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

Abstract

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.

• Authors: Paul M Panipinto, Anil K Singh, Farheen S Shaikh, Ruby J Siegel, Mukesh Chourasia, Salahuddin Ahmed
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 22 (Nov 22 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34830460 (Publication Type: Journal Article)

Chemical References

• 7-oxozeanol
• Benzamides
• Benzimidazoles
• Lactones
• Lipopolysaccharides
• NF-kappa B
• Resorcinols
• STAT3 Transcription Factor
• STAT3 protein, human
• takinib
• Janus Kinases
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Arthritis, Rheumatoid (drug therapy, genetics, pathology)
• Benzamides (pharmacology)
• Benzimidazoles (pharmacology)
• Fibroblasts (drug effects, metabolism)
• Humans
• Inflammation (drug therapy, genetics, pathology)
• Janus Kinases (genetics)
• Lactones (pharmacology)
• Lipopolysaccharides (pharmacology)
• MAP Kinase Kinase Kinases (genetics)
• Macrophages (drug effects)
• Monocytes (drug effects)
• NF-kappa B (genetics)
• Resorcinols (pharmacology)
• STAT3 Transcription Factor (genetics)
• Signal Transduction (drug effects)
• Synovial Fluid (drug effects, metabolism)
• Synovial Membrane (drug effects)