Tannic acid attenuates TGF‐β1‐induced epithelial‐to‐mesenchymal transition by effectively intervening TGF‐β signaling in lung epithelial cells

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and an irreversible lung disorder characterized by the accumulation of fibroblasts and myofibroblasts in the extracellular matrix. The transforming growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) is thought to be one of the possible sources for a substantial increase in the number of fibroblasts/myofibroblasts in IPF lungs. Tannic acid (TA), a natural dietary polyphenolic compound has been shown to possess diverse pharmacological effects. However, whether TA can inhibit TGF-β1-mediated EMT in lung epithelial cells remains enigmatic. Both the human adenocarcinomic alveolar epithelial (A549) and normal bronchial epithelial (BEAS-2B) cells were treated with TGF-β1 with or without TA. Results showed that TA addition, markedly inhibited TGF-β1-induced EMT as assessed by reduced expression of N-cadherin, type-1-collagen, fibronectin, and vimentin. Furthermore, TA inhibited TGF-β1-induced cell proliferation through inducing cell cycle arrest at G0/G1 phase. TGF-β1-induced increase in the phosphorylation of Smad (Smad2 and 3), Akt as well as that of mitogen activated protein kinase (ERK1/2, JNK1/2, and p38) mediators was effectively inhibited by TA. On the other hand, TA reduced the TGF-β1-induced increase in TGF-β receptors expression. Using molecular docking approach, FTIR, HPLC and Western blot analyses, we further identified the direct binding of TA to TGF-β1. Finally, we conclude that TA might directly interact with TGF-β1, thereby repressing TGF-β signaling and subsequent EMT process in lung epithelial cells. Further animal studies are needed to clarify its potential therapeutic benefit in pulmonary fibrosis.

Dual role of RACK1 in airway epithelial mesenchymal transition and apoptosis

“…To explain the relationship between RACK1 and TGF‐β1‐induced apoptosis and EMT process, we performed a mechanistic study to determine whether inhibition of RACK1 expression significantly attenuated TGF‐β1‐induced apoptosis and EMT in airway epithelial cells. TGF‐β1 has a marked induction effect in both apoptosis and EMT in airway epithelial cells. Our current study used 30 ng/mL TGF‐β1 stimulated cells for 72 hours and 10 ng/mL TGF‐β1 stimulated cells for 48 hours that induced apoptosis and EMT according to our previous work, both of which was the best dose to induce apoptosis and EMT, respectively.…”

Tannic acid modulates fibroblast proliferation and differentiation in response to pro‐fibrotic stimuli

“…In epithelial cells, we identified that TA directly interacts with TGF-β1, thereby inhibiting TGF-β1 binding to its receptors and activation of downstream signaling molecules in order to mitigate TGF-β1induced EMT process. 21 Therefore, inhibition of TGF-β1induced fibroblast proliferation and differentiation in TA-treated group could be explained by our previous report demonstrating the TA-mediated blockage on TGF-β1-binding to epithelial cells. Because TA is naturally present in some foods and available as a dietary supplement with variable pharmacological effects, it is noteworthy to discuss about the metabolism and safety intake levels of TA in vivo.…”

“…Our findings suggested that the inhibiting effect of TA on proliferation of fibroblasts depends on down-regulation of gene expression of Cyclins (Ccnb1, Ccnd1, and Ccne1), which confirms our previous observations of TA on epithelial cells and supports a potential therapeutic role for TA in preventing fibroblast accumulation following a pro-fibrotic injury. 21 Finally, TGF-β1 mediates its effects via Smad-dependent and Smad-independent pathways. 37 In the process of fibrosis, TGF-β1 interacts with cell surface receptor kinases (TGF-β receptor type I/ TGF-β receptor type II) (TβRI/TβRII), resulting in phosphorylation of Smad2/3, and/or activation of non-Smad signaling pathways, including MAP kinase.…”

Tannic Acid: Specific Form of Tannins in Cancer Chemoprevention and Therapy-Old and New Applications

“…It has recently been reported that TA treatment prevents TGFβ-induced EMT in breast cancer cells as well as in lung epithelial cells [46••, 47]. The direct interaction between TA and TGF-β1 was observed, attenuating the TGF-β signaling [47]. In lung epithelial cells, TA also decreased the expression of Ncadherin, type-1-collagen, fibronectin, and vimentin.…”