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

153 Citations (Scopus)

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

Fingerprint

Interleukin-17
Interleukin-1
Cytokines
Epithelial Cells
Mucins
Mucin 5AC
Chronic Disease
Binding Sites
Chromatin Immunoprecipitation
Reporter Genes
Genetic Promoter Regions
Cystic Fibrosis
Chronic Obstructive Pulmonary Disease
Small Interfering RNA
Asthma
Epithelium
Gene Expression
Cell Line
Messenger RNA
Proteins

ASJC Scopus subject areas

  • Immunology

Cite this

Regulation of airway MUC5AC expression by IL-1β and IL-17A; the NF-κB paradigm. / Fujisawa, Tomoyuki; Velichko, Sharlene; Thai, Philip; Hung, Li Yin; Huang, Fei; Wu, Reen.

In: Journal of Immunology, Vol. 183, No. 10, 15.11.2009, p. 6236-6243.

Research output: Contribution to journalArticle

Fujisawa, Tomoyuki ; Velichko, Sharlene ; Thai, Philip ; Hung, Li Yin ; Huang, Fei ; Wu, Reen. / Regulation of airway MUC5AC expression by IL-1β and IL-17A; the NF-κB paradigm. In: Journal of Immunology. 2009 ; Vol. 183, No. 10. pp. 6236-6243.
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