Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma

Cytokine effects on immunity and inflammation often depend on the transcrip tion factors termed signal transducers and activators of transcription (STA Ts), so STAT signaling pathways are candidates for influencing inflammatory disease. We reasoned that selective IFN responsiveness of the first STAT f amily member (Stat1) and Stat1-dependent immune-response genes such as inte rcellular adhesion molecule-1 (ICAM-1), IFN regulatory factor-1 (IRF-1), an d Stat1 itself in airway epithelial cells provides a basis for detecting cy tokine signaling abnormalities in inflammatory airway disease. On the basis of nuclear localization and phosphorylation, we found that epithelial Stat 1 (but not other control transcription factors) was invariably activated in asthmatic compared with normal control or chronic bronchitis subjects. Fur thermore, epithelial levels of activated Stat1 correlated with levels of ex pression for epithelial ICAM-1, IRF-1, and Stat1, and in turn, ICAM-1 level s correlated with T-cell accumulation in tissue. However, only low levels o f IFN-gamma or IFN-gamma-producing cells were detected in airway tissue in all subjects. The results therefore provide initial evidence linking abnorm al behavior of STAT pathways for cytokine signaling to the development of a n inflammatory disease. In that context, the results also change the curren t scheme for asthma pathogenesis to one that must include a localized gain in transcriptional signal ordinarily used for a T helper 1-type cytokine (I FN-gamma) in combination with allergy-driven overproduction of T helper 2-t ype cytokines.