title: Regulation of cigarette smoke-induced mucin expression by neuregulin1β/ErbB3 signalling in human airway epithelial cells.
abstract: Mucus hypersecretion is an important manifestation in patients with chronic obstructive pulmonary diseases (COPD). Cigarette smoke is importantly implicated in the pathogenesis of COPD. Previous studies have shown that cigarette smoke-induced MUC5AC (a major component of airway mucus) expression involving ErbB1 (EGF receptor) signalling pathway. Recently, it has been reported that cigarette smoke induces ErbB3 activation in airway epithelia to secret mucus, and the ligand of ErbB3, neuregulin (NRG) 1β, induces MU5AC expression in human bronchial epithelial cells. In the present study, we have suggested that NRG1β/ErbB3 signalling is activated by cigarette smoke, resulting in the activation of a variety of signal cascade pathways, leading to mucin production in human bronchial epithelial (16HBE) cells. We show that cigarette smoke increases NRG1β release, ErbB3 phosphorylation and MUC5AC production. These effects are prevented by an ErbB3-neutralizing antibody and by specific knockdown using small interfering RNA (siRNA) for NRG1β, implicating NRG1β-dependent ErbB3 activation in the responses. Cigarette smoke activates ERK1/2, c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3-K) signalling pathways, which are also inhibited by an ErbB3-neutralizing antibody and NRG1β siRNA, indicating the regulation of cigarette smoke-activated pathways by NRG1β/ErbB3 signalling. Furthermore, pre-treatments with metalloprotease inhibitor (TNF-α protease inhibitor-1) and specific knockdown of TNF-α-converting enzyme (TACE) with TACE siRNA prevented cigarette smoke-induced NRG1β release, ErbB3 phosphorylation and mucin production, suggesting the role of TACE in cigarette smoke-mediated NRG1β/ErbB3 signalling activation. These results suggest that NRG1β/ErbB3 signalling regulates cigarette smoke-induced mucin overproduction via the MAPK and PI3K signal pathways in 16HBE cells.
authors.affiliation: Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yu
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Victor P
authors.initials: VP
authors.lastname: Kolosov
authors.forename: Juliy M
authors.initials: JM
authors.lastname: Perelman
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Zhou
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D009077:Mucins / Q000187:drug effects* / Q000235:genetics; D020890:Neuregulin-1 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects*
chemical_list: D009077:Mucins; D020890:Neuregulin-1; D034741:RNA, Small Interfering; C117467:neuregulin beta; D020893:Receptor, ErbB-3; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human