Abstract
Airway epithelial cells contribute to the inflammatory response of the lung, and their innate immune response is primarily mediated via Toll-like receptor (TLR) signaling. Cystic fibrosis (CF) airways are chronically infected with Pseudomonas aeruginosa, suggesting a modified immune response in CF. We investigated the TLR-4 expression and the inflammatory profile (IL-8 and IL-6 secretion) in CF bronchial epithelial cell line CFBE41o- and its CF transmembrane ion condcutance regulator (CFTR)-corrected counterpart grown under air-liquid interface conditions after stimulation with lipopolysaccharide (LPS) from gram-negative bacteria. In CFTR-corrected cells, IL-8 and IL-6 secretions were constitutively activated but significantly increased after LPS stimulation compared with CFBE41o-. Blocking TLR-4 by a specific antibody significantly inhibited IL-8 secretion only in CFTR-corrected cells. Transfection with specific siRNA directed against TLR-4 mRNA significantly reduced the response to LPS in both cell lines. Fluorescence-activated cell sorter analysis revealed significantly higher levels of TLR-4 surface expression in CFTR-corrected cells. In histologic lung sections of patients with CF, the TLR-4 expression in the bronchial epithelium was significantly reduced compared with healthy control subjects. In CF the loss of CFTR function appears to decrease innate immune responses, possibly by altering the expression of TLR-4 on airway epithelial cells. This may contribute to chronic bacterial infection of CF airways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Antibodies / immunology
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Antibodies / pharmacology
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Bronchi / immunology
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Bronchi / metabolism
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Bronchi / pathology
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Cell Line
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Child
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Cystic Fibrosis / genetics
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Cystic Fibrosis / immunology*
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Cystic Fibrosis / metabolism
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Cystic Fibrosis / pathology
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Cystic Fibrosis Transmembrane Conductance Regulator / genetics
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Cystic Fibrosis Transmembrane Conductance Regulator / immunology*
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Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
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Epithelial Cells / immunology*
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Female
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology
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Humans
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Immunity, Innate*
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Interleukin-6 / biosynthesis
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Interleukin-6 / immunology
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Interleukin-8 / biosynthesis
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Interleukin-8 / immunology
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Lipopolysaccharides / pharmacology
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Male
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Pseudomonas Infections / genetics
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Pseudomonas Infections / immunology*
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Pseudomonas Infections / metabolism
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Pseudomonas Infections / pathology
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Pseudomonas aeruginosa / immunology*
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RNA, Messenger / biosynthesis
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RNA, Messenger / immunology
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Respiratory Mucosa / immunology*
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Respiratory Mucosa / metabolism
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Respiratory Mucosa / pathology
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / immunology
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Toll-Like Receptor 4 / antagonists & inhibitors
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Toll-Like Receptor 4 / biosynthesis
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology*
Substances
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Antibodies
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CFTR protein, human
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CXCL8 protein, human
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IL6 protein, human
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Interleukin-6
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Interleukin-8
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Lipopolysaccharides
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RNA, Messenger
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TLR4 protein, human
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Toll-Like Receptor 4
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Cystic Fibrosis Transmembrane Conductance Regulator