Document Detail


Loss of CFTR results in reduction of histone deacetylase 2 in airway epithelial cells.
MedLine Citation:
PMID:  19411311     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Inflammatory cytokines, particularly the neutrophil chemoattractant IL-8, are elevated in the cystic fibrosis (CF) airway, even in the absence of detectable infection. The transcriptional regulation of many inflammatory genes, including IL8 (CXCL8), involves chromatin remodeling through histone acetylation. NF-kappaB is known to facilitate histone acetylation of IL8 and other proinflammatory gene promoters, but we find that increased NF-kappaB activation cannot explain the elevated IL8 expression and promoter acetylation seen in CFTR-deficient cells. Recognized components of the NF-kappaB-coactivator complex, acetyltransferase CBP, p300, and the histone deacetylase HDAC1, are unchanged by CFTR activity. However, we find that the histone acetyltransferase (HAT)/HDAC balance is sensitive to CFTR function, as cells with reduced or absent CFTR function have decreased HDAC2 protein, resulting in hyperacetylation of the IL8 promoter and increased IL8 transcription. Reduced HDAC2 and HDAC2 activity, but not HDAC2 mRNA, is observed in cells deficient in CFTR. Suppressing HDAC2 expression with HDAC2 short hairpin RNA (shRNA) results in increased IL8 expression and promoter acetylation comparable with CFTR-deficient cells. Treating CFTR-deficient cells with N-acetyl-cysteine (NAC) increases HDAC2 expression to near control levels. Our data suggest that there is an intrinsic alteration in the HAT/HDAC balance in cells lacking CFTR function in vitro and in native CF tissue and that oxidative stress is likely contributing to this alteration. This mechanism, found in other inflammatory airway diseases, provides an explanation for the apparent dysregulation of inflammatory mediators seen in the CF airway, as reduced histone deacetylation would potentially influence many genes.
Authors:
Toni R Bartling; Mitchell L Drumm
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-05-01
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  297     ISSN:  1522-1504     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-29     Completed Date:  2009-08-11     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L35-43     Citation Subset:  IM    
Affiliation:
Department of Genetics, Case Western Reserve University and Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetylation / drug effects
Acetylcysteine / pharmacology
Cell Line
Cell Nucleus / drug effects,  metabolism
Cystic Fibrosis / enzymology,  pathology
Cystic Fibrosis Transmembrane Conductance Regulator / deficiency*,  metabolism
Epithelial Cells / drug effects,  enzymology*,  pathology
Gene Knockdown Techniques
Histone Deacetylase 2
Histone Deacetylases / metabolism*
Humans
Interleukin-8 / genetics,  metabolism
NF-kappa B / metabolism
Promoter Regions, Genetic / genetics
RNA Interference / drug effects
RNA, Messenger / genetics,  metabolism
RNA, Small Interfering / metabolism
Repressor Proteins / metabolism*
Respiratory System / cytology*
p300-CBP Transcription Factors / metabolism
Grant Support
ID/Acronym/Agency:
HL-68883/HL/NHLBI NIH HHS; P30-DK-27651/DK/NIDDK NIH HHS; T32-GM-08613/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Interleukin-8; 0/NF-kappa B; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Repressor Proteins; 126880-72-6/Cystic Fibrosis Transmembrane Conductance Regulator; 616-91-1/Acetylcysteine; EC 2.3.1.48/p300-CBP Transcription Factors; EC 3.5.1.98/Histone Deacetylase 2; EC 3.5.1.98/Histone Deacetylases
Comments/Corrections

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


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