Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 20, Pages E3993-E4001Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1700109114
Keywords
NF-kappa B; Brd4; eIF4E; I kappa B alpha resynthesis; Mnk2
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Funding
- University of Illinois at Urbana-Champaign
- NIH [AI117080, CA179511]
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Bromodomain-containing factor Brd4 has emerged as an important transcriptional regulator of NF-kappa B-dependent inflammatory gene expression. However, the in vivo physiological function of Brd4 in the inflammatory response remains poorly defined. We now demonstrate that mice deficient for Brd4 in myeloid-lineage cells are resistant to LPS-induced sepsis but are more susceptible to bacterial infection. Gene-expression microarray analysis of bone marrow-derived macrophages (BMDMs) reveals that deletion of Brd4 decreases the expression of a significant amount of LPS-induced inflammatory genes while reversing the expression of a small subset of LPS-suppressed genes, including MAP kinase-interacting serine/threonine-protein kinase 2 (Mknk2). Brd4-deficient BMDMs display enhanced Mnk2 expression and the corresponding eukaryotic translation initiation factor 4E (eIF4E) activation after LPS stimulation, leading to an increased translation of I.Ba mRNA in polysomes. The enhanced newly synthesized I.Ba reduced the binding of NF-kappa B to the promoters of inflammatory genes, resulting in reduced inflammatory gene expression and cytokine production. By modulating the translation of I.Ba via the Mnk2-eIF4E pathway, Brd4 provides an additional layer of control for NF-kappa B-dependent inflammatory gene expression and inflammatory response.
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