TWEAK/Fn14 promotes pro-inflammatory cytokine secretion in hepatic stellate cells via NF-κB/STAT3 pathways

Wang, Aixiu; Zhang, Feng; Xu, Hui; Xu, Mingcui; Cao, Yu; Wang, Chen; Xu, Yuanyuan; Su, Min; Zhang, Ming; Zhuge, Yuzheng

doi:10.1016/j.molimm.2017.04.003

Cited by 37 publications

(29 citation statements)

References 37 publications

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“…The phospho‐STAT3 levels are elevated in human atrial tissues from patients with AF, and angiotensin II (Ang II)‐induced JAK/STAT activation in a rat model localizes mainly to the atrium . In hepatic stellate cells, TWEAK up‐regulated the expression of Fn14 and pro‐inflammatory cytokine secretion through NF‐κB/STAT3 pathways . In the present study, activation of Fn14 up‐regulated both p‐JAK and p‐STAT3 level in HL‐1 atrial myocytes, while in vitro knockdown of Fn14 attenuated the increased expression of p‐JAK and p‐STAT3.…”

Section: Discussionmentioning

confidence: 46%

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TWEAK/Fn14 mediates atrial‐derived HL‐1 myocytes hypertrophy via JAK2/STAT3 signalling pathway

Ren

Rong

et al. 2018

J Cellular Molecular Medi

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Atrial myocyte hypertrophy is one of the most important substrates in the development of atrial fibrillation (AF). The TWEAK/Fn14 axis is a positive regulator of cardiac hypertrophy in cardiomyopathy. This study therefore investigated the effects of Fn14 on atrial hypertrophy and underlying cellular mechanisms using HL‐1 atrial myocytes. In patients with AF, Fn14 protein levels were higher in atrial myocytes from atrial appendages, and expression of TWEAK was increased in peripheral blood mononuclear cells, while TWEAK serum levels were decreased. In vitro, Fn14 expression was up‐regulated in response to TWEAK treatment in HL‐1 atrial myocytes. TWEAK increased the expression of ANP and Troponin T, and Fn14 knockdown counteracted the effect. Inhibition of JAK2, STAT3 by specific siRNA attenuated TWEAK‐induced HL‐1 atrial myocytes hypertrophy. In conclusion, TWEAK/Fn14 axis mediates HL‐1 atrial myocytes hypertrophy partly through activation of the JAK2/STAT3 pathway.

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Section: Discussionmentioning

confidence: 46%

“…The activation of JAK/STAT pathway by IL‐6 may contribute to the pathogenesis of cardiac hypertrophy, and phospho‐STAT3 levels are elevated in atrial tissues from AF patients . TWEAK/Fn14 up‐regulates pro‐inflammatory cytokine secretion via STAT3 pathways in hepatic stellate cells …”

Section: Introductionmentioning

confidence: 99%

TWEAK/Fn14 mediates atrial‐derived HL‐1 myocytes hypertrophy via JAK2/STAT3 signalling pathway

Ren

Rong

et al. 2018

J Cellular Molecular Medi

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“…However, the secreted cachexia‐inducing factor(s) were not identified. In hepatic stellate cells, the Fn14 ligand TWEAK has been shown to upregulate both transcription and secretion of inflammatory cytokines, including IL‐6 . This suggests that TWEAK and activin A may both work in a paracrine or autocrine manner in the tumours to stimulate IL‐6 secretion from cancer cells and facilitate the development of cachexia.…”

Section: Discussionmentioning

confidence: 99%

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Pettersen

Andersen

Veen

et al. 2019

J cachexia sarcopenia muscle

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Background The majority of patients with advanced cancer develop cachexia, a weight loss syndrome that severely reduces quality of life and limits survival. Our understanding of the underlying mechanisms that cause the condition is limited, and there are currently no treatment options that can completely reverse cachexia. Several tumour‐derived factors and inflammatory mediators have been suggested to contribute to weight loss in cachectic patients. However, inconsistencies between studies are recurrent. Activin A and interleukin 6 (IL‐6) are among the best studied factors that seem to be important, and several studies support their individual role in cachexia development. Methods We investigated the interplay between activin A and IL‐6 in the cachexia‐inducing TOV21G cell line, both in culture and in tumours in mice. We previously found that the human TOV21G cells secrete IL‐6 that induces autophagy in reporter cells and cachexia in mice. Using this established cachexia cell model, we targeted autocrine activin A by genetic, chemical, and biological approaches. The secretion of IL‐6 from the cancer cells was determined in both culture and tumour‐bearing mice by a species‐specific ELISA. Autophagy reporter cells were used to monitor the culture medium for autophagy‐inducing activities, and muscle mass changes were evaluated in tumour‐bearing mice. Results We show that activin A acts in an autocrine manner to promote the synthesis and secretion of IL‐6 from cancer cells. By inhibiting activin A signalling, the production of IL‐6 from the cancer cells is reduced by 40–50% (up to 42% reduction on protein level, P = 0.0048, and 48% reduction on mRNA level, P = 0.0308). Significantly reduced IL‐6 secretion (P < 0.05) from the cancer cells is consistently observed when using biological, chemical, and genetic approaches to interfere with the autocrine activin A loop. Inhibiting activin signalling also reduces the ability of the cancer cells to accelerate autophagy in non‐cancerous cells (up to 43% reduced autophagy flux, P = 0.0006). Coherent to the in vitro data, the use of an anti‐activin receptor 2 antibody in cachectic tumour‐bearing mice reduces serum levels of cancer cell‐derived IL‐6 by 62% (from 417 to 159 pg/mL, P = 0.03), and, importantly, it reverses cachexia and counteracts loss of all measured muscle groups (P < 0.0005). Conclusions Our data support a functional link between activin A and IL‐6 signalling pathways and indicate that interference with activin A‐induced IL‐6 secretion from the tumour has therapeutic potential for cancer‐induced cachexia.

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“…This trimeric structure induces the recruitment of TRAF2 and TRAF5 though the TRAF-binding motif (PIEET) in the cytoplasmic tail, and leads the activation of different signaling pathways [14,35]. TWEAK-Fn14 binding activates several signal transduction pathways that implicate both canonical and non-canonical NF-kB pathways [14,36], mitogen-activated protein kinases pathway (MAPK) [37], PI3K/AKT [38], JAK/STAT signaling pathway [39,40], and transforming growth factor-β-activated kinase 1 [41]. MAPK activation induced by recombinant soluble TWEAK (rTWEAK) has been reported in endothelial cells [33], Thp-1 monocytic cell line [26], and cardiomyocytes [30].…”

Section: Signaling Pathways Activated By Tweak-fn14 Interactionmentioning

confidence: 99%

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK)/Fibroblast Growth Factor-Inducible 14 (Fn14) Axis in Cardiovascular Diseases: Progress and Challenges

Gutiérrez-Muñoz

Blázquez-Serra

Martı́n-Ventura

et al. 2020

Cells

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Cardiovascular diseases (CVD) are the leading cause of mortality in Western countries. CVD include several pathologies, such as coronary artery disease, stroke, peripheral artery disease, and aortic aneurysm, among others. All of them are characterized by a pathological vascular remodeling in which inflammation plays a key role. Interaction between different members of the tumor necrosis factor superfamily and their cognate receptors induce several biological actions that may participate in CVD. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its functional receptor, fibroblast growth factor-inducible 14 (Fn14), are abundantly expressed during pathological cardiovascular remodeling. The TWEAK/Fn14 axis controls a variety of cellular functions, such as proliferation, differentiation, and apoptosis, and has several biological functions, such as inflammation and fibrosis that are linked to CVD. It has been demonstrated that persistent TWEAK/Fn14 activation is involved in both vessel and heart remodeling associated with acute and chronic CVD. In this review, we summarized the role of the TWEAK/Fn14 axis during pathological cardiovascular remodeling, highlighting the cellular components and the signaling pathways that are involved in these processes.

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TWEAK/Fn14 promotes pro-inflammatory cytokine secretion in hepatic stellate cells via NF-κB/STAT3 pathways

Cited by 37 publications

References 37 publications

TWEAK/Fn14 mediates atrial‐derived HL‐1 myocytes hypertrophy via JAK2/STAT3 signalling pathway

TWEAK/Fn14 mediates atrial‐derived HL‐1 myocytes hypertrophy via JAK2/STAT3 signalling pathway

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK)/Fibroblast Growth Factor-Inducible 14 (Fn14) Axis in Cardiovascular Diseases: Progress and Challenges

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