Abstract
Airway epithelial cells have a major role in initiating inflammation in response to bacterial pathogens. Through the immediate induction of CXCL8 and cytokine expression, polymorphonuclear cells are mobilized and activated to eradicate the infecting organisms. However, the influx of polymorphonuclear cells and the effects of their toxic exoproducts impede respiratory function. We postulated that respiratory epithelial cells must also participate in the regulation of their own proinflammatory signaling. Both Staphylococcus aureus and Pseudomonas aeruginosa were found to potently activate IL-6 expression immediately upon contact with epithelial cells, and by 1 h induced TNF-alpha converting enzyme (TACE) transcription. By 4 h of bacterial exposure, TACE colocalized with IL-6Ralpha on the apical surface of airway cells, and by 24 h, soluble IL-6Ralpha accumulated in the cell culture supernatant. Epithelial IL-6 and soluble IL-6Ralpha were shown to participate in trans-signaling, interacting with membrane-associated gp130 to activate CCL-2 expression and inhibit additional CXCL8 production. Thus, bacteria are physiological activators of TACE expression, which provides a mechanism to regulate inflammatory signaling that is initiated by airway epithelial cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ADAM Proteins
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ADAM17 Protein
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Bronchi / immunology
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Bronchi / microbiology
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Bronchi / pathology
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Cell Line
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Chemokine CCL2 / biosynthesis
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Enzyme Activation / immunology
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Humans
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Inflammation Mediators / metabolism
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Inflammation Mediators / physiology*
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Interleukin-6* / biosynthesis
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Interleukin-6* / physiology
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Interleukin-8 / biosynthesis
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Metalloendopeptidases / biosynthesis*
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Metalloendopeptidases / metabolism
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Nasal Polyps / enzymology
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Nasal Polyps / immunology
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Nasal Polyps / microbiology
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Nasal Polyps / pathology
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Pseudomonas aeruginosa / immunology*
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Receptors, Interleukin-6 / biosynthesis
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Receptors, Interleukin-6 / metabolism*
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Receptors, Interleukin-6 / physiology
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Respiratory Mucosa / enzymology
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Respiratory Mucosa / immunology*
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Respiratory Mucosa / microbiology
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Respiratory Mucosa / pathology
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Signal Transduction / immunology*
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Solubility
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Staphylococcus aureus / immunology*
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Substrate Specificity / immunology
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / physiology
Substances
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Chemokine CCL2
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Inflammation Mediators
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Interleukin-6
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Interleukin-8
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Receptors, Interleukin-6
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Tumor Necrosis Factor-alpha
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interleukin-6 receptor alpha
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ADAM Proteins
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Metalloendopeptidases
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ADAM17 Protein
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ADAM17 protein, human