Defective histone acetylation is responsible for the diminished expression of cyclooxygenase 2 in idiopathic pulmonary fibrosis.
Diminished cyclooxygenase 2 (COX-2) expression in fibroblasts, with a resultant defect in the production of the antifibrotic mediator prostaglandin E(2), plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we have characterized the molecular mechanism. We found that COX-2 mRNA levels in fibroblasts from patients with IPF (F-IPF) were significantly lower than those in fibroblasts from nonfibrotic lungs (F-NL) after transforming growth factor beta1 and interleukin-1beta treatment but that COX-2 mRNA degradation rates were similar, suggesting defective transcription. A reporter gene assay showed that there were no clear differences between F-IPF and F-NL in transcription factor involvement and activation in COX-2 gene transcription. However, a chromatin immunoprecipitation assay revealed that transcription factor binding to the COX-2 promoter in F-IPF was reduced compared to that in F-NL, an effect that was dynamically linked to reduced histone H3 and H4 acetylation due to decreased recruitment of histone acetyltransferases (HATs) and increased recruitment of transcriptional corepressor complexes to the COX-2 promoter. The treatment of F-IPF with histone deacetylase (HDAC) inhibitors together with cytokines increased histone H3 and H4 acetylation. Both HDAC inhibitors and the overexpression of HATs restored cytokine-induced COX-2 mRNA and protein expression in F-IPF. The results demonstrate that epigenetic abnormality in the form of histone hypoacetylation is responsible for diminished COX-2 expression in IPF.
Coward
William R
WR
Division of Respiratory Medicine, City Hospital, University of Nottingham, Hucknall Road, Nottingham, United Kingdom.
Watts
Keiria
K
Feghali-Bostwick
Carol A
CA
Knox
Alan
A
Pang
Linhua
L
D000107:Acetylation / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D053583:Interleukin-1beta / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D006657:Histones; D053583:Interleukin-1beta; D012333:RNA, Messenger; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D008156:Luciferases; D051546:Cyclooxygenase 2; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D015232:Dinoprostone