title: GSTM1 modulation of IL-8 expression in human bronchial epithelial cells exposed to ozone.
abstract: Exposure to the major air pollutant ozone can aggravate asthma and other lung diseases. Our recent study in human volunteers has shown that the glutathione S-transferase Mu 1 (GSTM1)-null genotype is associated with increased airway neutrophilic inflammation induced by inhaled ozone. The aim of this study was to examine the effect of GSTM1 modulation on interleukin 8 (IL-8) production in ozone-exposed human bronchial epithelial cells (BEAS-2B) and the underlying mechanisms. Exposure of BEAS-2B cells to 0.4 ppm ozone for 4 h significantly increased IL-8 release, with a modest reduction in intracellular reduced glutathione (GSH). Ozone exposure induced reactive oxygen species (ROS) production and NF-κB activation. Pharmacological inhibition of NF-κB activation or mutation of the IL-8 promoter at the κB-binding site significantly blocked ozone-induced IL-8 production or IL-8 transcriptional activity, respectively. Knockdown of GSTM1 in BEAS-2B cells enhanced ozone-induced NF-κB activation and IL-8 production. Consistently, an ozone-induced overt increase in IL-8 production was detected in GSTM1-null primary human bronchial epithelial cells. In addition, supplementation with reduced GSH inhibited ozone-induced ROS production, NF-κB activation, and IL-8 production. Taken together, GSTM1 deficiency enhances ozone-induced IL-8 production, which is mediated by generated ROS and subsequent NF-κB activation in human bronchial epithelial cells.
authors.affiliation: Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599, USA. Weidong_Wu@med.unc.edu
authors.forename: Weidong
authors.initials: W
authors.lastname: Wu
authors.forename: Vinod
authors.initials: V
authors.lastname: Doreswamy
authors.forename: David
authors.initials: D
authors.lastname: Diaz-Sanchez
authors.forename: James M
authors.initials: JM
authors.lastname: Samet
authors.forename: Matt
authors.initials: M
authors.lastname: Kesic
authors.forename: Lisa
authors.initials: L
authors.lastname: Dailey
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhang
authors.forename: Ilona
authors.initials: I
authors.lastname: Jaspers
authors.forename: David B
authors.initials: DB
authors.lastname: Peden
mesh_terms: D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005982:Glutathione Transferase / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*
chemical_list: D005982:Glutathione Transferase; D016209:Interleukin-8