Interactions between CBP, NF-kB, and CREB in the lungs after hemorrhage and endotoxemia

Shenkar, Robert, Ho-Kee Yum, John Arcaroli, John Kupfner, and Edward Abraham. Interactions between CBP, NF-kB, and CREB in the lungs after hemorrhage and endotoxemia. Am J Physiol Lung Cell Mol Physiol 281: L418–L426, 2001.—The transcriptional regulatory factor nuclear factor (NF)-kB has a central role in modulating expression of proinflammatory mediators that are important in acute lung injury. In vitro studies have shown that competition between NF-kB and cAMP response element binding protein (CREB) for binding to the coactivator CREB-binding protein (CBP) is important in regulating transcriptional activity of these factors. In the present study, we examined in vivo interactions between CBP, CREB, and NF-kB in hemorrhageor endotoxemia-induced acute lung injury. Association of CBP with CREB or the p65 subunit of NF-kB increased in the lungs after hemorrhage or endotoxemia. Inhibition of xanthine oxidase before hemorrhage, but not before endotoxemia, decreased p65-CBP interactions while increasing those between CREB and CBP. These alterations in CREB-CBP and p65-CBP interactions were functionally significant because xanthine oxidase inhibition before hemorrhage resulted in increased expression of the CREB-dependent gene c-Fos and decreased expression of macrophage inflammatory protein-2, a NF-kB-dependent gene. The present results show that the coactivator CBP has an important role in modulating transcription in vivo under clinically relevant pathophysiological conditions.