GSTM1 modulation of IL-8 expression in human bronchial epithelial cells exposed to ozone.

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.