PM 10 -mediated IL-8 Release from Epithelial Cells Involves Histone Acetylation

Abstract

Increases in the levels of environmental particulate matter (PM 10 ) in the air are associated with a variety of adverse health effects, particularly in susceptible patients with chronic lung and cardiovascular diseases. The adverse effects in the lungs are probably caused by oxidative stress leading to lung inflammation. The expression of many genes, including those encoding proinflammatory mediators, involves the remodelling of the chromatin structure provided by histone proteins. Chromatin is tightly coiled around histone proteins and therefore the access of transcription factors to the transcriptional machinery is inhibited. Histone acetylation causes the unwinding of the chromatin structure, thereby allowing transcription factor access to promoter sites, whereas histone deacetylation has the opposite effect of winding chromatin and inhibiting transcription. Nuclear histone acetylation is reversible and is regulated by a group of histone acetyltransferases (HATs), which promote acetylation, and histone deacetylases (HDACs), which promote deacetylation. There are several co-activators, transcription factors and nuclear proteins that have HAT activity. The aim of this study was to determine whether the PM 10 -mediated mRNA expression and release of interleukin-8 (IL-8) from alveolar airspace epithelial cells is associated with histone acetylation and oxidative stress. We studied the effects of PM 10 and an HDAC inhibitor (trichostatin-A, TSA) on the release of IL-8 by enzyme-linked immunosorbent assay, and the acetylation of histone 4 (H4) was assessed by immunocytochemistry in human alveolar type II cells. PM10 and H2O2 increased IL-8 protein release from A549 cells after 20 h treatment, and this was enhanced by HDAC inhibition (TSA co-treatment). PM 10 and H 2 O 2 treatment also increased the HAT activity. PM 10 enhanced H4 acetylation, which was mediated by oxidative stress, as shown by thiol antioxidant inhibition. The PM10and TSA-mediated increases in IL-8 and histone acetylation were associated with increases in nuclear factor-κB activation. These data suggest that the remodelling of chromatin by histone acetylation plays a role in the PM10-mediated pro-inflammatory responses in the lungs. This PM 10 response is mediated by oxidative stress.