Epigenetic regulation of defensin gene expression in lung epithelial cells and COPD

Abstract

Chronic obstructive pulmonary disease (COPD) includes emphysema and chronic bronchitis and is one of the most common diseases worldwide. Although inflammatory processes play an important role in the pathogenesis of COPD, the exact role of the innate immune system of the bronchial system and in particular the mode of action of epithelial cells in COPD remains poorly understood. Preliminary results of a recently started study with COPD patients of different clinical stages indicated an increased expression of human β-defensin (hBD)-1 (control group, n=8: 0.0258±0.0053 hBD-1/β2M vs. COPDIII, n=9: 0.119±0.033; P value 0.0183; vs. COPD I, n=4: 0.163±0.049; P value 0.002), but not other antimicrobial peptides such as hBD-2, RNase 7 or S100A7 protein (Psoriasin) compared with healthy controls. However, the mechanism by which the chronic inflammation of bronchial epithelial cells in COPD patients leads to a persisting overexpression of constitutively expressed hBD-1 is not very well understood. Thus, we investigated which epigenetic mechanism might be responsible for the enhanced hBD-1 mRNA expression. Whereas active promoters generally contain histone H3/H4 hyperacetylation and tri-methylation at H3 lysine 4, the histone H3 lysine 9 methylation (H3K9me3) has been extensively correlated with repression. Our first results with lung epithelial cell lines show the absence of active histone modifications under non-induced conditions around the transcription start, while H3K9me3 is present throughout the hBD-1 and -2 loci. The modulation of defensin gene expression in COPD might be, in part, a consequence of epigenetic alternations in the chromatin structure of the defensin genes. The understanding of the basic mechanisms that mediate epigenetic regulation of defensin gene expression may lead to a better understanding of the pathogenesis of COPD, thus providing an unique platform for the development of new therapeutic strategies (supported by DFG, SFB617, project A23).