Neutrophil elastase differentially regulates IL-8 and VEGF production by cigarette smoke extract [Signal Transduction]

October 9th, 2015 by Lee, K.-H., Lee, C.-H., Jeong, J., Jang, A.-H., Yoo, C.-G.

Inflammation by IL-8-induced neutrophil recruitment and apoptosis of epithelial cells by decreased expression of VEGF have been suggested as one of the complicated pathogenic mechanisms of COPD. The role of neutrophil elastase (NE) in the development of COPD is also well-known. However, little is known about how they interact. The objective of this study was to elucidate the effect of NE on the cigarette smoke extract (CSE)-induced IL-8 and VEGF production, and its molecular mechanism in bronchial epithelial cells. CSE increased both IL-8 and VEGF productions in human bronchial epithelial cell (BEAS-2B). While NE significantly enhanced CSE-induced IL-8 production, it suppressed VEGF production. This differential regulation was not CSE-specific. The effect of NE on IL-8 production, but not VEGF, was ERK-dependent. Interestingly, in contrast to decreased VEGF protein expression, NE accelerated VEGF transcription by CSE, suggesting post-translational modification. When cells were incubated with purified NE, it was detected in the cytoplasm, suggesting the intracellular translocation of NE. Furthermore, NE fragmented rhVEGF in vitro, but not rhIL-8. These results indicate that VEGF down-regulation is due to direct degradation by NE which is translocated into cells. Similar to in vitro cell experiments, elastase treatment increases CSE-induced IL-8, however, it suppresses VEGF production in bronchoalveolar lavage (BAL) fluid of CSE-treated mice. Moreover, elastase treatment enhances CSE-induced emphysema in mice. Considering the actions of IL-8 and VEGF, our results suggest that NE contributes to the pathogenesis of COPD by enhancing inflammation and apoptosis.