PMID- 28461486
OWN - NLM
STAT- MEDLINE
DCOM- 20180515
LR  - 20221129
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 114
IP  - 20
DP  - 2017 May 16
TI  - Brd4 modulates the innate immune response through Mnk2-eIF4E pathway-dependent 
      translational control of IkappaBalpha.
PG  - E3993-E4001
LID - 10.1073/pnas.1700109114 [doi]
AB  - Bromodomain-containing factor Brd4 has emerged as an important transcriptional 
      regulator of NF-kappaB-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 
      IkappaBalpha mRNA in polysomes. The enhanced newly synthesized IkappaBalpha reduced the binding 
      of NF-kappaB to the promoters of inflammatory genes, resulting in reduced 
      inflammatory gene expression and cytokine production. By modulating the 
      translation of IkappaBalpha via the Mnk2-eIF4E pathway, Brd4 provides an additional layer 
      of control for NF-kappaB-dependent inflammatory gene expression and inflammatory 
      response.
FAU - Bao, Yan
AU  - Bao Y
AD  - Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 
      IL 61801.
FAU - Wu, Xuewei
AU  - Wu X
AD  - Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 
      IL 61801.
FAU - Chen, Jinjing
AU  - Chen J
AD  - Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 
      IL 61801.
FAU - Hu, Xiangming
AU  - Hu X
AD  - Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 
      IL 61801.
FAU - Zeng, Fuxing
AU  - Zeng F
AD  - Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 
      IL 61801.
FAU - Cheng, Jianjun
AU  - Cheng J
AD  - Department of Materials Science and Engineering, University of Illinois at 
      Urbana-Champaign, Urbana, IL 61801.
FAU - Jin, Hong
AU  - Jin H
AD  - Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 
      IL 61801.
FAU - Lin, Xin
AU  - Lin X
AD  - Department of Basic Medical Science, Tsinghua University School of Medicine, 
      Beijing 100084, China.
FAU - Chen, Lin-Feng
AU  - Chen LF
AD  - Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 
      IL 61801; lfchen@life.illinois.edu.
AD  - College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 
      61801.
LA  - eng
GR  - R01 CA179511/CA/NCI NIH HHS/United States
GR  - R01 GM120552/GM/NIGMS NIH HHS/United States
GR  - R21 AI117080/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170501
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Brd4 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - EC 2.7.1.- (Mknk2 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Eukaryotic Initiation Factor-4E/metabolism
MH  - Gene Expression Regulation
MH  - *Immunity, Innate
MH  - Lipopolysaccharides
MH  - Lung/pathology
MH  - MAP Kinase Signaling System
MH  - Macrophages/metabolism
MH  - Mice, Knockout
MH  - NF-KappaB Inhibitor alpha/*metabolism
MH  - NF-kappa B/*metabolism
MH  - Nuclear Proteins/*physiology
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Shock, Septic/immunology/pathology
MH  - Transcription Factors/*physiology
PMC - PMC5441817
OTO - NOTNLM
OT  - Brd4
OT  - IkappaBalpha resynthesis
OT  - Mnk2
OT  - NF-kappaB
OT  - eIF4E
COIS- The authors declare no conflict of interest.
EDAT- 2017/05/04 06:00
MHDA- 2018/05/16 06:00
PMCR- 2017/11/16
CRDT- 2017/05/03 06:00
PHST- 2017/05/04 06:00 [pubmed]
PHST- 2018/05/16 06:00 [medline]
PHST- 2017/05/03 06:00 [entrez]
PHST- 2017/11/16 00:00 [pmc-release]
AID - 1700109114 [pii]
AID - 201700109 [pii]
AID - 10.1073/pnas.1700109114 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2017 May 16;114(20):E3993-E4001. doi: 
      10.1073/pnas.1700109114. Epub 2017 May 1.