title: COX-2 expression induced by diesel particles involves chromatin modification and degradation of HDAC1.
abstract: Cyclooxygenase-2 (COX-2) plays an important role in the inflammatory response induced by physiologic and stress stimuli. Exposure to diesel exhaust particulate matter (DEP) has been shown to induce pulmonary inflammation and exacerbate asthma and chronic obstructive pulmonary disease. DEP is a potent inducer of inflammatory reponses in human airway epithelial cells. The mechanism through which DEP inhalation induces inflammatory mediator expression is not understood. In this report, we demonstrate that DEP can induce the expression of COX-2 gene in a human bronchial epithelial cell line (BEAS-2B) at both transcriptional and protein levels. The induction of COX-2 gene expression involves chromatin modification, in particular acetylation and deacetylation of histones. We show that exposure to DEP increases the acetylation of histone H4 associated with the COX-2 promoter and causes degradation of histone deacetylase 1 (HDAC1). Further, we establish that HDAC1 plays a pivotal role in mediating the transcriptional activation of the COX-2 gene in BEAS-2B cells exposed to DEP, supported by evidence that the down-regulation of HDAC1 using siRNA leads to activation of COX-2 gene expression, whereas overexpression of HDAC1 results in its repression. Finally, DEP exposure induced recruitment of histone acetyltransferase (HAT) p300 to the promoter of the COX-2 gene, suggesting that acetylation is also important in regulating its expression in response to DEP exposure. These results show for the first time acetylation via selective degradation of HDAC1, and that recruitment of HAT plays an important role in DEP-induced expression of the COX-2 gene.
authors: Center for Environmental Medicine, Asthma and Lung Biology, University of North Carolina, USA.
authors: Dongsun
authors: D
authors: Cao
authors: Philip A
authors: PA
authors: Bromberg
authors: James M
authors: JM
authors: Samet
mesh_terms: D000393:Air Pollutants / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D052638:Particulate Matter / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D001335:Vehicle Emissions; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D000393:Air Pollutants; D002843:Chromatin; D006657:Histones; D008565:Membrane Proteins; D052638:Particulate Matter; D001335:Vehicle Emissions; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051548:Histone Acetyltransferases; D050880:p300-CBP Transcription Factors; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases