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 Previous Article

Molecular and Cellular Biology, August 2009, p. 4325-4339, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01776-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Defective Histone Acetylation Is Responsible for the Diminished Expression of Cyclooxygenase 2 in Idiopathic Pulmonary Fibrosis{triangledown} ,{dagger},{ddagger}

William R. Coward,1 Keiria Watts,1 Carol A. Feghali-Bostwick,2 Alan Knox,1 and Linhua Pang1*

Division of Respiratory Medicine, Centre for Respiratory Research and Nottingham Respiratory Biomedical Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Nottingham NG5 1PB, United Kingdom,1 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Montefiore 628 NW, Pittsburgh, Pennsylvania 152132

Received 20 November 2008/ Returned for modification 7 January 2009/ Accepted 26 May 2009

Diminished cyclooxygenase 2 (COX-2) expression in fibroblasts, with a resultant defect in the production of the antifibrotic mediator prostaglandin E2, 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 β1 and interleukin-1β 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.

* Corresponding author. Mailing address: Division of Respiratory Medicine, City Hospital, University of Nottingham, Hucknall Road, Nottingham NG5 1PB, United Kingdom. Phone: (44) 115 8404778. Fax: (44) 115 8404771. E-mail: linhua.pang{at}nottingham.ac.uk

{triangledown} Published ahead of print on 1 June 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} The authors have paid a fee to allow immediate free access to this article.

Molecular and Cellular Biology, August 2009, p. 4325-4339, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01776-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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