Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line.
The respiratory manifestations of cystic fibrosis (CF) are characterized by neutrophil-dominated airway inflammation. Since a variety of inflammatory stimuli are capable of inducing bronchial epithelial cells to express the gene for IL-8, a cytokine that attracts and activates neutrophils, mediators in respiratory epithelial lining fluid (ELF) of CF individuals might induce IL-8 production by epithelial cells, thus recruiting neutrophils to the airways. BET-1A human bronchial epithelial cells at rest or incubated with normal ELF showed little IL-8 gene expression, but after incubation with CF ELF, a marked increase in IL-8 transcript levels was observed. CF ELF contained high levels of neutrophil elastase (NE) and various serine protease inhibitors prevented CF ELF from inducing IL-8 gene expression in BET-1A cells, suggesting that NE was the dominant inducer for IL-8 production in CF ELF. The addition of purified NE caused BET-1A cells to increase IL-8 gene transcription with accumulation of mRNA transcripts and to release IL-8-like neutrophil chemotactic activity. These observations suggest a self-perpetuating inflammatory process on the CF bronchial surface where NE released by neutrophils induced the bronchial epithelium to secrete IL-8, which in turn recruits additional neutrophils to the bronchial surface.
Nakamura
H
H
Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Yoshimura
K
K
McElvaney
N G
NG
Crystal
R G
RG
D001483:Base Sequence; D001980:Bronchi / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid; D002460:Cell Line; D002634:Chemotaxis, Leukocyte; D003550:Cystic Fibrosis / Q000503:physiopathology*; D004848:Epithelium / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000201:enzymology*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010196:Pancreatic Elastase / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics
D016209:Interleukin-8; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D010196:Pancreatic Elastase