I-BET151 selectively regulates IL-6 production

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Orchestration of the inflammatory response is crucial for clearing pathogens. Although the production of multiple inflammatory cytokines has been thought to be regulated by common mechanisms, recent evidence indicates that the expression of some cytokines is differentially regulated by epigenetic regulatory mechanisms. In this study, we found that IL-6 production is selectively inhibited by the BET bromodomain protein (BRD) inhibitor I-BET151 in RAW264.7 cells stimulated with lipopolysaccharide (LPS), whereas I-BET151 did not alter the production of several other cytokines (TNFα, IL-1β and IL-10) at the concentration of IBET151 used. I-BET151 prevented the binding of CBP to the promoter of IL-6, but I-BET151 did not affect acetylation, phosphorylation, nuclear translocation, or DNA binding of p65-NF-κB. In vivo, I-BET151 treatment in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis decreased the early clinical symptoms, which are thought to be dependent on cytokine production. Altogether, these data suggest that targeting epigenetic-related proteins, such as BET proteins, may provide a strategy to reduce inflammation and the severity of inflammatory diseases, such as multiple sclerosis.

Original languageEnglish
Pages (from-to)1549-1555
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number9
DOIs
StatePublished - Jan 1 2014

Fingerprint

Interleukin-6
Cytokines
Epigenomics
Multiple Sclerosis
Proteins
Autoimmune Experimental Encephalomyelitis
Acetylation
Interleukin-1
Interleukin-10
Lipopolysaccharides
Phosphorylation
GSK1210151A
Inflammation
DNA

Keywords

  • Cytokines
  • I-BET151
  • Lipopolysaccharide
  • Macrophage
  • NF-κB

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

I-BET151 selectively regulates IL-6 production. / Barrett, Elyse; Brothers, Shaun P; Wahlestedt, Claes R; Beurel, Eleonore.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1842, No. 9, 01.01.2014, p. 1549-1555.

Research output: Contribution to journalArticle

@article{dad17a96e9d14c6ab999bfa9cc4faf46,
title = "I-BET151 selectively regulates IL-6 production",
abstract = "Orchestration of the inflammatory response is crucial for clearing pathogens. Although the production of multiple inflammatory cytokines has been thought to be regulated by common mechanisms, recent evidence indicates that the expression of some cytokines is differentially regulated by epigenetic regulatory mechanisms. In this study, we found that IL-6 production is selectively inhibited by the BET bromodomain protein (BRD) inhibitor I-BET151 in RAW264.7 cells stimulated with lipopolysaccharide (LPS), whereas I-BET151 did not alter the production of several other cytokines (TNFα, IL-1β and IL-10) at the concentration of IBET151 used. I-BET151 prevented the binding of CBP to the promoter of IL-6, but I-BET151 did not affect acetylation, phosphorylation, nuclear translocation, or DNA binding of p65-NF-κB. In vivo, I-BET151 treatment in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis decreased the early clinical symptoms, which are thought to be dependent on cytokine production. Altogether, these data suggest that targeting epigenetic-related proteins, such as BET proteins, may provide a strategy to reduce inflammation and the severity of inflammatory diseases, such as multiple sclerosis.",
keywords = "Cytokines, I-BET151, Lipopolysaccharide, Macrophage, NF-κB",
author = "Elyse Barrett and Brothers, {Shaun P} and Wahlestedt, {Claes R} and Eleonore Beurel",
year = "2014",
month = "1",
day = "1",
doi = "10.1016/j.bbadis.2014.05.013",
language = "English",
volume = "1842",
pages = "1549--1555",
journal = "Biochimica et Biophysica Acta - Molecular Basis of Disease",
issn = "0925-4439",
publisher = "Elsevier",
number = "9",

}

TY - JOUR

T1 - I-BET151 selectively regulates IL-6 production

AU - Barrett, Elyse

AU - Brothers, Shaun P

AU - Wahlestedt, Claes R

AU - Beurel, Eleonore

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Orchestration of the inflammatory response is crucial for clearing pathogens. Although the production of multiple inflammatory cytokines has been thought to be regulated by common mechanisms, recent evidence indicates that the expression of some cytokines is differentially regulated by epigenetic regulatory mechanisms. In this study, we found that IL-6 production is selectively inhibited by the BET bromodomain protein (BRD) inhibitor I-BET151 in RAW264.7 cells stimulated with lipopolysaccharide (LPS), whereas I-BET151 did not alter the production of several other cytokines (TNFα, IL-1β and IL-10) at the concentration of IBET151 used. I-BET151 prevented the binding of CBP to the promoter of IL-6, but I-BET151 did not affect acetylation, phosphorylation, nuclear translocation, or DNA binding of p65-NF-κB. In vivo, I-BET151 treatment in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis decreased the early clinical symptoms, which are thought to be dependent on cytokine production. Altogether, these data suggest that targeting epigenetic-related proteins, such as BET proteins, may provide a strategy to reduce inflammation and the severity of inflammatory diseases, such as multiple sclerosis.

AB - Orchestration of the inflammatory response is crucial for clearing pathogens. Although the production of multiple inflammatory cytokines has been thought to be regulated by common mechanisms, recent evidence indicates that the expression of some cytokines is differentially regulated by epigenetic regulatory mechanisms. In this study, we found that IL-6 production is selectively inhibited by the BET bromodomain protein (BRD) inhibitor I-BET151 in RAW264.7 cells stimulated with lipopolysaccharide (LPS), whereas I-BET151 did not alter the production of several other cytokines (TNFα, IL-1β and IL-10) at the concentration of IBET151 used. I-BET151 prevented the binding of CBP to the promoter of IL-6, but I-BET151 did not affect acetylation, phosphorylation, nuclear translocation, or DNA binding of p65-NF-κB. In vivo, I-BET151 treatment in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis decreased the early clinical symptoms, which are thought to be dependent on cytokine production. Altogether, these data suggest that targeting epigenetic-related proteins, such as BET proteins, may provide a strategy to reduce inflammation and the severity of inflammatory diseases, such as multiple sclerosis.

KW - Cytokines

KW - I-BET151

KW - Lipopolysaccharide

KW - Macrophage

KW - NF-κB

UR - http://www.scopus.com/inward/record.url?scp=84903716389&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903716389&partnerID=8YFLogxK

U2 - 10.1016/j.bbadis.2014.05.013

DO - 10.1016/j.bbadis.2014.05.013

M3 - Article

C2 - 24859008

AN - SCOPUS:84903716389

VL - 1842

SP - 1549

EP - 1555

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

SN - 0925-4439

IS - 9

ER -