CONTROL OF EPITHELIAL IMMUNE-RESPONSE GENES AND IMPLICATIONS FOR AIRWAY IMMUNITY AND INFLAMMATION

A major goal of our research is to understand how immune cells (especi ally T cells) infiltrate the pulmonary airway during host defense and inflammatory disease (especially asthma). In that context, we have pro posed that epithelial cells lining the airway provide critical biochem ical signals for immune-cell influx and activation and that this epith elial-immune cell interaction is a critical feature of airway inflamma tion and hyperreactivity. In this brief report, we describe our progre ss in defining a subset of epithelial immune-response genes the expres sion of which is coordinated for viral defense both directly in respon se to replicating virus and indirectly under the control of a specific interferon-gamma signal transduction pathway featuring the Stat1 tran scription factor as a critical relay signal between cytoplasm and nucl eus. Unexpectedly, the same pathway is also activated during asthmatic airway inflammation in a setting where there is no apparent infection and no increase in interferon-gamma levels. The findings provide the first evidence of an overactive Stat1-dependent gene network in asthma tic airways and a novel molecular link between mucosal immunity and in flammation. The findings also offer the possibility that overactivity of Stat1-dependent genes might augment a subsequent T helper cell (Th1 )-type response to virus or might combine with a heightened Th2-type r esponse to allergen to account for more severe exacerbations of asthma .