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Review
. 2021 Jul;48(1):132.
doi: 10.3892/ijmm.2021.4965. Epub 2021 May 20.

TGF‑β1: Gentlemanly orchestrator in idiopathic pulmonary fibrosis (Review)

Zhimin Ye  1 , Yongbin Hu  1
Affiliations
Review

TGF‑β1: Gentlemanly orchestrator in idiopathic pulmonary fibrosis (Review)

Zhimin Ye et al. Int J Mol Med. 2021 Jul.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a worldwide disease characterized by the chronic and irreversible decline of lung function. Currently, there is no drug to successfully treat the disease except for lung transplantation. Numerous studies have been devoted to the study of the fibrotic process of IPF and findings showed that transforming growth factor‑β1 (TGF‑β1) plays a central role in the development of IPF. TGF‑β1 promotes the fibrotic process of IPF through various signaling pathways, including the Smad, MAPK, and ERK signaling pathways. There are intersections between these signaling pathways, which provide new targets for researchers to study new drugs. In addition, TGF‑β1 can affect the fibrosis process of IPF by affecting oxidative stress, epigenetics and other aspects. Most of the processes involved in TGF‑β1 promote IPF, but TGF‑β1 can also inhibit it. This review discusses the role of TGF‑β1 in IPF.

Keywords: ERK; MAPK; Smad; TGF‑β1; idiopathic pulmonary fibrosis.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Role of TGF-β1 in Idiopathic pulmonary fibrosis. TGF-β1 plays a crucial role in idiopathic pulmonary fibrosis. It promotes the transformation of fibroblast into myofibroblast, epithelial cell into mesenchymal cell, and it promotes the production of collagen, filamentous actin and α-SMA.
Figure 2
Figure 2
TGF-β1/Smad signaling pathway. TGF-β1 influences the three key steps of idiopathic pulmonary fibrosis: EMT/EndMT, myofibroblast differentiation, and fibrogenesis by participating in Smad-related signaling pathways. TGF-β1 activates HMGB1, RELM-β, Slit2, and Fstl1 by combining with Smad2 and Smad3. However, this combination has both a positive promotion role, as well as an inhibitory role. In addition, Smad7 plays a negative regulatory role in these mechanisms. These are not three independent pathways, there are places where they cross each other.
Figure 3
Figure 3
PI3K signaling pathway. TGF-β1 activates the PKB, JNK, and AKT signaling pathways through the PI3K signaling pathway, and also activates AP-1 to promote the production of tissue factor, which ultimately lead to the formation of idiopathic pulmonary fibrosis.
Figure 4
Figure 4
MAPK signaling pathway. The JNK, P38 and ERK pathways constitute the canonical MAPK signaling pathway. The downstream of JNK signaling pathway has Smad3, α-SMA, and VEGF-D, which promote the former two and inhibit VEGF-D. Downstream of p38 are CIP, GF, TIMP3 and α-SMA. P38 inhibits CIP, CIP inhibits complement, and complement in turn inhibits TGF-β1. The ERK pathway is a very complex signaling pathway, in which there are many molecules, including FGF-2, AP-1, and γ-SMA. The final effect of these pathways is to promote the production of α-SMA and COL1, leading to idiopathic pulmonary fibrosis.
Figure 5
Figure 5
Wnt/β signaling pathway. The Wnt/β signaling pathway plays an important role in idiopathic fibrosis promoted by TGF-β1. After TGF-β1 activates Wnt/β-catenin, it degrades the complex formed by GSK-3β and β-catenin, axin and APC, then β-catenin is released. Additionally, TGF-β1 promotes the production of β-catenin by combining with Smad2/3, which ultimately leads to an increase in the production of CBP.
Figure 6
Figure 6
Feedback regulation signaling pathway. TGF-β1 promotes the production of EGFR by promoting the production of amphiregulin, but EGFR plays a negative feedback role, inhibiting the process by which TGF-β1 promotes the production of amphiregulin. TGF-β1 promotes the production of p21 by promoting the production of TNF-α, but p21 in turn inhibits the process that promotes its production. TGF-β1 promotes miR-133, but miR-133 inhibits the production of α-SMA, CTGF and COL I.
Figure 7
Figure 7
Other signaling pathways. TGF-β1 promotes Fas by activating caspase-3, and it can also promote the Wnt/β signaling pathway by promoting TRB3. In addition to positive promotion of idiopathic pulmonary fibrosis, it also has a negative inhibitory effect, such as TGF-β1 through the inhibition of PDGF-Rα protein transcription and inhibition of Cav-1 production to play a negative role in idiopathic pulmonary fibrosis.
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Grants and funding

This review was funded by the National Natural Science Foundation of China (grant no. 81673120).
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