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.

p53: A Regulator of Ferroptosis Induced by Galectin-1 Derived Peptide 3 in MH7A Cells

“…Although the etiology of RA remains unclear, recent evidence has suggested that activation of RA synovial fibroblasts, a complex network of cell regulation, plays a vital role in the pathogenesis of RA ( Pap et al, 2000 ; Turner and Filer, 2015 ). Thus, inhibiting RA synovial fibroblast proliferation and blocking its effects can significantly reduce RA symptoms and prevent bone destruction ( Panipinto et al, 2021 ).…”

STA‐21 regulates Th‐17/Treg balance and synovial fibroblasts functions in rheumatoid arthritis

“…8,18 Moreover, several studies have shown the benefits of STAT3 inhibition in SFs of patients with RA. [19][20][21][22] In this study, we investigated the effects of STA-21 on T cells and SFs of RA were included in the present study. The inclusion criteria were the active RA with the mentioned regimens of therapy.…”

“…STA‐21, as a dynamic inhibitor of STAT‐3, was reported to equally modulate Th17/Treg balance, through downregulating RORγt and upregulating Foxp3 expression in CD4 + T cells, which resulted in the inhibition of autoimmune inflammation and osteoclastogenesis in an experimental trial of RA 8,18 . Moreover, several studies have shown the benefits of STAT3 inhibition in SFs of patients with RA 19–22 . In this study, we investigated the effects of STA‐21 on T cells and SFs of RA patients and evaluated how this compound can alter the autoimmune inflammation by suppressing SFs and readjusting the Th17/Treg imbalance.…”

Neuroprotective effects of takinib on an experimental traumatic brain injury rat model via inhibition of transforming growth factor beta-activated kinase 1

“…It decreases TAK1 activation by noncompetitively binding within the ATP pocket, the rate limiting step of this enzyme [ 11 ]. Additionally, in the DFG-in confirmation Takinib can competitively inhibit ATP-binding of primarily activated TAK1, causing TNFα-induced apoptosis of the synovial fibroblasts involved in rheumatoid arthritis [ 12 ]. Takinib in general has shown therapeutic applications in inflammatory and autoimmune diseases as well as different types of cancer [ 11 , 12 ], however, the protective function of Takinib in TBI remains unknown.…”