title: Neutrophil Elastase Differentially Regulates Interleukin 8 (IL-8) and Vascular Endothelial Growth Factor (VEGF) Production by Cigarette Smoke Extract.
abstract: 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 chronic obstructive pulmonary disease (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 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 production in human bronchial epithelial cells (BEAS-2B). Although 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 recombinant human VEGF in vitro but not recombinant human IL-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 increased CSE-induced IL-8; however, it suppressed VEGF production in bronchoalveolar lavage fluid of CSE-treated mice. Moreover, elastase treatment enhanced 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul 110-744, Korea.
authors.forename: Kyoung-Hee
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul 110-744, Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul 110-744, Korea.
authors.forename: Jiyeong
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul 110-744, Korea.
authors.forename: An-Hee
authors.initials: AH
authors.lastname: Jang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul 110-744, Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. Electronic address: cgyoo@snu.ac.kr.
authors.forename: Chul-Gyu
authors.initials: CG
authors.lastname: Yoo
mesh_terms: D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D019272:Leukocyte Elastase / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012906:Smoke; D014026:Nicotiana / Q000737:chemistry*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D016209:Interleukin-8; D012906:Smoke; D042461:Vascular Endothelial Growth Factor A; D048049:Extracellular Signal-Regulated MAP Kinases; D019272:Leukocyte Elastase
keywords: CXCL-8; chronic obstructive pulmonary disease (COPD); cigarette smoke; cigarette smoke extract; interleukin; neutrophil; neutrophil elastase; vascular endothelial growth factor (VEGF)