Regulation of Airway MUC5AC Expression by IL-1β and IL-17A; the NF-κB Paradigm

  • Fujisawa T
  • Velichko S
  • Thai P
  • et al.
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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.

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APA

Fujisawa, T., Velichko, S., Thai, P., Hung, L.-Y., Huang, F., & Wu, R. (2009). Regulation of Airway MUC5AC Expression by IL-1β and IL-17A; the NF-κB Paradigm. The Journal of Immunology, 183(10), 6236–6243. https://doi.org/10.4049/jimmunol.0900614

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