Regulation of Neuregulin 1b1-Induced MUC5AC and MUC5B Expression in Human Airway Epithelium

Excessive mucus production has been linked to many of the pathological features of respiratory diseases including obstruction of the airways, decline in lung function, increased rates of mortality and increased infections. The mucins MUC5AC and MUC5B contribute to the viscoelastic properties of mucus and are found at elevated levels in the airways of individuals with chronic respiratory diseases. The Th2 cell cytokine interleukin-13 (IL-13) is known to regulate MUC5AC expression in goblet cells of the airways, though much less is known about the regulation of MUC5B expression. In a study to further understand the mediators of MUC5AC and MUC5B expression, NRG1b1 was identified as novel regulator of goblet cell formation in primary cultures of human bronchial epithelial cells (HBECs). NRG1b1 increased expression of MUCAC and MUC5B proteins in a time and dose-dependent fashion in HBEC cultures. NRG1b1-induced expression of MU5AC and MUC5B was shown to involve ErbB2 and ErbB3 receptors but not ErbB4. Treatment of HBECs with inhibitors of p38MAPK, ERK1/2 and PI3 kinase indicated that these kinases were involved in NRG1b1-induced MUC5AC and MUC5B expression. Additionally, NRG1b1 was shown to induce the phosphorylation of the ErbB2 receptor, AKT and ERK1/2. NRG1b1 protein was found increased in the airways of antigen challenged mice, together with increases in MUC5AC and MUC5B message. Together this data indicates that NRG1b1 is a novel mediator of MUC5AC and MUC5B expression in HBECs and may represent a novel therapeutic target for mucus hypersecretion in respiratory diseases