Abstract
BackgroundChronic airway inflammatory disorders, such as asthma, are characterized by airway inflammation and remodeling. Chronic inflammation and damage to the airway epithelium cause airway remodeling, which is associated with improper epithelial repair, and is characterized by elevated expression of transforming growth factor-β (TGF-β). Epithelial-mesenchymal transition (EMT) is an important mechanism during embryonic development and tissue remodeling whereby epithelial cells gain the capacity to increase motility by down-regulation of epithelial markers and up-regulation of mesenchymal markers. TGF-β is a central inducer of EMT, and TGF-β-induced EMT is enhanced by pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β. We investigated whether the pro-inflammatory cytokine TWEAK (TNF-like weak inducer of apoptosis) enhanced TGF-β1-induced EMT in the human bronchial epithelial cell line BEAS-2B.MethodsQuantitative RT-PCR and western blotting were used to define alterations in epithelial and mesenchymal marker expression in BEAS-2B cells. The cells were assessed for 48 h after stimulation with TGF-β1 alone or in combination with TWEAK.ResultsTGF-β1 induced spindle-like morphology and loss of cell contact, and reduced the expression of epithelial marker E-cadherin and increased the expression of mesenchymal markers N-cadherin and vimentin. Our data, for the first time, show that TWEAK reduced the expression of E-cadherin, and that co-treatment with TGF-β1 and TWEAK enhanced the TGF-β1-induced features of EMT. Moreover, hyaluronan synthase 2 expression was up-regulated by a combination with TGF-β1 and TWEAK, but not TNF-α. We also demonstrated that the Smad, p38 MAPK, and NF-κB signaling pathways, and the transcriptional repressor ZEB2 might mediate N-cadherin up-regulation by TGF-β1 in combination with TWEAK.ConclusionsThese findings suggest that the pro-inflammatory cytokine TWEAK and TGF-β1 have synergistic effects in EMT and may contribute to chronic airway changes and remodeling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0207-5) contains supplementary material, which is available to authorized users.
Highlights
Chronic airway inflammatory disorders, such as asthma, are characterized by airway inflammation and remodeling
Hyaluronan synthase 2 expression was up-regulated by a combination with TGF-β1 and TNF-like weak inducer of apoptosis (TWEAK), but not tumor necrosis factor-α (TNF-α)
We demonstrated that Smad-dependent and Smadindependent signaling pathways, including p38 mitogenactivated protein kinase (MAPK) and nuclear factor κB (NF-κB), and the transcriptional repressor ZEB2 might mediate N-cadherin up-regulation by TGF-β1 in combination with TWEAK
Summary
Chronic airway inflammatory disorders, such as asthma, are characterized by airway inflammation and remodeling. EMT is an essential component of embryonic development, tissue remodeling, and wound repair [6] During this transition, epithelial cells acquire the capacity to increase motility through down-regulating epithelial markers, such as E-cadherin, and increasing expression of mesenchymal proteins, such as N-cadherin and vimentin [7,8]. It has been reported that house dust mite and some pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL1β), can enhance TGF-β-induced EMT in bronchial epithelial cells [12,13,14]. In this regard, pro-inflammatory cytokines can contribute to airway remodeling in chronic inflammatory disorders
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
