Adenovirus E1A gene dysregulates ICAM-1 expression in transformed pulmonary epithelial cells.
Previous studies from our laboratory demonstrated that adenovirus E1A DNA and proteins are detected in lungs of patients with chronic obstructive pulmonary disease (COPD). Since adenovirus E1A gene products are known to regulate the expression of many genes by interacting with cellular transcription factors, we postulate that E1A enhances the production of inflammatory mediators and exacerbates the inflammatory process in smokers' lungs. To examine this possibility, we transfected A549 human pulmonary epithelial cells with a plasmid carrying the adenoviral E1A gene and isolated stable transfectants expressing E1A proteins. These E1A-producing clones were tested for intercellular adhesion molecule-1 (ICAM-1) expression. As compared with parental cells or cells transfected with control plasmid, ICAM-1 expression was suppressed after IFN-gamma stimulation but markedly increased by LPS stimulation of E1A-positive cells. This LPS-mediated ICAM-1 induction was serum-dependent but the LPS receptor, CD14, was not detected on the surface of the E1A transfectants. We conclude that E1A proteins modulate ICAM-1 induction by inflammatory stimuli and render lung epithelial cells sensitive to LPS, and suggest that dysregulation of inflammatory mediator expression by adenoviral E1A could amplify the inflammatory process present in airways of smokers to produce COPD.
Keicho
N
N
University of British Columbia Pulmonary Research Laboratory, Vancouver, Canada.
Elliott
W M
WM
Hogg
J C
JC
Hayashi
S
S
D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000502:physiology; D001769:Blood; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000378:metabolism; D005786:Gene Expression Regulation; D005814:Genes, Viral; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017500:Adenovirus E1A Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma