[Show abstract][Hide abstract] ABSTRACT: Deregulation of the expression human beta defensin 1 (DEFB1), an antimicrobial peptide, has been implicated in the pathogenesis of COPD and asthma. Since the molecular mechanisms that regulate DEFB1 gene expression are widely unknown, the epigenetic processes involved in the regulation of the constitutive expression of DEFB1 in lung epithelial cells (A549) were investigated. The data demonstrate that histone deacetylases (HDACs) participate in the regulation of DEFB1 gene expression. Inhibition of the class I HDACs, HDACs 1-3, increases DEFB1 gene expression in A549 cells. Chromatin immunoprecipitation (ChIP) assays revealed that the inhibition of the class I HDACs also results in modifications of the chromatin at the DEFB1 promoter. Histone modifications, histone H3 acetylation and H3K4 trimethylation, that are associated with transcriptional activation, were found to increase after inhibition of HDACs 1-3. Finally, RNAi knockdown experiments identified HDAC1 as the sole HDAC responsible for maintaining the constitutive level of DEFB1 transcription. Taken together, our data reveal epigenetic mechanisms which are the basis of the maintenance of the constitutive gene expression of human beta defensin 1.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Progressive airway inflammation and susceptibility to the airway colonisation and infection are characteristic for the pathophysiology of chronic obstructive pulmonary disease (COPD). Antimicrobial peptides (AMPs) are central to the function of the innate host immune response against microbial pathogens and are regulators of inflammation and immunity. S100A7/psoriasin, a recently described AMP, is an essential component of the human epithelia against invading pathogens and acts as an effector molecule of the host innate defence in the skin. We hypothesized that S100A7/psoriasin is involved in the airway mucosal immunity and differently regulated and expressed in the lung during progression of COPD.
S100A7/psoriasin gene expression was assessed in bronchial biopsies and bronchoalveolar lavage (BAL) fluid cells of healthy controls and COPD patients. Using confocal microscopy and immunohistochemistry, the protein expression of S100A7/psoriasin was investigated.
Here, we report that S100A7/psoriasin, the major antimicrobial peptide of the human skin, is constitutively expressed in perinuclear granules of human bronchial epithelial cells and alveolar macrophages. Whereas typical activators of the innate immune response like TLR ligands and cytokines induced the upregulation of CXCL-8 mRNA and release of CXCL-8 by epithelial cells, S100A7/psoriasin mRNA expression was not modulated. To investigate a potential association of S100A7/psoriasin with COPD, S100A7/psoriasin mRNA expression was assessed in bronchial biopsies and BAL fluid cells of patients at different stages of COPD and controls. Overall, 10 healthy individuals and 34 COPD patients were enrolled in this study. We found an association of S100A7/psoriasin mRNA expression with bacterial detection in the tracheobronchial system (p = 0.0304), which was the strongest in individuals positive for with S. aureus (p = 0.0005). However, S100A7/psoriasin mRNA expression was not altered during the progression of COPD.
S100A7/psoriasin gene expression is unchanged in the airways during COPD. The newly identified association of S100A7/psoriasin with S. aureus may provide new insights into the antimicrobial defence response of the human airways, leading to the induction of S100A7/psoriasin upon microbial challenge.
Full-text · Article · Feb 2011 · BMC Pulmonary Medicine
[Show abstract][Hide abstract] ABSTRACT: Expression of human beta defensin-1 is related to progressive lung function
impairment in COPD
, Gunar Guenther
, Hany Sahly
, Nicole Fischer
, Christoph Lange
Divison of Innate Immunity, Research Center
Borstel, Borstel, Germany;
Division of Clinical Infectious Diseases, Research
Center Borstel, Borstel, Germany;
Institute of Immunology, Clinical Pathology
and Molecular Medicine, Labor Lademannbogen, Hamburg, Germany;
for Medical Microbiology and Virology, University Medical Center Eppendorf,
Antimicrobial peptides (AMPs) are major components of the innate
host response against infections and are regulators of inflammation and immunity.
Progressive airway inflammation and susceptibility to airway colonization and
infection is a hallmark of chronic obstructive pulmonary disease (COPD). We
studied the role of AMPs in patients with COPD.
Gene expression of human beta-defensin-1 (DEFB1), and -2 (DEFB4),
RNase7 and S100A7/psoriasin were analyzed in bronchial epithelium and BAL
fluid cells of healthy controls and patients at different stages of COPD. Using Chro-
matin Immunoprecipitation assay, the relation of the DEFB1 mRNA expression
level to different chromatin modifications was investigated.
34 patients and 10 healthy volunteers were enrolled in the study. Among
the AMPs that were investigated, only DEFB1 mRNA expression in bronchial ep-
ithelial cells was correlated to COPD pr
ogression (FEV1, p=0.003; ITGV, p=0.031;
and St. George Resp. Questionnaire,
p=0.009). Upregulation of DEFB1 mRNA
also correlates with H3K4 trimethylation in the vicinity of the transcriptional start
site of the DEFB1 gene, but is unrelated to bacterial or viral colonization.
In COPD, increased DEFB1 mRNA expression is associated with the
establishment of an active histone stat
e, including histone H3K4 trimethylation,
and correlates with progressive lung function impairment. Investigation of the
causative relationship of DEFB1 expression and chronic airway obstruction could
lead to novel therapeutic interven
tions in COPD (supported by DFG, SFB617,