Regulation of Neuregulin 1β1–Induced MUC5AC and MUC5B Expression in Human Airway Epithelium

Abstract

Excessive mucus production has been linked to many of the pathologic 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 T helper type 2 cell cytokine, IL-13, is known to regulate MUC5AC expression in goblet cells of the airways, although much less is known about the regulation of MUC5B expression. In a study to further understand the mediators of MUC5AC and MUC5B expression, neuregulin (NRG) 1beta1 was identified as novel regulator of goblet cell formation in primary cultures of human bronchial epithelial cells (HBECs). NRG1beta1 increased expression of MUCAC and MUC5B proteins in a time- and dose-dependent fashion in HBEC cultures. NRG1beta1-induced expression of MU5AC and MUC5B was shown to involve v-erb-b2 erythroblastic leukemia viral oncogene homolog (ErbB) and ErbB3 receptors, but not ErbB4 receptors. Treatment of HBECs with inhibitors of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase1/2, and phosphatidylinositol 3-kinase indicated that these kinases were involved in NRG1beta1-induced MUC5AC and MUC5B expression. Additionally, NRG1beta1 was shown to induce the phosphorylation of the ErbB2 receptor, AKT, and extracellular signal-regulated kinase 1/2. NRG1beta1 protein was found increased in the airways of antigen-challenged mice, together with increases in MUC5AC and MUC5B message. Together, these data indicate that NRG1beta1 is a novel mediator of MUC5AC and MUC5B expression in HBECs, and may represent a novel therapeutic target for mucus hypersecretion in respiratory diseases.

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

“…Customprepared monoclonal mouse anti-human MUC5B (clone C12/3FB) from Novartis (Horsham, West Sussex, UK) was generated and validated as previously reported. 10 …”

“…Controls were performed with differentiation media, LPS (E. coli strain 055:B5, Sigma-Aldrich) 1.67 mg/ml, and recombinant human (rh) IL-13 1 ng/ml (Peprotech, Rocky Hill, NJ, USA) to induce MUC5AC. 10,13 Additionally, HBEC were exposed to a combination of rh cytokines (R&D Systems, Minneapolis, MN, USA) prepared in differentiation media at concentrations equivalent to mean values from MDM supernatant (Figure 4b). Controls included also rh neuregulin-1b1 50 nM.…”

“…Controls included also rh neuregulin-1b1 50 nM. 10 Each condition was assayed in four to six replicas. At all stages of culture, cells were maintained at 37 1C in 5% CO 2 in an air incubator.…”

“…6 MUC5B and MUC5AC can be upregulated when human bronchus epithelial cells (HBEC) are cultured with retinoic acid, interleukin (IL)-6, IL-17, and neuroregulin1b1. [7][8][9][10][11] MUC5AC can also be induced in normal HBEC by IL-13, [12][13][14] although inhibited by thyroid hormone and epidermal growth factor. 8 Furthermore, MUC5AC þ GCH induced by IL-13 in normal HBEC depends on activation of IL-13R-JAK-STAT6 and EGFR-MAPK signaling pathways, as well as NF-kB, 15 relevant in allergic asthma as IL-13 is related to the pathogenesis of this disease.…”

Time-Dependent Proteomic iTRAQ Analysis of Nasal Lavage of Hairdressers Challenged by Persulfate

“…This high-molecular-weight protein is a gel-forming mucin and is secreted from the lacrimal gland 28 as well as from the small airways. 29 In general, excessive mucus production is commonly seen in respiratory disease 30 and increased levels of the mucins 5B have been found in persons suffering from chronic rhinosinusitis. 31 Extracellular glycoprotein lacritin was increased in the symptomatic and atopic groups at 20 min.…”