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Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells

It is a well-documented event that fibroblast growth factors (FGFs) regulate liver development and homeostasis in autocrine, paracrine, and endocrine manners via binding and activating FGF receptors (FGFRs) tyrosine kinase in hepatocytes. Recent research reveals that hepatic stellate cells (HSCs) pl...

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Autores principales: Wang, Cong, Li, Yuelong, Li, Hao, Zhang, Yali, Ying, Zhangguo, Wang, Xuye, Zhang, Tingting, Zhang, Wenshu, Fan, Zhichao, Li, Xiaokun, Ma, Jisheng, Pan, Xuebo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387415/
https://www.ncbi.nlm.nih.gov/pubmed/32793588
http://dx.doi.org/10.3389/fcell.2020.00601
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author Wang, Cong
Li, Yuelong
Li, Hao
Zhang, Yali
Ying, Zhangguo
Wang, Xuye
Zhang, Tingting
Zhang, Wenshu
Fan, Zhichao
Li, Xiaokun
Ma, Jisheng
Pan, Xuebo
author_facet Wang, Cong
Li, Yuelong
Li, Hao
Zhang, Yali
Ying, Zhangguo
Wang, Xuye
Zhang, Tingting
Zhang, Wenshu
Fan, Zhichao
Li, Xiaokun
Ma, Jisheng
Pan, Xuebo
author_sort Wang, Cong
collection PubMed
description It is a well-documented event that fibroblast growth factors (FGFs) regulate liver development and homeostasis in autocrine, paracrine, and endocrine manners via binding and activating FGF receptors (FGFRs) tyrosine kinase in hepatocytes. Recent research reveals that hepatic stellate cells (HSCs) play a fundamental role in liver immunology. However, how FGF signaling in HSCs regulates liver inflammation remains unclear. Here, we report that FGF promoted NF-κB signaling, an inflammatory pathway, in human HSCs, which was associated with FGFR1 expression. Both FGF and NF-κB signaling in HSCs were compromised by FGFR1 tyrosine kinase inhibitor. After stimulating HSCs with proinflammatory cytokines, expression of multiple FGF ligands was significantly increased. However, disruption of FGF signaling with FGFR inhibitors prominently reduced the apoptosis, inflammatory response, NF-κB nuclear translocation, and expression of matrix metalloproteinase-9 (MMP-9) induced by TNFα in HSCs. Interestingly, FGF21 significantly alleviated the inflammation responses in the concanavalin A (Con A)-induced acutely injured liver. Unlike canonic FGFs that elicit signals through activating the FGFR–heparan sulfate complex, FGF21 activates the FGFR–KLB complex and elicits a different set of signals. Therefore, the finding here indicates the urgency of developing pathway-specific inhibitors that only suppress canonical FGF, but not non-canonical FGF21, signaling for alleviating inflammation in the liver, which is presented in all stages of diseased liver.
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spelling pubmed-73874152020-08-12 Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells Wang, Cong Li, Yuelong Li, Hao Zhang, Yali Ying, Zhangguo Wang, Xuye Zhang, Tingting Zhang, Wenshu Fan, Zhichao Li, Xiaokun Ma, Jisheng Pan, Xuebo Front Cell Dev Biol Cell and Developmental Biology It is a well-documented event that fibroblast growth factors (FGFs) regulate liver development and homeostasis in autocrine, paracrine, and endocrine manners via binding and activating FGF receptors (FGFRs) tyrosine kinase in hepatocytes. Recent research reveals that hepatic stellate cells (HSCs) play a fundamental role in liver immunology. However, how FGF signaling in HSCs regulates liver inflammation remains unclear. Here, we report that FGF promoted NF-κB signaling, an inflammatory pathway, in human HSCs, which was associated with FGFR1 expression. Both FGF and NF-κB signaling in HSCs were compromised by FGFR1 tyrosine kinase inhibitor. After stimulating HSCs with proinflammatory cytokines, expression of multiple FGF ligands was significantly increased. However, disruption of FGF signaling with FGFR inhibitors prominently reduced the apoptosis, inflammatory response, NF-κB nuclear translocation, and expression of matrix metalloproteinase-9 (MMP-9) induced by TNFα in HSCs. Interestingly, FGF21 significantly alleviated the inflammation responses in the concanavalin A (Con A)-induced acutely injured liver. Unlike canonic FGFs that elicit signals through activating the FGFR–heparan sulfate complex, FGF21 activates the FGFR–KLB complex and elicits a different set of signals. Therefore, the finding here indicates the urgency of developing pathway-specific inhibitors that only suppress canonical FGF, but not non-canonical FGF21, signaling for alleviating inflammation in the liver, which is presented in all stages of diseased liver. Frontiers Media S.A. 2020-07-22 /pmc/articles/PMC7387415/ /pubmed/32793588 http://dx.doi.org/10.3389/fcell.2020.00601 Text en Copyright © 2020 Wang, Li, Li, Zhang, Ying, Wang, Zhang, Zhang, Fan, Li, Ma and Pan. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Wang, Cong
Li, Yuelong
Li, Hao
Zhang, Yali
Ying, Zhangguo
Wang, Xuye
Zhang, Tingting
Zhang, Wenshu
Fan, Zhichao
Li, Xiaokun
Ma, Jisheng
Pan, Xuebo
Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells
title Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells
title_full Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells
title_fullStr Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells
title_full_unstemmed Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells
title_short Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells
title_sort disruption of fgf signaling ameliorates inflammatory response in hepatic stellate cells
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387415/
https://www.ncbi.nlm.nih.gov/pubmed/32793588
http://dx.doi.org/10.3389/fcell.2020.00601
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