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Regulation of Airway MUC5AC Expression by IL-1β and IL-17A; the NF-B Paradigm¹

Center of Comparative Respiratory Biology and Medicine, University of California, Davis, CA 95616

Mucin over-production is one of the hallmarks of chronic airway diseases such as chronic obstructive pulmonary disease, asthma, and cystic fibrosis. NF-B activation in airway epithelial cells has been shown to play a positive inflammatory role in chronic airway diseases; however, the role of NF-B 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-B 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-B inhibitor III, as well as p65 small-interfering RNA, suggesting that the regulation of MUC5AC expression by these cytokines is via an NF-B-based transcriptional mechanism. Further investigation of the promoter region identified a putative NF-B 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-B subunit p50 to this region following cytokine stimulation. We conclude that an NF-B-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-B and its specific binding site in cytokine-mediated airway MUC5AC expression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported in part by grants from National Institutes of Health (HL077902, HL077315, ES00628) and California Tobacco-Related Disease Research Program (16RT-0127).

² Address correspondence and reprint requests to Dr. Reen Wu, Center for Comparative Respiratory Biology and Medicine, Genome and Biomedical Science Facility, Suite 6510, University of California at Davis, 451 Health Sciences Drive, Davis, CA 95616. E-mail address: rwu{at}ucdavis.edu

³ Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; MUC, mucin; IKK, IB kinase; hBD-2, human β-defensin-2; NHBE, normal human bronchial epithelial; ALI, air-liquid interface; siRNA, small-interfering RNA; RO, random oligomer; ChIP, chromatin immunoprecipitation; CTL, control nuclear protein extract.