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This Article Full Text Full Text (PDF) All Versions of this Article: 291/3/L407    most recent 00471.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Kuwahara, I. Articles by Kim, K. C. Search for Related Content PubMed PubMed Citation Articles by Kuwahara, I. Articles by Kim, K. C.

Neutrophil elastase induces IL-8 gene transcription and protein release through p38/NF-B activation via EGFR transactivation in a lung epithelial cell line

¹Respiratory Immunology and Asthma Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico; ²Department of Pharmaceutical Sciences, School of Pharmacy, and ³Departments of Pediatrics and Medicine, School of Medicine, University of Maryland, Baltimore, Maryland; and ⁴Department of Chemico-Pharmacology, Graduate School of Medicine and Pharmacy, Kumamoto University, Kumamoto, Japan

Submitted 7 November 2005 ; accepted in final form 26 March 2006

In this study, we investigated the regulation and mechanism of IL-8 expression by A549 human lung carcinoma cells treated with neutrophil elastase (NE). NE-treated cells exhibited significantly higher IL-8 protein levels in culture media compared with cells treated with vehicle alone. Blocking of gene transcription with actinomycin D suggested that NE stimulated IL-8 synthesis via increased mRNA expression, which was verified by real-time RT-PCR. NE activated the IL-8 promoter but did not alter the stability of its mRNA, confirming that the protease induced IL-8 synthesis through increased gene transcription. The results from the use of chemical inhibitors and mutant gene constructs against various signal transduction components seem to suggest the linear signaling pathway involving the activation of PKC- dual oxidase 1 reactive oxygen species TNF--converting enzyme EGF receptor p38 NF-B for NE-activated IL-8 gene expression. A NF-B potential binding site, located between nucleotides –82 and –69 of the IL-8 promoter, was identified as necessary for NE-induced IL-8 transcription. We conclude that NE increases IL-8 transcription through p38/NF-B activation via EGFR transactivation.

protease; signal; airway; epithelial; epidermal growth factor receptor

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