| First Author | Tian B | Year | 2018 |
| Journal | Cell Rep | Volume | 23 |
| Issue | 4 | Pages | 1138-1151 |
| PubMed ID | 29694891 | Mgi Jnum | J:271304 |
| Mgi Id | MGI:6278571 | Doi | 10.1016/j.celrep.2018.03.106 |
| Citation | Tian B, et al. (2018) Selective Antagonists of the Bronchiolar Epithelial NF-kappaB-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation. Cell Rep 23(4):1138-1151 |
| abstractText | The mechanisms by which the mammalian airway detects invading viral pathogens to trigger protective innate neutrophilic inflammation are incompletely understood. We observe that innate activation of nuclear factor kappaB (NF-kappaB)/RelA transcription factor indirectly activates atypical BRD4 histone acetyltransferase (HAT) activity, RNA polymerase II (Pol II) phosphorylation, and secretion of neutrophilic chemokines. To study this pathway in vivo, we developed a conditional knockout of RelA in distal airway epithelial cells; these animals have reduced mucosal BRD4/Pol II activation and neutrophilic inflammation to viral patterns. To further understand the role of BRD4 in vivo, two potent, highly selective small-molecule BRD4 inhibitors were developed. These well-tolerated inhibitors disrupt the BRD4 complex with Pol II and histones, completely blocking inducible epithelial chemokine production and neutrophilia. We conclude that RelA-BRD4 signaling in distal tracheobronchiolar epithelial cells mediates acute inflammation in response to luminal viral patterns. These potent BRD4 antagonists are versatile pharmacological tools for investigating BRD4 functions in vivo. |
