8742

TNFSF12

BACKGROUND: Chronic 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-beta (TGF-beta). 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-beta is a central inducer of EMT, and TGF-beta-induced EMT is enhanced by pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta. We investigated whether the pro-inflammatory cytokine TWEAK (TNF-like weak inducer of apoptosis) enhanced TGF-beta1-induced EMT in the human bronchial epithelial cell line BEAS-2B. METHODS: Quantitative 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-beta1 alone or in combination with TWEAK. RESULTS: TGF-beta1 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-beta1 and TWEAK enhanced the TGF-beta1-induced features of EMT. Moreover, hyaluronan synthase 2 expression was up-regulated by a combination with TGF-beta1 and TWEAK, but not TNF-alpha. We also demonstrated that the Smad, p38 MAPK, and NF-kappaB signaling pathways, and the transcriptional repressor ZEB2 might mediate N-cadherin up-regulation by TGF-beta1 in combination with TWEAK. CONCLUSIONS: These findings suggest that the pro-inflammatory cytokine TWEAK and TGF-beta1 have synergistic effects in EMT and may contribute to chronic airway changes and remodeling.