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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: IL-8 production in human lung fibroblasts and epithelial cells activated by the Pseudomonas autoinducer N-3-oxododecanoyl homoserine lactone is transcriptionally regulated by NF-kappa B and activator protein-2.

Authors: Smith, R S; Fedyk, E R; Springer, T A; Mukaida, N; Iglewski, B H; Phipps, R P

Published In J Immunol, (2001 Jul 01)

Abstract: The destructive pulmonary inflammation associated with Pseudomonas aeruginosa colonization is caused, in part, by the production of the chemokine IL-8, which recruits neutrophils into the lung. The Pseudomonas autoinducer, N-3-oxododecanoyl homoserine lactone (3-O-C12-HSL), is a small lipid-soluble molecule that is essential in the regulation of many P. aeruginosa virulence factors, but little is known about how it affects eukaryotic cells. In this report we demonstrate that 3-O-C12-HSL is a potent stimulator of both IL-8 mRNA and protein from human fibroblasts and epithelial cells in vitro. The IL-8 produced from these 3-O-C12-HSL-stimulated cells was found to be functionally active by inducing the chemotaxis of neutrophils. To determine a mechanism for this IL-8 induction, deletion constructs of the IL-8 promoter were examined. It was found that the DNA region between nucleotides -1481 and -546 and the transcription factor NF-kappaB were essential for the maximal induction of IL-8 by 3-O-C12-HSL. This was confirmed by EMSAs, where 3-O-C12-HSL induced a shift with both AP-2 and NF-kappaB consensus DNA. The activation of NF-kappaB and subsequent production of IL-8 were found to be regulated by a mitogen-activated protein kinase pathway. These findings support the concept that the severe lung damage that accompanies P. aeruginosa infections is caused by an exuberant neutrophil response stimulated by 3-O-C12-HSL-induced IL-8. Understanding the mechanisms of 3-O-C12-HSL activation of lung structural cells may provide a means to help control lung damage during infections with P. aeruginosa.

PubMed ID: 11418672 Exiting the NIEHS site

MeSH Terms: 4-Butyrolactone/analogs & derivatives; 4-Butyrolactone/pharmacology; 4-Butyrolactone/physiology*; 5' Untranslated Regions/physiology; Cell Line; Cell-Free System/physiology; Cells, Cultured; Chemotaxis, Leukocyte/immunology; DNA-Binding Proteins/biosynthesis; DNA-Binding Proteins/physiology*; Electrophoresis, Polyacrylamide Gel; Enzyme Activation/drug effects; Enzyme Activation/immunology; Epithelial Cells/drug effects; Epithelial Cells/immunology; Epithelial Cells/metabolism*; Fibroblasts/drug effects; Fibroblasts/immunology; Fibroblasts/metabolism*; Homoserine/analogs & derivatives; Homoserine/pharmacology; Homoserine/physiology*; Humans; Interleukin-8/biosynthesis*; Interleukin-8/genetics; Interleukin-8/physiology; Lung/cytology; Lung/immunology; Lung/metabolism*; NF-kappa B/biosynthesis; NF-kappa B/physiology*; Neutrophils/immunology; Promoter Regions, Genetic/immunology; Pseudomonas aeruginosa/pathogenicity; Pseudomonas aeruginosa/physiology*; Transcription Factor AP-1/biosynthesis; Transcription Factor AP-2; Transcription Factors/biosynthesis; Transcription Factors/physiology*; Transcription, Genetic*/immunology

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