TGF-β Upregulated Mitochondria Mass through the SMAD2/3→C/EBPβ→PRMT1 Signal Pathway in Primary Human Lung Fibroblasts

Sun, Qingzhu; Fang, Lei; Tang, Xuemei; Lu, Shemin; Tamm, Michael; Stolz, Daiana; Roth, Michael

doi:10.4049/jimmunol.1800782

Cited by 56 publications

(59 citation statements)

References 53 publications

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“…However, there are many other ways in TGFβ can modulate mitochondrial activities. TGFβ was reported to increase mitochondrial mass in primary human lung fibroblasts (82). In this study, TGFβ signaling via the canonical pathway culminated in the upregulation of PGC-1α expression.…”

Section: Tgfβ and Mitochondrial Structure And Functionmentioning

confidence: 57%

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Slattery

Gardiner

2019

Front. Immunol.

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NK cells are innate lymphocytes which play an essential role in protection against cancer and viral infection. Their functions are dictated by many factors including the receptors they express, cytokines they respond to and changes in the external environment. These cell processes are regulated within NK cells at many levels including genetic, epigenetic and expression (RNA and protein) levels. The last decade has revealed cellular metabolism as another level of immune regulation. Specific immune cells adopt metabolic configurations that support their functions, and this is a dynamic process with cells undergoing metabolic reprogramming during the course of an immune response. Upon activation with pro-inflammatory cytokines, NK cells upregulate both glycolysis and oxphos metabolic pathways and this supports their anti-cancer functions. Perturbation of these pathways inhibits NK cell effector functions. Anti-inflammatory cytokines such as TGFβ can inhibit metabolic changes and reduce functional outputs. Although a lot remains to be learned, our knowledge of potential molecular mechanisms involved is growing quickly. This review will discuss our current knowledge on the role of TGFβ in regulating NK cell metabolism and will draw on a wider knowledge base regarding TGFβ regulation of cellular metabolic pathways, in order to highlight potential ways in which TGFβ might be targeted to contribute to the exciting progress that is being made in terms of adoptive NK cell therapies for cancer.

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Section: Tgfβ and Mitochondrial Structure And Functionmentioning

confidence: 57%

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Slattery

Gardiner

2019

Front. Immunol.

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“…Available evidence suggests that hypoxia-induced expression of connective tissue growth factor (CTGF), resulting in pulmonary fibrosis, was dependent on C/EBPβ activation [17]. Besides, a previous study confirmed that C/EBPβ was a key mediator of TGF-β-dependent fibroblast remodelling in asthma [25]. Similarly, C/EBPβ may play a pivotal role in the development of pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 95%

TGF-β-induced α-SMA expression is mediated by C/EBPβ acetylation in human alveolar epithelial cells in vitro

Ding

Chen

Qin

et al. 2020

Preprint

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Background This study sought to determine whether binding of acetylated C/EBPβ to α-SMA promoter could affect its activity and was essential for EMT and extracellular matrix deposition in IPF using in vitro model. Methods Through western blotting, the expression of EMT and C/EBPβ were detected in A549 cells with TGF-β as pulmonary fibrotic model in vitro. Moreover, the expression of C/EBPβ mRNA via Real Time-PCR and Collagen-I expression using ELISA were performed. The luciferase activity assay was used to examine the activity of C/EBPβ. The knockdown expression of C/EBPβ gene was prepared in A549 cells with C/EBPβ siRNA. We also investigated the effect of deacetylation of C/EBPβ on EMT using SIRT1. The binding ability of C/EBPβ with the α-SMA promoter was affirmed via ChIP and EMSA. Furthermore, the relationship between α-SMA and acetylated C/EBPβ was investigated using the co-immunoprecipitation. Results SiRNA-mediated knockdown of C/EBPβ in A549 cells attenuated TGF-β1-induced myofibroblast differentiation and ECM deposition. The extent of association between acetylated C/EBPβ and the α-SMA promoter was dynamically monitored. Furthermore, it was confirmed that deacetylation of C/EBPβ in A549 cells successfully ameliorated TGF-β1-induced EMT, as shown by reduction in α-SMA expression and excessive collagen-I accumulation. Conclusions Collectively, our data suggested that the EMT and fibrotic effect of TGF-β1 could be dependent on acetylated C/EBPβ-mediated regulation of α-SMA gene activity. This thus suggests that C/EBPβ acetylation may play a central role in pulmonary fibrosis.

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“…C/EBP-β also participates in the fibrosis of many organs, such as liver, 50 kidney, 30,39,54 and lung. 55 Especially, C/EBP-β can inhibit the progress of renal fibrosis. For example, C/EBP-β reduced fibronectin synthesis by regulating the transcription of TINag while the deficiency of C/EBP-β aggravated renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

IRF‐1 promotes renal fibrosis by downregulation of Klotho

Liu

Huang

et al. 2020

FASEB j.

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Although the key role of renal fibrosis in the progression of chronic kidney disease (CKD) is well known, the causes of renal fibrosis are not fully clarified. In this study, interferon regulatory factor 1 (IRF‐1), a mammalian transcription factor, was highly expressed in fibrotic kidney of CKD patients. Concordantly, the expression level of IRF‐1 was significantly elevated in the kidney of unilateral ureteral obstruction (UUO) and Adriamycin nephropathy (ADR) mice. In tubular epithelial cells, overexpression of IRF‐1 could induce profibrotic markers expression, which accompanied by dramatic downregulation of Klotho, an important inhibitor of renal fibrosis. Luciferase reporter analysis and ChIP assay revealed that IRF‐1 repressed Klotho expression by downregulation of C/EBP‐β, which regulates Klotho gene transcription via directly binding to its promoter. Further investigation showed that tumor necrosis factor‐alpha may be an important inducement for the increase of IRF‐1 in tubular epithelial cells after UUO and genetic deletion of IRF‐1 attenuated renal fibrosis in UUO mice. Hence, these findings demonstrate that IRF‐1 contributes to the pathogenesis of renal fibrosis by downregulation of Klotho, and suppresses IRF‐1 may be a potential therapeutic target for CKD.

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TGF-β Upregulated Mitochondria Mass through the SMAD2/3→C/EBPβ→PRMT1 Signal Pathway in Primary Human Lung Fibroblasts

Cited by 56 publications

References 53 publications

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

TGF-β-induced α-SMA expression is mediated by C/EBPβ acetylation in human alveolar epithelial cells in vitro

IRF‐1 promotes renal fibrosis by downregulation of Klotho

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