Expression of TRB3 promotes epithelial‑mesenchymal transition of MLE‑12 murine alveolar type II epithelial cells through the TGF‑β1/Smad3 signaling pathway

Abstract

The aim of the present study was to investigate whether the expression of tribbles pseudokinase 3 (TRB3) is involved in pulmonary interstitial fibrosis and to examine the possible mechanisms. The expression of TRB3 in murine alveolar type II epithelial cells (MLE-12 cells) following transforming growth factor β1 (TGF-β1) stimulation was assessed using various techniques, including western blot and reverse transcription-quantitative polymerase chain reaction assays. TRB3 overexpression and downregulation models were used to evaluate the impact of TRB3 on the TGF-β1-induced epithelial-mesenchymal transition (EMT) of MLE-12 cells. The downregulation of TRB3 was induced by RNA interference. The expression of TRB3 was significantly increased in MLE-12 cells following the activation of TGF-β1 (P<0.05). The overexpression of TRB3 was found to promote activation of the TGF-β1/Smad3 signaling pathway, EMT, and the upregulated expression of β-catenin and EMT-related genes and proteins (P<0.05), whereas the downregulation of TRB3 attenuated the promoting effect on EMT induced by TGF-β1. In addition, the overexpression of TRB3 inhibited MLE-12 cell proliferation by stimulating apoptosis, leading to the formation of pulmonary fibrosis (PF). The positive feedback loop demonstrated that TGF-β1 induced the expression of TRB3, and TRB3, in turn, stimulated EMT and promoted the onset of PF through activation of the TGF-β1/Smad3 signaling pathway. Therefore, TRB3 may promote the formation of PF through the TGF-β1/Smad3 signaling pathway.

Tribbles Homolog 3 Mediates the Development and Progression of Diabetic Retinopathy

“…In a study that used human umbilical vein endothelial cells treated with oxidized phospholipids, the induction of vascular endothelial growth factor (VEGF) strongly correlated with the highest level of TRIB3 ( 3 ). Mechanistically, TRIB3 reportedly regulates the nuclear factor-κB (NF-κB) pathway ( 4 ), promotes activation of transforming growth factor-β1 signaling ( 5 ), controls cytokine expression ( 6 ), and governs macrophage health ( 7 ).…”

Molecular Pathogenesis of Pulmonary Fibrosis, with Focus on Pathways Related to TGF-β and the Ubiquitin-Proteasome Pathway

“…TRB3 is a mammalian Tribble-related protein that is involved in various cellular processes as a scaffold or adaptor to promote degradation of target proteins such as Smurf1/2 and to regulate multiple signal transduction pathways such as TGF-β and MAPK signaling [ 93 ]. In mouse type II alveolar epithelial cells (MLE-12), TGF-β induces TRB3 and depletion of TRB3 decreases of pSmad3 and fibrosis-related genes such as vimentin and fibronectin [ 94 ]. Additionally, TRB3 promotes EMT through the Wnt/β-catenin signaling pathway induced by TGF-β in MLE-12 cells [ 95 ].…”