Abstract
Steroid-resistant asthma is a common cause of refractory asthma. Type 2 inflammation is the main inflammatory response in asthma, and the mechanism underlying the steroid-resistance of type 2 inflammation has not been completely elucidated. Tumor-necrosis-factor-like apoptosis-inducing factor (TWEAK) and transforming growth factor (TGF)-β1 are involved in epithelial-mesenchymal transition (EMT) and the production of thymic stromal lymphopoietin (TSLP) and C-C motif chemokine ligand 5 (CCL5). We herein hypothesize that the combined exposure to TWEAK and TGF-β1 may result in the development of steroid resistance in bronchial epithelial cells. The bronchial epithelial cell line BEAS-2B was cultured with or without TGF-β1 or TWEAK, in the presence or absence of dexamethasone (DEX). The roles of Smad-independent pathways and MAP kinase phosphatase 1 (MKP-1) were also explored. Co-stimulation of TWEAK and TGF-β1 induced E-cadherin reduction, N-cadherin upregulation, and TSLP and CCL5 production, which were not suppressed by DEX. Inhibition of the nuclear factor kappa beta (NF-κB) and mitogen-activated protein kinase pathways downregulated steroid-unresponsive TSLP and CCL5 production, whereas knockdown of MKP-1 improved steroid-unresponsive TSLP production, induced by co-stimulation with TWEAK and TGF-β1. Therefore, co-stimulation with TWEAK and TGF-β1 can induce the steroid-insensitive production of TSLP and CCL5 in the bronchial epithelium and may contribute to airway inflammation.