Interactions between CBP, NF-kappaB, and CREB in the lungs after hemorrhage and endotoxemia.
The transcriptional regulatory factor nuclear factor (NF)-kappaB 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-kappaB 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-kappaB in hemorrhage- or endotoxemia-induced acute lung injury. Association of CBP with CREB or the p65 subunit of NF-kappaB 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-kappaB-dependent gene. The present results show that the coactivator CBP has an important role in modulating transcription in vivo under clinically relevant pathophysiological conditions.
Shenkar
R
R
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Yum
H K
HK
Arcaroli
J
J
Kupfner
J
J
Abraham
E
E
D000818:Animals; D050882:CREB-Binding Protein; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D019446:Endotoxemia / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006470:Hemorrhage / Q000503:physiopathology*; D008168:Lung / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology*; D051996:Transcription Factor RelA; D014158:Transcription, Genetic / Q000502:physiology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014969:Xanthine Oxidase; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse