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Published ahead of print on December 2, 2004, doi:10.1165/rcmb.2004-0231OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 3, March 2005, 225-231

A more recent version of this article appeared on March 1, 2005
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Submitted on July 26, 2004
Revised on December 2, 2004

German cockroach proteases regulate IL-8 expression via NF-IL6 in human bronchial epithelial cells

Kristen Page1*, Valerie S Hughes1, Kelli K Odoms1, Katherine E Dunsmore1, and Marc B Hershenson2

1 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA, 2 Division of Pediatric Pulmonology, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA

* To whom correspondence should be addressed. E-mail: Kristen.page{at}cchmc.org.

German cockroach extract synergistically regulates tumor necrosis factor alpha (TNF{alpha})-induced interleukin (IL)-8 expression in human airway epithelial cells. The IL-8 promoter contains nuclear factor (NF)-{kappa}B, activating protein (AP)-1 and NF for IL-6 (NF-IL6) transcription factor binding regions. Since cockroach extract activates extracellular regulated kinase (ERK), a known activator of AP-1 and NF-IL6, we focused on the regulation of these transcription factors. While TNF{alpha} and cockroach extract both increased AP-1 translocation, mutation of the AP-1 site in the context of the wild type promoter had no effect on cockroach extract-induced synergy. Mutation of the NF-IL6 site in the context of the wild-type IL-8 promoter, or overexpression of a dominant-negative NF-IL6 mutant, each abolished cockroach extract-induced synergy. Cockroach extract induced NF-IL6 translocation and DNA binding, an effect that was further increased in the presence of TNF{alpha}. Cockroach extract-induced regulation of NF-IL6 was due to active serine proteases in the extract as well as activation of protease activated receptor (PAR)-2, but not PAR-1. Chemical inhibition of ERK also attenuated cockroach extract-induced NF-IL6-DNA binding. We conclude that proteases in German cockroach extract regulate PAR-2 and ERK to increase NF-IL6 activity and synergistically regulate TNF{alpha}-induced IL-8 promoter activity in human airway epithelium.




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