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-κB and activator protein-2

被引:215
作者
Smith, RS
Fedyk, ER
Springer, TA
Mukaida, N
Iglewski, BH
Phipps, RP
机构
[1] Univ Rochester, Sch Med & Dent, Ctr Canc, Rochester, NY 14642 USA
[2] Univ Rochester, Sch Med & Dent, Dept Microbiol & Immunol, Rochester, NY 14642 USA
[3] Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[5] Kanazawa Univ, Canc Res Inst, Dept Mol Oncol, Kanazawa, Ishikawa 920, Japan
关键词
D O I
10.4049/jimmunol.167.1.366
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-KB 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-KB 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.
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页码:366 / 374
页数:9
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