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

The transcriptional regulatory factor nuclear factor (NF)-kappaB has a cent ral role in modulating expression of proinflammatory mediators that are imp ortant in acute lung injury. In vitro studies have shown that competition b etween NF-kappaB and cAMP response element binding protein (CREB) for bindi ng to the coactivator CREB-binding protein (CBP) is important in regulating transcriptional activity of these factors. In the present study, we examin ed in vivo interactions between CBP, CREB, and NF-kappaB in hemorrhage-or e ndotoxemia-induced acute lung injury. Association of CBP with CREB or the p 65 subunit of NF-kappaB increased in the lungs after hemorrhage or endotoxe mia. Inhibition of xanthine oxidase before hemorrhage, but not before endot oxemia, decreased p65-CBP interactions while increasing those between CREB and CBP. These alterations in CREB-CBP and p65-CBP interactions were functi onally significant because xanthine oxidase inhibition before hemorrhage re sulted in increased expression of the CREB-dependent gene c-Fos and decreas ed expression of macrophage inflammatory protein-2, a NF-kappaB-dependent g ene. The present results show that the coactivator CBP has an important rol e in modulating transcription in vivo under clinically relevant pathophysio logical conditions.