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B Activation via EGFR Transactivation in a Lung Epithelial Cell Line
1 Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States
2 Department of Pediatrics, University of Maryland, Baltimore, Maryland, United States
3 Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, United States
4 Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States
5 Department of Chemico-Pharmacology, Kumamoto University Graduate School, Kumamoto, Japan
6 Asthma and Immunology Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States
* To whom correspondence should be addressed. E-mail: kckim{at}lrri.org.
In this study, we investigated the regulation and mechanism of IL-8 expression by A549 human lung carcinoma cells treated with 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
Duox1 ROS TACE EGFR 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.
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