Type IV collagen reduces mucin 5AC secretion in three-dimensional cultured human primary airway epithelial cells.

Mucin 5AC (MUC5AC) hypersecretion induces airway narrowing in patients with asthma, which leads to breathing problems. We investigated the regulation of MUC5AC secretion by extracellular matrix (ECM) proteins in human primary airway epithelial cells from patients with asthma. The addition of type IV collagen to three-dimensional cultured human primary airway epithelial cells, which mimics the airway surface, reduced MUC5AC secretion in the medium, while the addition of laminin increased MUC5AC secretion. Furthermore, the addition of fibronectin did not affect MUC5AC secretion. In particular, the repeated addition of a low concentration of type IV collagen demonstrated a cumulative effect on the reduction in MUC5AC secretion. Human primary cells incubated with type IV collagen showed downregulated extracellular signal-regulated kinase (ERK) activity, which induced MUC5AC hypersecretion but did not affect Akt activity. These results suggest that the addition of type IV collagen to the apical surface of primary cells downregulates MUC5AC secretion and has a cumulative effect on MUC5AC secretion which might be effected via the ERK signaling pathway.

MUC5B mucin production is upregulated by fibronectin and laminin in human lung epithelial cells via the integrin and ERK dependent pathway.

MUC5B mucin is a principal component of airway mucus and plays a key role in biodefense. We investigated the regulation of MUC5B production using the signals from extracellular matrix (ECM) components in NCI-H292 human lung epithelial cells. We found that MUC5B production in NCI-H292 cells cultured on fibronectin or laminin increased by 4-5-fold, with the increase occurring in a dose- and time-dependent manner. In contrast, MUC5B production was unchanged on type-IV collagen. Inhibition of integrin ß1 induced upregulation of MUC5B and MUC5AC; however, inhibition of p38 MAPK did not show any remarkable change in overproduced MUC5B. Inhibition of extracellular signal-regulated kinase (ERK) pathway or the transcription factor NF-κB induced the recovery of overproduced MUC5B on fibronectin and laminin. These results suggest that MUC5B production can be regulated by ECM components and that MUC5B is upregulated by fibronectin and laminin via the integrin, ERK, and NF-κB dependent pathway.

Akt induces down regulation of MUC5AC production in NCI-H292 human airway epithelial cells cultured on extracellular matrix.

MUC5AC mucin overproduction is a key feature of asthma as contributes to airway obstruction. The production of MUC5AC is regulated in part by signals from extracellular matrix via integrin pathways, but it remains largely unclear. We investigated the role of Akt, a typical signal transducer in the integrin pathway, in the regulation of MUC5AC production. When NCI-H292 human airway epithelial cells were cultured on laminin or Matrigel, we found that the activity of Akt was suppressed, as compared to control cells with upregulated MUC5AC production. In contrast, Akt was activated in cells cultured on type IV collagen with downregulated MUC5AC production. The Akt inhibitor induced upregulation of MUC5AC. In contrast, overexpression of active Akt induced downregulation of MUC5AC production. These results suggest that a signal from laminin or Matrigel induces upregulation of MUC5AC by suppressing Akt activity, whereas a signal from type IV collagen induces downregulation of MUC5AC, mediated by Akt activation.