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German Cockroach Proteases Regulate Interleukin-8 Expression via Nuclear Factor for Interleukin-6 in Human Bronchial Epithelial Cells

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio; and Division of Pediatric Pulmonology, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Kristen Page, Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, ML7006, Cincinnati, OH 45229. E-mail: kristen.page{at}chmcc.org

German cockroach extract synergistically regulates tumor necrosis factor- (TNF-)–induced interleukin (IL)-8 expression in human airway epithelial cells. The IL-8 promoter contains nuclear factor (NF)-B, activating protein (AP)-1, and NF for IL-6 (NF-IL6) transcription factor binding regions. Because 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. Although TNF- 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-. 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-–induced IL-8 promoter activity in human airway epithelium.

Key Words: Blattella germanica • mitogen activated protein kinase • protease activated receptor-2 • serine protease

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