Document Detail

Nitric oxide modifies chromatin to suppress ICAM-1 expression during colonic inflammation.
MedLine Citation:
PMID:  22517771     Owner:  NLM     Status:  MEDLINE    
Nitric oxide (NO) is an established inflammatory mediator. However, it remains controversial whether NO enhances the inflammatory response in the colon or suppresses it. We investigated the epigenetic regulation of Icam-1 expression by NO following induction of colonic inflammation in rats by 2,4,6-trinitrobenzene sulfonic (TNBS) acid and obtaining colonic muscularis externae tissues 24 h later. TNBS inflammation induced intercellular adhesion molecule-1 (ICAM-1) expression by translocating NF-κB to the nucleus. The incubation of inflamed tissues with S-nitrosoglutathione (GSNO) did not affect the nuclear translocation of NF-κB; however, it suppressed the NF-κB binding to DNA. Chromatin immunoprecipitation analysis (ChIP)-qPCR assays showed that the increase in NF-κB/DNA interaction following inflammation is due to the transcriptional downregulation of global HDAC3 and a decrease in its interaction with the DNA on the Icam-1 promoter containing the binding motifs of NF-κB. The decrease in the association of histone deacetylase (HDAC) 3 with the Icam-1 promoter increased the acetylation of histone 4 lysine residue 12 (H4K12), which would favor chromatin relaxation and greater access of NF-κB to its DNA binding sites. HDAC3 dissociation from the DNA did not affect the acetylation levels of H4K8 and H4K16. The NO release by GSNO countered the upregulation of Icam-1 by increasing the transcription of global HDAC3 and its association with the Icam-1 promoter, and by suppressing H4K12 acetylation. We conclude that chromatin modification by transcriptional downregulation of HDAC3 plays a critical role in the induction of the inflammatory response. NO may serve as an anti-inflammatory mediator during the acute stage of inflammation by blunting the downregulation of global HDAC3, increasing HDAC3 interaction with the nucleosomes containing the binding moieties of NF-κB, reducing H4K12Ac to restrict the access of NF-κB to DNA, and suppressing ICAM-1 expression.
Qingjie Li; Sushil K Sarna
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-04-19
Journal Detail:
Title:  American journal of physiology. Gastrointestinal and liver physiology     Volume:  303     ISSN:  1522-1547     ISO Abbreviation:  Am. J. Physiol. Gastrointest. Liver Physiol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-03     Completed Date:  2012-09-07     Revised Date:  2013-07-02    
Medline Journal Info:
Nlm Unique ID:  100901227     Medline TA:  Am J Physiol Gastrointest Liver Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  G103-10     Citation Subset:  IM    
Division of Gastroenterology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555-1083, USA.
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MeSH Terms
Blotting, Western
Cells, Cultured
Chromatin / drug effects*
Chromatin Immunoprecipitation
Colitis / chemically induced,  metabolism*
Down-Regulation / drug effects
Histone Deacetylases / biosynthesis,  genetics
Histones / metabolism
Inflammation Mediators / pharmacology
Intercellular Adhesion Molecule-1 / biosynthesis*
Lysine / metabolism
NF-kappa B / metabolism
Nitric Oxide / pharmacology*
Polymerase Chain Reaction
RNA, Messenger / biosynthesis
Rats, Sprague-Dawley
Translocation, Genetic / drug effects
Trinitrobenzenesulfonic Acid
Grant Support
Reg. No./Substance:
0/Chromatin; 0/Histones; 0/Inflammation Mediators; 0/NF-kappa B; 0/RNA, Messenger; 10102-43-9/Nitric Oxide; 126547-89-5/Intercellular Adhesion Molecule-1; 2508-19-2/Trinitrobenzenesulfonic Acid; 56-87-1/Lysine; EC Deacetylases; EC deacetylase 3

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

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