Regulation of airway MUC5AC expression by IL-1β and IL-17A; the NF-κB paradigm

Tomoyuki Fujisawa, Sharlene Velichko, Philip Thai, Li Yin Hung, Fei Huang, Reen Wu

Research output: Contribution to journalArticle

155 Scopus citations

Abstract

Mucin over-production is one of the hallmarks of chronic airway diseases such as chronic obstructive pulmonary disease, asthma, and cystic fibrosis. NF-κB activation in airway epithelial cells has been shown to play a positive inflammatory role in chronic airway diseases; however, the role of NF-κB in mucin gene expression is unresolved. In this study, we have shown that the proinflammatory cytokines, IL-1β and IL-17A, both of which utilize the NF-κB pathway, are potent inducers of mucin (MUC)5AC mRNA and protein synthesis by both well-differentiated primary normal human bronchial epithelial cells and the human bronchial epithelial cell line, HBE1. MUC5AC induction by these cytokines was both time- and dose-dependent and occurred at the level of promoter activation, as measured by a reporter gene assay. These effects were attenuated by the small molecule inhibitor NF-κB inhibitor III, as well as p65 small-interfering RNA, suggesting that the regulation of MUC5AC expression by these cytokines is via an NF-κB-based transcriptional mechanism. Further investigation of the promoter region identified a putative NF-κB binding site at position-3594/-3582 in the promoter of MUC5AC as critical for the regulation of MUC5AC expression by both IL-1β and IL-17A. Chromatin immunoprecipitation analysis confirmed enhanced binding of the NF-κB subunit p50 to this region following cytokine stimulation. We conclude that an NF-κB-based transcriptional mechanism is involved in MUC5AC regulation by IL-1β and IL-17A in the airway epithelium. This is the first demonstration of the participation of NF-κB and its specific binding site in cytokine-mediated airway MUC5AC expression.

Original languageEnglish (US)
Pages (from-to)6236-6243
Number of pages8
JournalJournal of Immunology
Volume183
Issue number10
DOIs
StatePublished - Nov 15 2009

ASJC Scopus subject areas

  • Immunology

Fingerprint Dive into the research topics of 'Regulation of airway MUC5AC expression by IL-1β and IL-17A; the NF-κB paradigm'. Together they form a unique fingerprint.

  • Cite this