Abstract
Tumor necrosis factor (TNF)-like cytokine 1A (TL1A), a member of the TNF family, exists in the form of membrane-bound (mTL1A) and soluble protein (sTL1A). TL1A binding its only known functional receptor death domain receptor 3 (DR3) affects the transmission of various signals. This study first proposed that the TL1A/DR3 axis was significantly upregulated in patients and mice with both asthma and high TNF-a expression and in TNF-a-stimulated epithelial Beas-2B cells. Two independent approaches were used to demonstrate that the TL1A/DR3 axis of mice was strongly correlated with TNF-a in terms of exacerbating asthmatic epithelial–mesenchymal transformation (EMT). First, high expression levels of EMT proteins (e.g., collagen I, fibronectin, N-cadherin, and vimentin) and TL1A/DR3 axis were observed when mice airways were stimulated by recombinant mouse TNF-a protein. Moreover, EMT protein and TL1A/DR3 axis expression synchronously decreased after mice with OVA-induced asthma were treated with infliximab by neutralizing TNF-a activity. Furthermore, the OVA-induced EMT of asthmatic mice was remarkably improved upon the deletion of the TL1A/DR3 axis by knocking out the TL1A gene. TL1A siRNA remarkably intervened EMT formation induced by TNF-a in the Beas-2B cells. In addition, EMT was induced by the addition of high concentrations of recombinant human sTL1A with the cell medium. The TL1A overexpression via pc-mTL1A in vitro remarkably increased the EMT formation induced by TNF-a. Overall, these findings indicate that the TL1A/DR3 axis may have a therapeutic role for asthmatic with high TNF-a level.
Highlights
Asthma, a heterogeneous disease, is characterized by chronic inflammation, epithelial–mesenchymal transformation (EMT), and airway remodeling [1]
TL1A/domain receptor 3 (DR3) Axis Is Overexpressed in the Asthmatic Mice With High tumor necrosis factor (TNF)-a Expression Induced by OVA
These results suggest that TNF receptor superfamily and death receptor might be related to remodeling or EMT
Summary
A heterogeneous disease, is characterized by chronic inflammation, epithelial–mesenchymal transformation (EMT), and airway remodeling [1]. Most patients with asthma rely on drugs such as glucocorticoids and bronchodilators to improve disease progression. Chronic airway inflammation disorder exacerbates the progression of asthma [4]. Macrophages, T cells, and other cells gather and secrete various factors, such as interleukin-1b, 4, 5, 10, and 13 and tumor necrosis factor (TNF)-a, which break the anti-inflammatory balance and aggravate asthma progression [5, 6]. TNF-a, a member of the TNF superfamily, has promising applications in the pathophysiological progress of autoimmune diseases, such as Crohn’s disease, and the development and application of related drugs [8]. The mechanism in which TNF-a acts in mucus secretion, airway hyperreactivity, and airway remodeling of human asthma remains unclear
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