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TGF-β activates NLRP3 inflammasome by an autocrine production of TGF-β in LX-2 human hepatic stellate cells
Inflammation contributes to the pathogenesis of liver disease, and inflammasome activation has been identified as a major contributor to the amplification of liver inflammation. Transforming growth factor-beta (TGF-β) is a key regulator of liver physiology, contributing to all stages of liver diseas...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989865/ https://www.ncbi.nlm.nih.gov/pubmed/35138513 http://dx.doi.org/10.1007/s11010-022-04369-5 |
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author | Kang, Hwansu Seo, Eunhui Oh, Yoon Sin Jun, Hee-Sook |
author_facet | Kang, Hwansu Seo, Eunhui Oh, Yoon Sin Jun, Hee-Sook |
author_sort | Kang, Hwansu |
collection | PubMed |
description | Inflammation contributes to the pathogenesis of liver disease, and inflammasome activation has been identified as a major contributor to the amplification of liver inflammation. Transforming growth factor-beta (TGF-β) is a key regulator of liver physiology, contributing to all stages of liver disease. We investigated whether TGF-β is involved in inflammasome-mediated fibrosis in hepatic stellate cells. Treatment with TGF-β increased priming of NLRP3 inflammasome signaling by increasing NLRP3 levels and activating TAK1-NF-kB signaling. Moreover, TGF-β increased the expression of p-Smad2/3-NOX4 in LX-2 cells and consequently increased ROS content, which is a trigger for NLRP3 inflammasome activation. Elevated expression of NEK7 and active caspase-1 was also shown in TGF-β-induced LX-2 cells, and this level was reduced by (5Z)-oxozeaenol, a TAK inhibitor. Finally, TGF-β-treated cells significantly increased TGF-β secretion levels, and their production was inhibited by IL-1β receptor antagonist treatment. In conclusion, TGF-β may represent an endogenous danger signal to the active NLRP3 inflammasome, by which IL-1β mediates TGF-β expression in an autocrine manner. Therefore, targeting the NLRP3 inflammasome may be a promising approach for the development of therapies for TGF-β-induced liver fibrosis. |
format | Online Article Text |
id | pubmed-8989865 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-89898652022-04-22 TGF-β activates NLRP3 inflammasome by an autocrine production of TGF-β in LX-2 human hepatic stellate cells Kang, Hwansu Seo, Eunhui Oh, Yoon Sin Jun, Hee-Sook Mol Cell Biochem Article Inflammation contributes to the pathogenesis of liver disease, and inflammasome activation has been identified as a major contributor to the amplification of liver inflammation. Transforming growth factor-beta (TGF-β) is a key regulator of liver physiology, contributing to all stages of liver disease. We investigated whether TGF-β is involved in inflammasome-mediated fibrosis in hepatic stellate cells. Treatment with TGF-β increased priming of NLRP3 inflammasome signaling by increasing NLRP3 levels and activating TAK1-NF-kB signaling. Moreover, TGF-β increased the expression of p-Smad2/3-NOX4 in LX-2 cells and consequently increased ROS content, which is a trigger for NLRP3 inflammasome activation. Elevated expression of NEK7 and active caspase-1 was also shown in TGF-β-induced LX-2 cells, and this level was reduced by (5Z)-oxozeaenol, a TAK inhibitor. Finally, TGF-β-treated cells significantly increased TGF-β secretion levels, and their production was inhibited by IL-1β receptor antagonist treatment. In conclusion, TGF-β may represent an endogenous danger signal to the active NLRP3 inflammasome, by which IL-1β mediates TGF-β expression in an autocrine manner. Therefore, targeting the NLRP3 inflammasome may be a promising approach for the development of therapies for TGF-β-induced liver fibrosis. Springer US 2022-02-09 2022 /pmc/articles/PMC8989865/ /pubmed/35138513 http://dx.doi.org/10.1007/s11010-022-04369-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kang, Hwansu Seo, Eunhui Oh, Yoon Sin Jun, Hee-Sook TGF-β activates NLRP3 inflammasome by an autocrine production of TGF-β in LX-2 human hepatic stellate cells |
title | TGF-β activates NLRP3 inflammasome by an autocrine production of TGF-β in LX-2 human hepatic stellate cells |
title_full | TGF-β activates NLRP3 inflammasome by an autocrine production of TGF-β in LX-2 human hepatic stellate cells |
title_fullStr | TGF-β activates NLRP3 inflammasome by an autocrine production of TGF-β in LX-2 human hepatic stellate cells |
title_full_unstemmed | TGF-β activates NLRP3 inflammasome by an autocrine production of TGF-β in LX-2 human hepatic stellate cells |
title_short | TGF-β activates NLRP3 inflammasome by an autocrine production of TGF-β in LX-2 human hepatic stellate cells |
title_sort | tgf-β activates nlrp3 inflammasome by an autocrine production of tgf-β in lx-2 human hepatic stellate cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989865/ https://www.ncbi.nlm.nih.gov/pubmed/35138513 http://dx.doi.org/10.1007/s11010-022-04369-5 |
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