Oxidative stress causes IL8 promoter hyperacetylation in cystic fibrosis airway cell models.
Dysregulated inflammation has been implicated in cystic fibrosis (CF) airway pathophysiology. The expression of inflammatory genes, like interleukin 8 (IL8), involves chromatin remodeling through histone acetylation. Inflammatory gene hyperacetylation could explain inflammatory mediator dysregulation seen in CF airways. CF airways are exposed to high levels of oxidative stress, and oxidative stress increases histone acetylation and inflammatory gene transcription. Loss of cystic fibrosis transmembrane conductance regulator (CFTR) may even reduce protection against oxidative stress. Consequently, increasing oxidative stress would likely lead to an imbalance of histone acetyl-transferase (HAT) and deacetylase (HDAC) stoichiometry and contribute to the heightened inflammatory response seen in the CF airway. We hypothesize that oxidative stress in CF airways causes increased acetylation of inflammatory gene promoters, contributing to transcriptional activity of these loci. Messenger RNA levels of IL8, IL6, CXCL1, CXCL2, CXCL3, and IL1 are significantly elevated in CF epithelial cell models. Histone H4 acetylation is lower at the IL8 promoter of the non-CF cell lines than the CF models. The reducing agent N-acetyl-cysteine decreases IL8 message and promoter H4 acetylation to non-CF levels, suggesting that oxidative stress contributes to IL8 expression in these models. H(2)O(2) treatment causes increased IL-8 acetylation and mRNA in all cells, but less in the CF-model cells. Together these data suggest a model in which cells without functional CFTR are under increased oxidative stress. Our data suggest intrinsic alterations in the HAT/HDAC balance in CFTR-deficient cells, and that oxidative stress contributes to this alteration.
Bartling
Toni R
TR
Department of Genetics, Case Western Reserve University, Cleveland, OH 44106-4948, USA.
Drumm
Mitchell L
ML
D000107:Acetylation; D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D011401:Promoter Regions, Genetic; D020545:Respiratory Mucosa / Q000166:cytology*; D014158:Transcription, Genetic
D016207:Cytokines; D016166:Free Radical Scavengers; D016209:Interleukin-8; D016877:Oxidants; D006861:Hydrogen Peroxide; D000111:Acetylcysteine