EFFECT OF INFLAMMATORY MEDIATORS ON MUCIN GENE EXPRESSION

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Excessive respiratory secretions are a major cause of the airway obstruction in Asthma, Chronic Bronchitis and Cystic Fibrosis. A variety of mediators of immediate hypersensitivity and of acute inflammation have been shown to increase secretion of respiratory mucin glycoprotein. Little data is available on the effect of mediators of inflammation on gene expression of respiratory mucins. The goal of this study is to define the effect of inflammation and of the known mediators of respiratory mucosal inflammation on respiratory mucin gene expression. These studies utilize respiratory epithelial cells from human subjects and experimental animals and from a human cell line. Polymerase chain reaction is used to quantitate mucin message utilizing PCR probes designed from previously published mucin gene structure. This data is correlated with secretory studies using an Elisa specific for respiratory mucin. Endotoxin, TNFalpha, IL-I and IL-6 have been found capable of inducing mucin gene expression in respiratory epithelial cells. The intracellular events involved in this process are under investigation. Activation of ProteinKinase C appears to be involved in the induction of MUC-2 in RNA by TNF. Studies are currently underway to evaluate the role of NFKB in this process. In addition II--10 has been found to inhibit TNF induced mucin hypersecretion and studies are currently underway to determine the mechanism of the IL-10 effect. This project may allow for new insight into cytokine modulation of epithelial cell gene expression.