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Am J Physiol Lung Cell Mol Physiol 291: L407-L416, 2006. First published April 21, 2006; doi:10.1152/ajplung.00471.2005
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Neutrophil elastase induces IL-8 gene transcription and protein release through p38/NF-{kappa}B activation via EGFR transactivation in a lung epithelial cell line

Ippei Kuwahara,1,2 Erik P. Lillehoj,3 Wenju Lu,2 Ishwar S. Singh,3 Yoichiro Isohama,4 Takeshi Miyata,4 and K. Chul Kim1,2

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-{delta} -> dual oxidase 1 -> reactive oxygen species -> TNF-{alpha}-converting enzyme -> EGF receptor -> p38 -> NF-{kappa}B for NE-activated IL-8 gene expression. A NF-{kappa}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-{kappa}B activation via EGFR transactivation.

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


Address for reprint requests and other correspondence: K. C. Kim, Lovelace Respiratory Research Institute, Albuquerque, NM 87108 (e-mail: kckim{at}lrri.org)




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