IL-1β induction of MUC5AC gene expression is mediated by CREB and NF-κB and repressed by dexamethasone

Chronic airway diseases are characterized by inflammation and mucus overproduction. The MUC5AC mucin gene is upregulated by the proinflammatory cytokine interleukin-1 beta (IL-1 beta) via activation of cAMP response element-binding protein (CREB) in the NCI-H292 cancer cell line and nuclear factor-kappa B (NF-kappa B) in the HBE1 transformed cell line, with each transcription factor binding to a cognate cis site in the proximal or distal region, respectively, of the MUC5AC promoter. We utilized primary differentiated human bronchial epithelial (HBE) and A549 lung adenocarcinoma cells to further investigate the contributions of CREB and NF-kappa B subunits to the IL-1 beta-induced upregulation of MUC5AC. Data show that ligand binding of IL-1 beta to the IL-1 beta receptor is required to increase MUC5AC mRNA abundance. Chromatin immunoprecipitation analyses show direct binding of CREB to the previously identified cAMP response element site and binding of p65 and p50 subunits to a novel NF-kappa B site in a mucin-regulatory domain in the proximal promoter and to a previously identified NF-kappa B site in the distal promoter. P50 binds to both NF-kappa B sites at 1 h following IL-1 beta exposure, but is replaced at 2 h by p65 in A549 cells and by a p50/p65 heterodimer in HBE cells. Thus IL-1 beta activates multiple domains in the MUC5AC promoter but exhibits some cell-specific responses, highlighting the complexity of MUC5AC transcriptional regulation. Data show that dexamethasone, a glucocorticoid that transcriptionally represses MUC5AC gene expression under constitutive conditions, also represses IL-1 beta-mediated upregulation of MUC5AC gene expression. A further understanding of mechanisms mediating MUC5AC regulation should lead to a honing of therapeutic approaches for the treatment of mucus overproduction in inflammatory lung diseases.