Verproside inhibits TNF-α-induced MUC5AC expression through suppression of the TNF-α/NF-κB pathway in human airway epithelial cells

• Published in: Cytokine (Philadelphia, Pa.) Vol. 77; pp. 168 - 175
• Main Authors: Lee, Su Ui, Sung, Min Hee, Ryu, Hyung Won, Lee, Jinhyuk, Kim, Hui-Seong, In, Hyun Ju, Ahn, Kyung-Seop, Lee, Hyun-Jun, Lee, Hyeong-Kyu, Shin, Dae-Hee, Lee, Yongnam, Hong, Sung-Tae, Oh, Sei-Ryang
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2016
• Subjects: Cell Line, Tumor; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Gene Expression - drug effects; Humans; IKK; Immunoblotting; Iridoid Glucosides - pharmacology; Lactones - pharmacology; Lung - metabolism; Lung - pathology; MAP Kinase Kinase Kinases - metabolism; MUC5AC; Mucin 5AC - genetics; Mucin 5AC - metabolism; NF-kappa B - metabolism; NF-κB; Nitriles - pharmacology; Nuclear Pore Complex Proteins - metabolism; Phosphorylation - drug effects; Protein Binding - drug effects; Protein Kinases - metabolism; Receptors, Tumor Necrosis Factor, Type I - metabolism; Resorcinols - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; RNA-Binding Proteins - metabolism; Signal Transduction - drug effects; Sulfones - pharmacology; TNF Receptor-Associated Death Domain Protein - metabolism; TNF Receptor-Associated Factor 2 - metabolism; TNF-α; TRADD; TRAF2; Tumor Necrosis Factor-alpha - pharmacology; Verproside; TNFR; NFκB; TRADD; Verproside; IKK; TRAF2; ChIP; MUC5AC; NF-κB; TAK1; TNF-α; TNF-RSC; GAPDH; RIP1; COPD
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2015.08.262

•Verproside inhibits TNF-α-induced MUC5AC expression.•Verproside inhibits TNF-α-activated IKK/NF-κB signaling.•Verproside inhibits TNF-RSC formation. Airway mucus secretion is an essential innate immune response for host protection. However, overproduction and hypersecretion of mucus, mainly composed of MUC5AC, are significant risk factors in asthma and chronic obstructive pulmonary disease (COPD) patients. Previously, we reported that verproside, a catalpol derivative iridoid glycoside isolated from Pseudolysimachion rotundum var. subintegrum, is a potent anti-asthmatic candidate drug in vivo. However, the molecular mechanisms underlying the pharmacological actions of verproside remain unknown. Here, we found that verproside significantly reduces the expression levels of tumor necrosis factor alpha (TNF-α)-induced MUC5AC mRNA and protein by inhibiting both nuclear factor kappa B (NF-κB) transcriptional activity and the phosphorylation of its upstream effectors such as IκB kinase (IKK)β, IκBα, and TGF-β-activated kinase 1 (TAK1) in NCI-H292 cells. Moreover, verproside attenuated TNF-α-induced MUC5AC transcription more effectively when combined with an IKK (BAY11-7082) or a TAK1 (5z-7-oxozeaenol) inhibitor than when administered alone. Importantly, we demonstrated that verproside negatively modulates the formation of the TNF-α-receptor (TNFR) 1 signaling complex [TNF-RSC; TNFR1-recruited TNFR1-associated death domain protein (TRADD), TNFR-associated factor 2 (TRAF2), receptor-interacting protein kinase 1 (RIP1), and TAK1], the most upstream signaling factor of NF-κB signaling. In silico molecular docking studies show that verproside binds between TRADD and TRAF2 subunits. Altogether, these results suggest that verproside could be a good therapeutic candidate for treatment of inflammatory airway diseases such as asthma and COPD by blocking the TNF-α/NF-κB signaling pathway.