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TGF‐β‐activated kinase‐1 inhibitor LL‐Z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF‐α and RANKL expression
OBJECTIVES: Aberrant NLRP3 inflammasome activation has been demonstrated in rheumatoid arthritis (RA), which may contribute to debilitating inflammation and bone destruction. Here, we explored the efficacy of the potent TGF‐β‐activated kinase‐1 (TAK1) inhibitor LL‐Z1640‐2 (LLZ) on joint inflammation...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770968/ https://www.ncbi.nlm.nih.gov/pubmed/35079379 http://dx.doi.org/10.1002/cti2.1371 |
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author | Tenshin, Hirofumi Teramachi, Jumpei Ashtar, Mohannad Hiasa, Masahiro Inoue, Yusuke Oda, Asuka Tanimoto, Kotaro Shimizu, So Higa, Yoshiki Harada, Takeshi Oura, Masahiro Sogabe, Kimiko Hara, Tomoyo Sumitani, Ryohei Maruhashi, Tomoko Sebe, Mayu Tsutsumi, Rie Sakaue, Hiroshi Endo, Itsuro Matsumoto, Toshio Tanaka, Eiji Abe, Masahiro |
author_facet | Tenshin, Hirofumi Teramachi, Jumpei Ashtar, Mohannad Hiasa, Masahiro Inoue, Yusuke Oda, Asuka Tanimoto, Kotaro Shimizu, So Higa, Yoshiki Harada, Takeshi Oura, Masahiro Sogabe, Kimiko Hara, Tomoyo Sumitani, Ryohei Maruhashi, Tomoko Sebe, Mayu Tsutsumi, Rie Sakaue, Hiroshi Endo, Itsuro Matsumoto, Toshio Tanaka, Eiji Abe, Masahiro |
author_sort | Tenshin, Hirofumi |
collection | PubMed |
description | OBJECTIVES: Aberrant NLRP3 inflammasome activation has been demonstrated in rheumatoid arthritis (RA), which may contribute to debilitating inflammation and bone destruction. Here, we explored the efficacy of the potent TGF‐β‐activated kinase‐1 (TAK1) inhibitor LL‐Z1640‐2 (LLZ) on joint inflammation and bone destruction in collagen‐induced arthritis (CIA). METHODS: LL‐Z1640‐2 was administered every other day in CIA mice. Clinical and histological evaluation was performed. Priming and activation of NLRP3 inflammasome and osteoclastogenic activity were assessed. RESULTS: NLRP3 inflammasome formation was observed in synovial macrophages and osteoclasts (OCs) in CIA mice. TACE and RANKL were also overexpressed in synovial macrophages and fibroblasts, respectively, in the CIA joints. Treatment with LLZ mitigated all the above changes. As a result, LLZ markedly suppressed synovial hypertrophy and pannus formation to alleviate pain and inflammation in CIA mice. LLZ could block the priming and activation of NLRP3 inflammasome in RAW264.7 macrophage cell line, primary bone marrow macrophages and OCs upon treatment with LPS followed by ATP, thereby suppressing their IL‐1β production. LLZ also suppressed LPS‐induced production of TACE and TNF‐α in bone marrow macrophages and abolished IL‐1β‐induced production of MMP‐3, IL‐6 and RANKL in synovial fibroblasts. In addition, LLZ directly inhibits RANKL‐mediated OC formation and activation. CONCLUSION: TAK1 inhibition with LLZ may become a novel treatment strategy to effectively alleviate inflammasome‐mediated inflammation and RANKL‐induced osteoclastic bone destruction in joints alongside its potent suppression of TNF‐α and IL‐6 production and proteinase‐mediated pathological processes in RA. |
format | Online Article Text |
id | pubmed-8770968 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-87709682022-01-24 TGF‐β‐activated kinase‐1 inhibitor LL‐Z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF‐α and RANKL expression Tenshin, Hirofumi Teramachi, Jumpei Ashtar, Mohannad Hiasa, Masahiro Inoue, Yusuke Oda, Asuka Tanimoto, Kotaro Shimizu, So Higa, Yoshiki Harada, Takeshi Oura, Masahiro Sogabe, Kimiko Hara, Tomoyo Sumitani, Ryohei Maruhashi, Tomoko Sebe, Mayu Tsutsumi, Rie Sakaue, Hiroshi Endo, Itsuro Matsumoto, Toshio Tanaka, Eiji Abe, Masahiro Clin Transl Immunology Original Articles OBJECTIVES: Aberrant NLRP3 inflammasome activation has been demonstrated in rheumatoid arthritis (RA), which may contribute to debilitating inflammation and bone destruction. Here, we explored the efficacy of the potent TGF‐β‐activated kinase‐1 (TAK1) inhibitor LL‐Z1640‐2 (LLZ) on joint inflammation and bone destruction in collagen‐induced arthritis (CIA). METHODS: LL‐Z1640‐2 was administered every other day in CIA mice. Clinical and histological evaluation was performed. Priming and activation of NLRP3 inflammasome and osteoclastogenic activity were assessed. RESULTS: NLRP3 inflammasome formation was observed in synovial macrophages and osteoclasts (OCs) in CIA mice. TACE and RANKL were also overexpressed in synovial macrophages and fibroblasts, respectively, in the CIA joints. Treatment with LLZ mitigated all the above changes. As a result, LLZ markedly suppressed synovial hypertrophy and pannus formation to alleviate pain and inflammation in CIA mice. LLZ could block the priming and activation of NLRP3 inflammasome in RAW264.7 macrophage cell line, primary bone marrow macrophages and OCs upon treatment with LPS followed by ATP, thereby suppressing their IL‐1β production. LLZ also suppressed LPS‐induced production of TACE and TNF‐α in bone marrow macrophages and abolished IL‐1β‐induced production of MMP‐3, IL‐6 and RANKL in synovial fibroblasts. In addition, LLZ directly inhibits RANKL‐mediated OC formation and activation. CONCLUSION: TAK1 inhibition with LLZ may become a novel treatment strategy to effectively alleviate inflammasome‐mediated inflammation and RANKL‐induced osteoclastic bone destruction in joints alongside its potent suppression of TNF‐α and IL‐6 production and proteinase‐mediated pathological processes in RA. John Wiley and Sons Inc. 2022-01-19 /pmc/articles/PMC8770968/ /pubmed/35079379 http://dx.doi.org/10.1002/cti2.1371 Text en © 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Tenshin, Hirofumi Teramachi, Jumpei Ashtar, Mohannad Hiasa, Masahiro Inoue, Yusuke Oda, Asuka Tanimoto, Kotaro Shimizu, So Higa, Yoshiki Harada, Takeshi Oura, Masahiro Sogabe, Kimiko Hara, Tomoyo Sumitani, Ryohei Maruhashi, Tomoko Sebe, Mayu Tsutsumi, Rie Sakaue, Hiroshi Endo, Itsuro Matsumoto, Toshio Tanaka, Eiji Abe, Masahiro TGF‐β‐activated kinase‐1 inhibitor LL‐Z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF‐α and RANKL expression |
title | TGF‐β‐activated kinase‐1 inhibitor LL‐Z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF‐α and RANKL expression |
title_full | TGF‐β‐activated kinase‐1 inhibitor LL‐Z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF‐α and RANKL expression |
title_fullStr | TGF‐β‐activated kinase‐1 inhibitor LL‐Z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF‐α and RANKL expression |
title_full_unstemmed | TGF‐β‐activated kinase‐1 inhibitor LL‐Z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF‐α and RANKL expression |
title_short | TGF‐β‐activated kinase‐1 inhibitor LL‐Z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF‐α and RANKL expression |
title_sort | tgf‐β‐activated kinase‐1 inhibitor ll‐z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting nlrp3 inflammasome, tace, tnf‐α and rankl expression |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770968/ https://www.ncbi.nlm.nih.gov/pubmed/35079379 http://dx.doi.org/10.1002/cti2.1371 |
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