Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway

TGF β-activated kinase 1 (TAK1) is an important participant in inflammatory pathogenesis for diseases such as rheumatoid arthritis (RA) and gouty arthritis. The central position it occupies between the mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways makes it an at...

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Autores principales:	Paul M. Panipinto, Anil K. Singh, Farheen S. Shaikh, Ruby J. Siegel, Mukesh Chourasia, Salahuddin Ahmed
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	takinib TAK1 rheumatoid arthritis RASFs THP-1 MAPK Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/1df7c4f3cbea4badb20b7882c94b1202
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spelling	oai:doaj.org-article:1df7c4f3cbea4badb20b7882c94b12022021-11-25T17:58:02ZTakinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway10.3390/ijms2222125801422-00671661-6596https://doaj.org/article/1df7c4f3cbea4badb20b7882c94b12022021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12580https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067TGF β-activated kinase 1 (TAK1) is an important participant in inflammatory pathogenesis for diseases such as rheumatoid arthritis (RA) and gouty arthritis. The central position it occupies between the mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways makes it an attractive therapeutic target. As this field has developed in recent years, several novel inhibitors have been presented as having specific activity that reduces the TAK1 function either covalently as in the case of 5Z-7-oxozeanol (5Z7O) or reversibly (NG-25). However, the mechanism through which takinib elicits its anti-inflammatory activity remains elusive. While this inhibitor shows great promise, a thorough analysis of its inhibitor function and its potential off-target effects is necessary before addressing its clinical potential or its use in inflammatory conditions. An analysis through Western blot showed an unexpected increase in IL-1β-induced TAK1 phosphorylation—a prerequisite for and indicator of its functional potential—by takinib while simultaneously demonstrating the inhibition of the JAK/STAT pathway in human rheumatoid arthritis synovial fibroblasts (RASFs) in vitro. In THP-1 monocyte-derived macrophages, takinib again led to the lipopolysaccharide-induced phosphorylation of TAK1 without a marked inhibition of the TAK1 downstream effectors, namely, of c-Jun N-terminal kinase (JNK), phospho-c-Jun, NF-κB phospho-p65 or phospho-IκBα. Taken together, these findings indicate that takinib inhibits inflammation in these cells by targeting multiple signaling pathways, most notably the JAK/STAT pathway in human RASFs.Paul M. PanipintoAnil K. SinghFarheen S. ShaikhRuby J. SiegelMukesh ChourasiaSalahuddin AhmedMDPI AGarticletakinibTAK1rheumatoid arthritisRASFsTHP-1MAPKBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12580, p 12580 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	takinib TAK1 rheumatoid arthritis RASFs THP-1 MAPK Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	takinib TAK1 rheumatoid arthritis RASFs THP-1 MAPK Biology (General) QH301-705.5 Chemistry QD1-999 Paul M. Panipinto Anil K. Singh Farheen S. Shaikh Ruby J. Siegel Mukesh Chourasia Salahuddin Ahmed Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway
description	TGF β-activated kinase 1 (TAK1) is an important participant in inflammatory pathogenesis for diseases such as rheumatoid arthritis (RA) and gouty arthritis. The central position it occupies between the mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways makes it an attractive therapeutic target. As this field has developed in recent years, several novel inhibitors have been presented as having specific activity that reduces the TAK1 function either covalently as in the case of 5Z-7-oxozeanol (5Z7O) or reversibly (NG-25). However, the mechanism through which takinib elicits its anti-inflammatory activity remains elusive. While this inhibitor shows great promise, a thorough analysis of its inhibitor function and its potential off-target effects is necessary before addressing its clinical potential or its use in inflammatory conditions. An analysis through Western blot showed an unexpected increase in IL-1β-induced TAK1 phosphorylation—a prerequisite for and indicator of its functional potential—by takinib while simultaneously demonstrating the inhibition of the JAK/STAT pathway in human rheumatoid arthritis synovial fibroblasts (RASFs) in vitro. In THP-1 monocyte-derived macrophages, takinib again led to the lipopolysaccharide-induced phosphorylation of TAK1 without a marked inhibition of the TAK1 downstream effectors, namely, of c-Jun N-terminal kinase (JNK), phospho-c-Jun, NF-κB phospho-p65 or phospho-IκBα. Taken together, these findings indicate that takinib inhibits inflammation in these cells by targeting multiple signaling pathways, most notably the JAK/STAT pathway in human RASFs.
format	article
author	Paul M. Panipinto Anil K. Singh Farheen S. Shaikh Ruby J. Siegel Mukesh Chourasia Salahuddin Ahmed
author_facet	Paul M. Panipinto Anil K. Singh Farheen S. Shaikh Ruby J. Siegel Mukesh Chourasia Salahuddin Ahmed
author_sort	Paul M. Panipinto
title	Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway
title_short	Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway
title_full	Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway
title_fullStr	Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway
title_full_unstemmed	Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway
title_sort	takinib inhibits inflammation in human rheumatoid arthritis synovial fibroblasts by targeting the janus kinase-signal transducer and activator of transcription 3 (jak/stat3) pathway
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1df7c4f3cbea4badb20b7882c94b1202
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Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway

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