Summary of Work: The tracheobronchial epithelium produces mucins, which protect the epithelium against toxic chemicals and microbial agents. However, hypersecretion of mucin is a common and often severe complication of many inflammatory diseases of the airways. The purpose of our studies is to determine factors and mechanisms regulating mucin genes and mucin secretion. We found that the expression of several mucin genes including MUC2, MUC4, MUC5AC and MUC5B is dependent on the presence of retinol (vitamin A) or its major metabolic derivative, retinoic acid (RA). Addition of RA to RA-deficient cultures ( which no longer express the mucous phenotype), leads to sequential induction of MUC2, MUC5AC, and MUC5B mRNA, respectively, culminating in the full restoration of the mucous phenotype. Most RA effects are thought to be mediated by the nuclear receptors, RAR and RXR and their isotypes. Studies with retinoid receptor isotype-selective agonists and antagonists indicated that RA-binding to RAR-alpha is the main, early event in the induction of mucin genes by RA. RA-binding to RAR-gamma also seems to play a role, albeit a minor one. Transient transfection analysis with MUC5AC promoter-luciferase reporter construct showed that RA increased luciferase reporter activity driven by MUC5AC promoter, and currently, studies are in progress to identify elements in the MUC5AC promoter region involved in the regulation of MUC5AC expression by RA. Other studies aimed at the regulation of mucin gene expression and the secretion of mucin by inflammatory mediators showed that tumor necrosis factor-alpha, interleukin-1beta, lipopolysaccharides, and neutrophil elastase significantly increase the expression of MUC2, MUC5AC, and MUC5B and induce mucin hypersecretion. - airway disease, bronchitis, mucins, hypersecretion, retinoids, bronchial epithelium
NIH ExPorter
NIH ExPorter