset is involved in cAMP-induced CD40L have important ramifications with respect to pathogenesis and treatment of asthma. Our central hypothesis is that regulation of CD40L by cAMP/p-agonists is altered in asthma, and is critically regulated by a novel asthma-associated NK cell subset. We further hypothesize that alterations in the expression of CD40L protein provide a molecular basis for adverse beta-agonist drug effects and contribute to disease pathogenesis. The specific aims of the project are to: I) Identify how interactions between cAMP and calcium-dependent signaling pathways determine whether CD40L gene expression is inhibited or enhanced. II) Identify functional and phenotypic characteristics of the asthma-associated NK subset with respect to cytokine production profiles and expression of cell surface receptors. Ill) Determine how NK cells affect T cell calcium-dependent signaling pathways and contribute to elevated CD40L protein. The proposed studies are expected to further the understanding of how molecular and cellular interactions between T cells, the asthma-associated NK subset, and commonly used medications enhance CD40L in asthma and contribute to disease pathogenesis.