Document Detail


Induction of Bcl-3 by acute binge alcohol results in toll-like receptor 4/LPS tolerance.
MedLine Citation:
PMID:  22782967     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Acute alcohol binge results in immunosuppression and impaired production of proinflammatory cytokines, including TNF-α. TNF-α production is induced by LPS, a TLR4 ligand, and is tightly regulated at various levels of the signaling cascade, including the NF-κB transcription factor. Here, we hypothesized that acute alcohol induces TLR4/LPS tolerance via Bcl-3, a nuclear protein and member of the NF-κB family. We found that acute alcohol pretreatment resulted in the same attenuating effect as LPS pretreatment on TLR4-induced TNF-α production in human monocytes and murine RAW 264.7 macrophages. Acute alcohol-induced Bcl-3 expression and IP studies revealed increased association of Bcl-3 with NF-κB p50 homodimers in alcohol-treated macrophages and in mice. ChIP assays revealed increased occupancy of Bcl-3 and p50 at the promoter region of TNF-α in alcohol-pretreated cells. To confirm that the Bcl-3-p50 complex regulates transcription/production of TNF-α during acute alcohol exposure, we inhibited Bcl-3 expression using a targeted siRNA. Bcl-3 knockdown prevented the alcohol-induced inhibition of TNF-α mRNA and protein production. In a mouse model of binge alcohol, an increase in Bcl-3 and a concomitant decrease in TNF-α but no change in IL-10 production were found in mice that received alcohol followed by LPS challenge. In summary, our novel data suggest that acute alcohol treatment in vitro and in vivo induces molecular signatures of TLR4/LPS tolerance through the induction of Bcl-3, a negative regulator of TNF-α transcription via its association with NF-κB p50/p50 dimers.
Authors:
Shashi Bala; Alexander Tang; Donna Catalano; Jan Petrasek; Odette Taha; Karen Kodys; Gyongyi Szabo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-07-10
Journal Detail:
Title:  Journal of leukocyte biology     Volume:  92     ISSN:  1938-3673     ISO Abbreviation:  J. Leukoc. Biol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-31     Completed Date:  2012-10-31     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  8405628     Medline TA:  J Leukoc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  611-20     Citation Subset:  IM    
Affiliation:
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
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MeSH Terms
Descriptor/Qualifier:
Alcohol Drinking / adverse effects,  immunology*,  metabolism
Animals
Blotting, Western
Electrophoretic Mobility Shift Assay
Enzyme-Linked Immunosorbent Assay
Female
Gene Expression / drug effects
Humans
Immune Tolerance / drug effects*,  immunology
Lipopolysaccharides / immunology*
Macrophages / drug effects,  immunology
Mice
Mice, Inbred C57BL
Monocytes / drug effects,  immunology
Oligonucleotide Array Sequence Analysis
Proto-Oncogene Proteins / immunology,  metabolism*
Real-Time Polymerase Chain Reaction
Toll-Like Receptor 4 / immunology*
Transcription Factors / immunology,  metabolism*
Grant Support
ID/Acronym/Agency:
AA011576/AA/NIAAA NIH HHS
Chemical
Reg. No./Substance:
0/Lipopolysaccharides; 0/Proto-Oncogene Proteins; 0/Toll-Like Receptor 4; 0/Transcription Factors; 0/proto-oncogene protein bcl-3
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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