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.
Idiopathic pulmonary fibrosis (IPF) is a chronic, lethal and irreversible disease, which is characterized by fibroblast proliferation and excessive deposition of extracellular matrix in the lung (
At present, many studies have focused on the pathogenesis mechanisms, which mainly include the Smad, MAPK, and ERK signaling pathways (
Both basic research and clinical research have proven that TGF-β1 plays an important role in the pathogenesis of IPF (
The Smads family comprises three subfamilies, including five receptor-activated Smads (R-Smads), one common mediator Smad (Co-Smad) and two inhibitory Smads (I-Smads). Smad6 and Smad7 are the third type of Smads known as 'inhibitory Smads' or 'anti-Smads'. They are structurally different from other members of the family, and have been proven to be inhibitors of the Smad signaling pathway by disturbing the activation of R-Smads (
When TGF-β type I receptor kinase was activated by TGF-β1 signal, R-Smads (Smad2 and Smad3) were phosphorylated; of note is that Smad3 is more sensitive to TGF-β1 than Smad2 (
TGF-β1 regulates the terminal differentiation of human lung fibroblasts (HLF) and promotes the synthesis of fibroblast extracellular matrix (
It was also reported that TGF-β1 stimulated primary human bronchial epithelial cells (HBEC) to the status of EMT
The expression of peroxisome proliferator-activated receptor γ (PPAPγ), a negative regulator of TGF-β1-induced fibrosis, is mainly controlled by TGF-β1. Cells lacking Smad3 showed that the down-regulation effect of TGF-β1 on PPARγ was weakened, suggesting that TGF-β1 regulates the PPARγ in a Smad3-dependent manner (
A great number of studies indicated that phosphatidylinositol-3-kinase (PI3K) was involved in the pathomechanism of pulmonary fibrosis (
As mentioned previously, CTGF is a functional intermediate product between TGF-β1 and ECM protein. CTGF derived from epithelial cells can activate fibroblasts and further accelerate the fibrosis process in an autocrine manner (
Mitogen-activated protein kinase (MAPK), mainly consisting of three distinctive cascades, the JNK, p38 and ERK pathways, is a well-known and crucial signaling pathway in multiple diseases (
Coagulation factor XII (FXII) is a serine protease relevant to fibrinolysis, it was demonstrated that the production of FXII induced by TGF-β1 in HLF was mediated with JNK/Smad3 signaling pathways (
Notably, TGF-β1/MAPK signal not only contributed to the phenotypic modulation to myofibroblast, but also showed a protective effect on myofibroblasts. For example, TGF-β1 attenuates the apoptosis of fibroblast by inducing the production of a p38-dependent growth factor, which activates PI3K/AKT successively (
TGF-β1 regulates the autocrine of basic fibroblast growth factor (bFGF) in HLF, which activated the expression of ERK pathway and the induction of activator protein-1 (AP-1), accelerating pulmonary fibrogenesis (
The Wnt/β-catenin pathway is the canonical Wnt signaling pathway, also known as the 'β-catenin-dependent' Wnt pathway. Wnt/β-catenin has been proven to play an important role in body development and growth, tumor, cardiovascular disease, musculoskeletal diseases, and also respiratory disease (
Increasing evidence suggested that Wnt/β-catenin was involved in the TGF-β1-relevant IPF. TGF-β1 initiated the Wnt/β-catenin cascade via upregulating β-catenin and GSK-3β, promoting the fibrotic differentiation of lung resident mesenchymal stem cells (LR-MSCs) (
Feedback regulation is a crucial aspect in molecule cascades. Both positive and negative feedback are revealed in TGF-β1-involved pathway in IPF.
TGF-β1 strongly downregulated Cub domain-containing protein 1 (CDCP1), which promoted myofibroblast differentiation through inhibition of the potential negative feedback effect of CDCP1 expression on TGF-β1 stimulation (
Besides the signaling pathways discussed above, other molecules cascades were also revealed to be involved in the TGF-β1 relevant mechanisms of IPF.
The proliferation of fibroblasts is mainly mediated by platelet-derived growth factor (PDGF) isoforms, whose activity was potentially regulated by TGF-β1 (
Currently, findings have shown that TGF-β1 may contribute to the development of IPF through epigenetic regulation. In fibroblasts from patients with IPF, TGF-β1 induces the upregulation of DNA methyltransferase (DNMT3a) and tetmethylcytosine dioxygenase 3 (TET3) (
TGF-β1 may promote IPF by reducing the production of antioxidant substance and inducing oxidative stress. TGF-β1 disturbs the homeostasis of the messenger RNA (mRNA) of the γ-glutamylcysteine synthase (
IPF is an irreversible lung disease, and there is no exact cause (
TGF-β1 activates Smads through the transmembrane receptor serine/threonine kinase, thereby continuously regulating the transcription of target genes (
There are crosstalks and self-regulating loop in different pathways involved in TGF-β1-induced IPF. The Rho/Rock and Smad signaling pathways may cross talk in lung fibroblast differentiation (
However, some mechanisms and pathways involved in TGF-β1 have not been clarified; thus, greater efforts to identify these should be made with regard to TGF-β1. Although some pathways have been proven, fewer drugs are actually converted into clinical applications. As for further studies on TGF-β1 in IPF, the focus should be on the intersection of various pathways, to facilitate the development of more effective drugs. At the same time, in addition to study on the various signal pathways involved in TGF-β1, an in-depth study of its role in epigenetics, and oxidative stress should also be conducted. After all, the purpose of research is to serve the clinic and solve the problem of clinical IPF treatment.
TGF-β1 plays a crucial role in the development of IPF as it regulates the pathomechanism of IPF through a number of signaling pathways, including Smad, MAPK, Wnt, and ERK pathways. The effect of TGF-β1 on IPF is one of stimulation. Nevertheless, there are some self-limiting mechanisms. Furthermore, some TGF-β1-relevant mechanisms in IPF remain to be elucidated.
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ZY substantially contributed to the conception and design of the work and wrote the manuscript. YH revised the manuscript critically for important intellectual content. Both authors approved the final version of the manuscript.
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The authors declare that they have no competing interests.
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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.
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.
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.
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.
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.
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.
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.
The association between IPF incidence with age.
Studies | <50 years | 50-59 years (%) | 60-69 years (%) | >70 years (%) | (Refs.) |
---|---|---|---|---|---|
Miyake | 2.9% | 14.7 | 54.9 | 27.5 | ( |
Kim | NA | 17.1 | 25.7 | 57.2 | ( |
The association between IPF incidence with sex.
Studies | Male (%) | Female (%) | (Refs.) |
---|---|---|---|
Baumgartner | 60 | 40 | ( |
Miyake | 90.2 | 9.8 | ( |
García-Sancho Figueroa | 73.2 | 26.8 | ( |
Awadalla | 47.3 | 42.7 | ( |
Kim | 75.7 | 24.3 | ( |
Koo | 70.5 | 29.5 | ( |
Paolocci | 72.5 | 27.5 | ( |
Targeting molecules and signaling pathways initiated by TGF-β1 in IPF.
Author, year | Cell/tissue type | Target gene | Potential signaling pathways | Biological effect | (Refs.) |
---|---|---|---|---|---|
Canonical TGF-β1/Smad signaling pathway | |||||
Gu |
Human fetal lung fibroblasts | Smad3 | TGF-β1/Smad3/α-SMA | Promoting myofibroblast differentiation | ( |
Ramirez |
Murine lung fibroblasts | Smad3 | TGF-β1/Smad3/PPARγ | Promoting pulmonary fibrogenesis | ( |
Li |
Human embryonic lung fibroblasts | Smad3 | TGF-β1/Smad3/CTGF | Promoting pulmonary fibrogenesis | ( |
Huang |
Human lung fibroblasts | Smad3 | TGF-β1/Smad3/miR-424/Slit2 | Promoting myofibroblast differentiation | ( |
Zheng |
Mouse pulmonary fibroblasts | Smad3 | TGF-β1/Smad3/c-Jun/Fstl | Promoting fibrogenesis | ( |
Hecker |
Human fetal lung mesenchymal cells | Smad3 | TGF-β1/Smad3/NOX4/H2O2 | Promoting myofibroblast differentiation | ( |
Guo |
Normal human lung fibroblasts | Smad3 | TGF-β1/Smad3/NOX4/ROS | Promoting myofibroblast differentiation | ( |
Fierro-Fernández |
Human fetal lung fibroblasts | Smad3 | TGF-β1/Smad3/NOX4/ROS/miR-9-5p/NOX4 | Attenuating myofibroblast | ( |
Huang |
Mouse lung fibroblasts | Smad3 | TGF-β1/Smad3/FENDRR | Promoting pulmonary fibrogenesis | ( |
Kadoya |
Human lung fibroblasts | Smad3 | TGF-β1/Smad3/ERK5 | Promoting pulmonary fibrogenesis | ( |
Cushing |
Human fetal lung fibroblast | Smad3 | TGF-β1/Smad3/miR-29 | Promoting pulmonary fibrogenesis | ( |
Yang |
( | ||||
Xiao |
( | ||||
Kang |
Murine lung | Smad3 | TGF-β1/Smad3/SEMA 7A | Promoting pulmonary fibrogenesis | ( |
Selvarajah |
Primary human lung fibroblasts | Smad3 | TGF-β1/Smad3/mTORC1/4E-BP1/ATF4 | Promoting collagen biosynthesis | ( |
Jiang |
Human endothelial cells | Smad2/3/4 | TGF-β1/Smad2/3/4/RELM-β | Attenuating EndMT | ( |
Câmara and Jarai, 2010 | Human bronchial epithelial cells | Smad2/3 | TGF-β1/Smad2/3 | Promoting EMT | ( |
Li |
Human alveolar epithelial cell (A549) | Smad2/3 | TGF-β1/Smad2/3 | Promoting EMT | ( |
Guan and Zhou, 2017 | Mice lung endothelial cells | Smad2/3 | TGF-β1/Smad2/3/CXCR7/TGF-β1/Jag1-Notch | Attenuating EndMT | ( |
Chen |
Human embryonic lung fibroblasts | Smad2/3 | TGF-β1/Smad2/3/miR-182-5p/Smad7 | Promoting pulmonary fibrogenesis | ( |
Kasai |
Human alveolar epithelial cell (A549) | Smad2 | TGF-β1/Smad2 | Promoting EMT | ( |
Ji |
Human embryonic lung fibroblasts | Smad2 | TGF-β1/Smad2/RhoA | Promoting myofibroblast differentiation | ( |
PI3K relevant signaling pathway | |||||
Shi |
Human alveolar epithelial cells | PI3K | TGF-β1/PI3K/CTGF | Promoting EMT and fibrogenesis | ( |
Wygrecka |
Human lung fibroblasts | PI3K | TGF-β1/PI3K/JNK/AKT/TF | Promoting pulmonary fibrogenesis | ( |
MAPK relevant signaling pathway | |||||
JNK pathway | |||||
Chen |
Human alveolar epithelial | JNK-p38 | TGF-β1/JNK-p38 | Promoting EMT | ( |
Khalil |
( | ||||
Jablonska |
Human lung fibroblasts | JNK | TGF-β1/JNK/Smad3/FXII | Promoting pulmonary fibrogenesis | ( |
MAPK relevant signaling pathway | |||||
Hashimoto |
Human lung fibroblasts | JNK | TGF-β1/JNK | Promoting myofibroblast differentiation | ( |
Cui |
Human lung fibroblasts | JNK | TGF-β1/JNK/VEGF-D | Promoting pulmonary fibrogenesis | ( |
p38 signaling pathway | |||||
Kulasekaran |
Human lung fibroblasts | p38 | TGF-β1/p38/PI3K/AKT | Attenuates apoptosis | ( |
Deng |
Human lung fibroblasts | p38 | TGF-β1/p38/α-SMA | Promoting pulmonary fibrogenesis | ( |
García-Alvarez |
Human lung fibroblasts | p38 | TGF-β1/p38/TIMP3/VEGF | Promoting pulmonary fibrogenesis | ( |
Gu |
Human small airway epithelial cells | p38 | TGF-β1//p38/CIPs/complement | Promoting epithelial injury in IPF | ( |
ERK signaling pathway | |||||
Caraci |
Human lung fibroblasts | ERK1/2 | TGF-β1/ERK1/2/GSK-3β/β-catenin | Promoting myofibroblast differentiation | ( |
Ghatak |
Human lung fibroblasts | ERK | TGFβ1/ERK/EGR1-AP-1/CD44v6 | Promoting myofibroblast differentiation | ( |
Wnt/β-catenin relevant signaling pathway | |||||
Lu |
Lung resident mesenchymal stem cells | β-catenin | TGF-β1/β-catenin | Promoting myofibroblast differentiation | ( |
Zhou |
Human alveolar epithelial cell | β-catenin | TGF-β1/β-catenin/CBP | Promoting EMT | ( |
Wang |
Human embryonic lung fibroblasts | Wnt3a/β-catenin | TGF-β1/Wnt3a/β-catenin/miR-29 | Promoting cell proliferation | ( |
Other signaling pathway | |||||
Arsalane |
Human alveolar epithelial | γ-GCS | TGF-β/γ-GCS/ROS | Promoting pulmonary fibrogenesis | ( |
Jardine |
cell (A549) | ( | |||
Boustani |
( | ||||
Yu |
Mouse alveolar epithelial cells | TRB3 | TGF-β/TRB3/Wnt/β-catenin | Promoting EMT | ( |
Yamasaki |
Murine lung epithelial cells | TNF-α | TGF-β/TNF-α/p21 | Attenuating fibrosis, and alveolar remodeling | ( |
Zhang |
Human fetal lung fibroblasts | SIRT6 | TGF-β1/SIRT6/TGF-β1/Smad2 | Attenuating myofibroblast differentiation | ( |
Kang |
Murine lung | SEMA 7A | TGF-β1/SEMA 7A/PI3K/PKB/AKT | Promoting pulmonary fibrogenesis | ( |
Kolosionek |
Human alveolar epithelial cells | Rho | TGF-β1/Rho/PDE4 | Promoting EMT | ( |
Wei |
Human lung fibroblasts | miR-133a | TGF-β1/miR-133a/CTGF-Col1a1 | Attenuating myofibroblast differentiation and pulmonary fibrosis | ( |
Lu |
Alveolar interstitial cells | Integrin α8β1 | TGF-β1-LAPT/integrin α8β1/ERK | Promoting cell adhesion | ( |
Lim |
Fibroblast cell lines | Gal-1 | TGF-β1/Gal-1/Smad2 | Promoting myofibroblast differentiation | ( |
Xiao |
Human alveolar epithelial cell | FGF-2 | TGFβ1/FGF-2/ERK1/2 | Promoting fibroblast proliferation and fibrogenesis | ( |
Noskovičová |
Human lung fibroblasts | CDCP1 | TGF-β1/CDCP1 | Attenuating myofibroblast differentiation | ( |
Hagimoto |
Human bronchiolar epithelial cells | caspase-3 | TGF-β/caspase-3/Fas | Promoting cell apoptosis and lung injury | ( |
Finlay |
Human lung fibroblasts | bFGF | TGF-β1/bFGF/ERK-AP1 | Promoting pulmonary fibrogenesis | ( |
Uhal |
Primary human lung fibroblasts | ANG | TGF-β1/ANG | Promoting development of IPF | ( |
Zhou |
Human alveolar epithelial cell (A549) | Amphiregulin | TGF-β1/amphiregulin/EGFR/TGF-β1 | Promoting pulmonary fibrosis | ( |