P20, MOLECULAR SHORTSTOP FOR INFLAMMATORY LUNG DISEASES

The transcription factor CAAT enhancer binding protein beta (C/EBPbeta) is a key factor orchestrating the inflammatory response. Specifically, expression of the genes encoding the pro-inflammatory cytokines IL-6 and on IL-8 are regulated by C/EBPbeta. C/EBPbeta can be either an activator or an inhibitor of inflammation depending on the dominant isoforms produced. Our data indicate that airway epithelial cells in culture terminate production of IL-6 and IL-8 increasing production of inhibitory C/EBPbeta isoform (p20) and that cells that have an exaggerated inflammatory response produce decreased amounts of this isoform. In addition, when animals are given endotoxin there is a decrease in lung production of the inhibitory C/EBPbeta isoform and an increase in production of the activator isoform. Since IL-6 production correlates with severity of sepsis in humans and interventions that decrease IL-6 improve outcome in that setting, we believe that increasing the inhibitory C/EBPbeta isoform in the lungs could be therapeutic for the pulmonary complications of sepsis.