Transforming Growth Factor β Inhibits MUC5AC Expression by Smad3/HDAC2 Complex Formation and NF-κB Deacetylation at K310 in NCI-H292 Cells

Airway mucus secretion is an essential innate immune response for host protection. However, overproduction and hypersecretion of mucus, mainly composed of the gel-forming MUC5AC protein, are significant risk factors for patients with asthma and chronic obstructive pulmonary disease (COPD). The transforming growth factor beta (TGF beta) signaling pathway negatively regulates MUC5AC expression; however, the underlying molecular mechanism is not fully understood. Here, we showed that TGF beta significantly reduces the expression of MUC5AC mRNA and its protein in NCI-H292 cells, a human mucoepidermoid carcinoma cell line. This reduced MUC5AC expression was restored by a TGF beta receptor inhibitor (SB431542), but not by the inhibition of NF-kappa B (BAY11-7082 or Triptolide) or PI3K (LY294002) activities. TGF beta-activated Smad3 dose-dependently bound to MUC5AC promoter. Notably, TGF beta-activated Smad3 recruited HDAC2 and facilitated nuclear translocation of HDAC2, thereby inducing the deacetylation of NF-kappa B at K310, which is essential for a reduction in NF-kappa B transcriptional activity. Both TGF beta-induced nuclear translocation of Smad3/HDAC2 and deacetylation of NF-kappa B at K310 were suppressed by a Smad3 inhibitor (SIS3). These results suggest that the TGF beta-activated Smad3/HDAC2 complex is an essential negative regulator for MUC5AC expression and an epigenetic regulator for NF-kappa B acetylation. Therefore, these results collectively suggest that modulation of the TGF beta 1/Smad3/HDAC2/NF-kappa B pathway axis can be a promising way to improve lung function as a treatment strategy for asthma and COPD.

Automated summary

TGF beta activates Smad3/HDAC2 complex as a negative regulator for MUC5AC expression and mediates deacetylation of NF-kappa B at K310, reducing NF-kappa B transcriptional activity. Modulation of the TGF beta 1/Smad3/HDAC2/NF-kappa B pathway axis may be a promising approach to improve lung function in asthma and COPD.