Cargando…

KMU-1170, a Novel Multi-Protein Kinase Inhibitor, Suppresses Inflammatory Signal Transduction in THP-1 Cells and Human Osteoarthritic Fibroblast-Like Synoviocytes by Suppressing Activation of NF-κB and NLRP3 Inflammasome Signaling Pathway

Protein kinases regulate protein phosphorylation, which are involved in fundamental cellular processes such as inflammatory response. In this study, we discovered a novel multi-protein kinase inhibitor, KMU-1170, a derivative of indolin-2-one, and investigated the mechanisms of its inflammation-inhi...

Descripción completa

Detalles Bibliográficos
Autores principales: Baek, Hye Suk, Hong, Victor Sukbong, Kim, Sang Hyon, Lee, Jinho, Kim, Shin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865241/
https://www.ncbi.nlm.nih.gov/pubmed/33530480
http://dx.doi.org/10.3390/ijms22031194
_version_ 1783647799841128448
author Baek, Hye Suk
Hong, Victor Sukbong
Kim, Sang Hyon
Lee, Jinho
Kim, Shin
author_facet Baek, Hye Suk
Hong, Victor Sukbong
Kim, Sang Hyon
Lee, Jinho
Kim, Shin
author_sort Baek, Hye Suk
collection PubMed
description Protein kinases regulate protein phosphorylation, which are involved in fundamental cellular processes such as inflammatory response. In this study, we discovered a novel multi-protein kinase inhibitor, KMU-1170, a derivative of indolin-2-one, and investigated the mechanisms of its inflammation-inhibiting signaling in both THP-1 cells and human osteoarthritic fibroblast-like synoviocytes (FLS). We demonstrated that in THP-1 cells, KMU-1170 inhibited lipopolysaccharide (LPS)-induced upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and, furthermore, suppressed LPS-induced phosphorylation of transforming growth factor-β-activated kinase 1, JNK, ERK, inhibitor of NF-κB kinase α/β (IKKα/β), and NF-κB p65 as well as nuclear translocation of NF-κB p65. Moreover, KMU-1170 suppressed LPS-induced upregulation of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6, and, notably, inhibited LPS-induced upregulation of the NLRP3 inflammasome in THP-1 cells. Importantly, KMU-1170 attenuated LPS-mediated inflammatory responses in human osteoarthritic FLS, such as the upregulation of IL-1β, TNF-α, IL-6, iNOS, and COX-2 and the phosphorylation of IKKα/β and NF-κB p65. Collectively, these results suggest that KMU-1170 inhibits inflammatory signal transduction and could be developed as a potential anti-inflammatory agent.
format Online
Article
Text
id pubmed-7865241
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-78652412021-02-07 KMU-1170, a Novel Multi-Protein Kinase Inhibitor, Suppresses Inflammatory Signal Transduction in THP-1 Cells and Human Osteoarthritic Fibroblast-Like Synoviocytes by Suppressing Activation of NF-κB and NLRP3 Inflammasome Signaling Pathway Baek, Hye Suk Hong, Victor Sukbong Kim, Sang Hyon Lee, Jinho Kim, Shin Int J Mol Sci Article Protein kinases regulate protein phosphorylation, which are involved in fundamental cellular processes such as inflammatory response. In this study, we discovered a novel multi-protein kinase inhibitor, KMU-1170, a derivative of indolin-2-one, and investigated the mechanisms of its inflammation-inhibiting signaling in both THP-1 cells and human osteoarthritic fibroblast-like synoviocytes (FLS). We demonstrated that in THP-1 cells, KMU-1170 inhibited lipopolysaccharide (LPS)-induced upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and, furthermore, suppressed LPS-induced phosphorylation of transforming growth factor-β-activated kinase 1, JNK, ERK, inhibitor of NF-κB kinase α/β (IKKα/β), and NF-κB p65 as well as nuclear translocation of NF-κB p65. Moreover, KMU-1170 suppressed LPS-induced upregulation of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6, and, notably, inhibited LPS-induced upregulation of the NLRP3 inflammasome in THP-1 cells. Importantly, KMU-1170 attenuated LPS-mediated inflammatory responses in human osteoarthritic FLS, such as the upregulation of IL-1β, TNF-α, IL-6, iNOS, and COX-2 and the phosphorylation of IKKα/β and NF-κB p65. Collectively, these results suggest that KMU-1170 inhibits inflammatory signal transduction and could be developed as a potential anti-inflammatory agent. MDPI 2021-01-26 /pmc/articles/PMC7865241/ /pubmed/33530480 http://dx.doi.org/10.3390/ijms22031194 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Baek, Hye Suk
Hong, Victor Sukbong
Kim, Sang Hyon
Lee, Jinho
Kim, Shin
KMU-1170, a Novel Multi-Protein Kinase Inhibitor, Suppresses Inflammatory Signal Transduction in THP-1 Cells and Human Osteoarthritic Fibroblast-Like Synoviocytes by Suppressing Activation of NF-κB and NLRP3 Inflammasome Signaling Pathway
title KMU-1170, a Novel Multi-Protein Kinase Inhibitor, Suppresses Inflammatory Signal Transduction in THP-1 Cells and Human Osteoarthritic Fibroblast-Like Synoviocytes by Suppressing Activation of NF-κB and NLRP3 Inflammasome Signaling Pathway
title_full KMU-1170, a Novel Multi-Protein Kinase Inhibitor, Suppresses Inflammatory Signal Transduction in THP-1 Cells and Human Osteoarthritic Fibroblast-Like Synoviocytes by Suppressing Activation of NF-κB and NLRP3 Inflammasome Signaling Pathway
title_fullStr KMU-1170, a Novel Multi-Protein Kinase Inhibitor, Suppresses Inflammatory Signal Transduction in THP-1 Cells and Human Osteoarthritic Fibroblast-Like Synoviocytes by Suppressing Activation of NF-κB and NLRP3 Inflammasome Signaling Pathway
title_full_unstemmed KMU-1170, a Novel Multi-Protein Kinase Inhibitor, Suppresses Inflammatory Signal Transduction in THP-1 Cells and Human Osteoarthritic Fibroblast-Like Synoviocytes by Suppressing Activation of NF-κB and NLRP3 Inflammasome Signaling Pathway
title_short KMU-1170, a Novel Multi-Protein Kinase Inhibitor, Suppresses Inflammatory Signal Transduction in THP-1 Cells and Human Osteoarthritic Fibroblast-Like Synoviocytes by Suppressing Activation of NF-κB and NLRP3 Inflammasome Signaling Pathway
title_sort kmu-1170, a novel multi-protein kinase inhibitor, suppresses inflammatory signal transduction in thp-1 cells and human osteoarthritic fibroblast-like synoviocytes by suppressing activation of nf-κb and nlrp3 inflammasome signaling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865241/
https://www.ncbi.nlm.nih.gov/pubmed/33530480
http://dx.doi.org/10.3390/ijms22031194
work_keys_str_mv AT baekhyesuk kmu1170anovelmultiproteinkinaseinhibitorsuppressesinflammatorysignaltransductioninthp1cellsandhumanosteoarthriticfibroblastlikesynoviocytesbysuppressingactivationofnfkbandnlrp3inflammasomesignalingpathway
AT hongvictorsukbong kmu1170anovelmultiproteinkinaseinhibitorsuppressesinflammatorysignaltransductioninthp1cellsandhumanosteoarthriticfibroblastlikesynoviocytesbysuppressingactivationofnfkbandnlrp3inflammasomesignalingpathway
AT kimsanghyon kmu1170anovelmultiproteinkinaseinhibitorsuppressesinflammatorysignaltransductioninthp1cellsandhumanosteoarthriticfibroblastlikesynoviocytesbysuppressingactivationofnfkbandnlrp3inflammasomesignalingpathway
AT leejinho kmu1170anovelmultiproteinkinaseinhibitorsuppressesinflammatorysignaltransductioninthp1cellsandhumanosteoarthriticfibroblastlikesynoviocytesbysuppressingactivationofnfkbandnlrp3inflammasomesignalingpathway
AT kimshin kmu1170anovelmultiproteinkinaseinhibitorsuppressesinflammatorysignaltransductioninthp1cellsandhumanosteoarthriticfibroblastlikesynoviocytesbysuppressingactivationofnfkbandnlrp3inflammasomesignalingpathway