Nuclear factor (NF)-κB p65 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-β

Sun, Xing‐Guo; Chen, Erjun; Dong, Rui; Chen, Weiguo; Hu, Ying

doi:10.1016/j.lfs.2014.11.033

Cited by 34 publications

(33 citation statements)

References 33 publications

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“…Transforming growth factor beta 1 (TGF- β 1) known for its role in fibrogenesis was used to imitate the in vivo microenvironment during fibrosis. 23 Cells were divided into five groups: control, NC, p65-si, NC+TGF- β 1, and p65-si+TGF- β 1. Transfection with p65-si significantly reduced cell proliferation (Figure 5a) and increased apoptosis (Figure 5b) in Fbs cultures irrespectively of TGF- β 1 pre-treatment, suggesting that p65 supported Fbs growth during fibrogenesis through inhibition of apoptosis.…”

Section: Resultsmentioning

confidence: 99%

“…23 Cells were transfected at 50% confluence with negative control siRNA or p65-specific siRNA using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions; the sequences of siRNAs are shown in Supplementary Table 3. Six hours after transfection, the medium was replaced by normal fresh medium, and cells were then used for evaluation.…”

Section: Methodsmentioning

confidence: 99%

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RelA/p65 inhibition prevents tendon adhesion by modulating inflammation, cell proliferation, and apoptosis

et al. 2017

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Peritendinous tissue fibrosis which leads to poor tendon function is a worldwide clinical problem; however, its mechanism remains unclear. Transcription factor RelA/p65, an important subunit in the NF-κB complex, is known to have a critical role in many fibrotic diseases. Here, we show that RelA/p65 functions as a core fibrogenic regulator in tendon adhesion and that its inhibition exerts an anti-fibrogenic effect on peritendinous adhesion. We detected the upregulation of the NF-κB pathway in human tendon adhesion using a gene chip microarray assay and revealed the overexpression of p65 and extracellular matrix (ECM) proteins Collagen I, Collagen III, and α-smooth muscle actin (α-SMA) in human fibrotic tissues by immunohistochemistry and western blotting. We also found that in a rat model of tendon injury, p65 expression correlated with tendon adhesion, whereas its inhibition by small interfering (si)RNA prevented fibrous tissue formation and inflammatory reaction as evidenced by macroscopic, biomechanical, histological, immunohistochemical, and western blotting analyses. Furthermore, in cultured fibroblasts, p65-siRNA, p65-specific inhibitor, Helenalin and JSH23 suppressed cell proliferation and promoted apoptosis, whereas inhibiting the mRNA and protein expression of ECM components and cyclo-oxygenase-2, an inflammatory factor involved in tendon adhesion. Our findings indicate that p65 has a critical role in peritendinous tissue fibrosis and suggest that p65 knockdown may be a promising therapeutic approach to prevent tendon adhesion.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

RelA/p65 inhibition prevents tendon adhesion by modulating inflammation, cell proliferation, and apoptosis

et al. 2017

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“…The RelA signalling pathway is associated with the pathogenesis of fibrosis including organs such as kidney, liver and lung 5, 6, 7, 8, 9, 10, 11, 12, 13. In unstimulated cells, the cytoplasmic NF‐κB is bound to the inhibitory protein IκB; the complex prevents NF‐κB activation ( i.e .…”

Section: Introductionmentioning

confidence: 99%

“…The ECM is deposited by myofibroblasts under the influence of pro-fibrotic cytokines, such as transforming growth factor beta 1 (TGFb1) [1,2]. TGFb1 is one of the most potent pro-fibrotic cytokines known to be involved in the activation of fibroblasts into myofibroblasts, a key process associated with fibrosis that seems to be dependent, among others, on the activation of the nuclear factor kappa B (NF-jB) pathway [3][4][5][6], especially NF-jB subunit p65 (= RelA).…”

Section: Introductionmentioning

confidence: 99%

The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

Mia

Bank

2015

J Cellular Molecular Medi

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Excessive accumulation of a collagen‐rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGFβ1) is a strong inducer of myofibroblast formation and subsequent collagen production. Currently, there are no remedies for the treatment of fibrosis. Activation of the nuclear factor kappa B (NF‐κB) pathway by phosphorylating IκB with the enzyme IκB kinase (IKK) plays a major role in the induction of fibrosis. ACHP {2‐Amino‐6‐[2‐(cyclopropylmethoxy)‐6‐hydroxyphenyl]‐4‐(4‐piperidinyl)‐3 pyridinecarbonitrile}, a selective inhibitor of IKK, prohibits the activation of the NF‐κB pathway. It is not known whether ACHP has potential anti‐fibrotic properties. Using adult human dermal and lung fibroblasts we have investigated whether ACHP has the ability to inhibit the TGFβ1‐induced transition of fibroblasts into myofibroblasts and its excessive synthesis of ECM. The presence of ACHP strongly suppressed the induction of the myofibroblast markers alpha‐smooth muscle actin (αSMA) and SM22α, as well as the deposition of the ECM components collagen type I and fibronectin. Furthermore, post‐treatment with ACHP partly reversed the expression of αSMA and collagen type I production. Finally, ACHP suppressed the expression of the three collagen‐modifying enzymes lysyl hydroxylase (PLOD1,PLOD2 and PLOD3) in dermal fibroblasts, but did not do so in lung fibroblasts. We conclude that the IKK inhibitor ACHP has potent antifibrotic properties, and that the NF‐κB pathway plays an important role in myofibroblast biology.

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“…Smad3 is a downstream molecule of the TGF‐β signaling pathway and regulates many biological processes. Smad3 knockdown can inhibit TGF‐β‐induced expression of NF‐κB p65 and lung fibroblast differentiation, suggesting that to some extent, Smad3 activation contributes to TGF‐β‐induced p65 expression (Sun, Chen, Dong, Chen, & Hu, ).…”

Section: Discussionmentioning

confidence: 99%

Let‐7e inhibits TNF‐α expression by targeting the methyl transferase EZH2 in DENV2‐infected THP‐1 cells

Zhang

Gui

et al. 2018

Journal Cellular Physiology

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Tumor necrosis factor α (TNFα), an important inflammatory cytokine, is associated with dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), a severe pathological manifestation of dengue virus (DENV) infection. However, the regulatory mechanism of microRNA on TNFα is currently unknown. Our study showed that the TNFα expression increased immediately and then later decreased, while a marked increase for the miRNA let-7e was detected in dengue virus type 2 (DENV2)-infected peripheral blood mononuclear cells (PBMCs). From this study, we found that let-7e was able to inhibit TNFα expression, but bioinformatics analysis showed that the enhancer of zeste homolog 2 (EZH2) was the potential direct target of let-7e instead of TNFα. EZH2 methyl transferase can produce H3K27me3 and has a negative regulatory role. Using a dual-luciferase reporter assay and Western blotting, we confirmed that EZH2 was a direct target of let-7e and found that siEZH2 could inhibit TNFα expression. In the further study of the regulatory mechanism of EZH2 on TNFα expression, we showed that siEZH2 promoted EZH1 and H3K4me3 expression and inhibited H3K27me3 expression. More importantly, we revealed that siEZH2 down-regulated NF-κB p65 within the nucleus. These findings indicate that the let-7e/EZH2/H3K27me3/NF-κB p65 pathway is a novel regulatory axis of TNFα expression. In addition, we determined the protein differences between siEZH2 and siEZH2-NC by iTRAQ and found a number of proteins that might be associated with TNFα.

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Nuclear factor (NF)-κB p65 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-β

Cited by 34 publications

References 33 publications

RelA/p65 inhibition prevents tendon adhesion by modulating inflammation, cell proliferation, and apoptosis

RelA/p65 inhibition prevents tendon adhesion by modulating inflammation, cell proliferation, and apoptosis

The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

Let‐7e inhibits TNF‐α expression by targeting the methyl transferase EZH2 in DENV2‐infected THP‐1 cells

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