title: Increased expression of beta-defensin 1 (DEFB1) in chronic obstructive pulmonary disease.
abstract: On-going airway inflammation is characteristic for the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the key factors determining the decrease in lung function, an important clinical parameter of COPD, are not clear. Genome-wide linkage analyses provide evidence for significant linkage to airway obstruction susceptibility loci on chromosome 8p23, the location of the human defensin gene cluster. Moreover, a genetic variation in the defensin beta 1 (DEFB1) gene was found to be associated with COPD. Therefore, we hypothesized that DEFB1 is differently regulated and expressed in human lungs during COPD progression. Gene expression of DEFB1 was assessed in bronchial epithelium and BAL fluid cells of healthy controls and patients with COPD and using bisulfite sequencing and ChIP analysis, the epigenetic control of DEFB1 mRNA expression was investigated. We can demonstrate that DEFB1 mRNA expression was significantly increased in bronchopulmonary specimen of patients with COPD (n = 34) vs. healthy controls (n = 10) (p<0.0001). Furthermore, a significant correlation could be detected between DEFB1 and functional parameters such as FEV(1) (p = 0.0024) and the FEV(1)/VC ratio (p = 0.0005). Upregulation of DEFB1 mRNA was paralleled by changes in HDAC1-3, HDAC5 and HDAC8 mRNA expression. Whereas bisulfite sequencing revealed no differences in the methylation state of DEFB1 promoter between patients with COPD and controls, ChIP analysis showed that enhanced DEFB1 mRNA expression was associated with the establishment of an active histone code. Thus, expression of human DEFB1 is upregulated and related to the decrease in pulmonary function in patients with COPD.
authors.affiliation: Section of Immunoregulation, Division of Innate Immunity, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Andresen
authors.forename: Gunar
authors.initials: G
authors.lastname: Günther
authors.forename: Jörn
authors.initials: J
authors.lastname: Bullwinkel
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.forename: Holger
authors.initials: H
authors.lastname: Heine
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D001980:Bronchi / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008239:Lysine / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D055815:Young Adult; D023083:beta-Defensins / Q000235:genetics* / Q000378:metabolism
chemical_list: C406407:DEFB1 protein, human; C106641:DEFB4A protein, human; D006657:Histones; D012333:RNA, Messenger; D023083:beta-Defensins; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D008239:Lysine