Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug

Abstract

Background: Proper blocking of toll-like receptor (TLR) activation during disease progression has been reported to have inhibitory effect on the pathogenesis of rheumatoid arthritis (RA). We tested whether the TLR4 inhibitor TAK-242 had potential as a remedy for rheumatoid arthritis. Methods: The therapeutic effect of TAK-242 was tested in vitro using the human rheumatoid fibroblast-like synoviocyte (FLS) line MH7A or primary human FLS and in an adjuvant-induced arthritis (AIA) rat model. Results: TAK-242 dose dependently inhibited the increased expression of IL-6, IL-8, MMP-1, and VEGF in LPSstimulated MH7A cells. It also inhibited the expression of IL-6 and IL-8 in poly(I:C), TLR3 activator-stimulated primary FLS, but not in IL-1β-stimulated primary FLS. These findings suggest that TAK-242 blocks a specific signaling pathway to some degree. Further, TAK-242 slightly inhibited mobilization of NF-κB into nuclei. In the AIA rat model, TAK-242 significantly reversed the body weight and paw thickness of AIA rats to the normal state at a dose of 5 mg/kg, but not at 3 mg/kg, and reduced the increased serum level of IL-6 and VEGF in AIA rats. It also significantly ameliorated inflammatory symptoms of joint tissues at day 21 of treatment, according to histology and RT-PCR. Conclusions: Based on the drug repositioning concept, TAK-242, which is used for the treatment of TLR4-mediated inflammatory diseases, shows potential for cost-effective development as a remedy for rheumatoid arthritis or to control the progression of RA.

Inhibitory role of long non‐coding RNA OIP5‐AS1 in rheumatoid arthritis progression through the microRNA‐448–paraoxonase 1–toll‐like receptor 3–nuclear factor κB axis

“…In addition, our study identified that overexpression of OIP5‐AS1 decreased TLR3 activity and NF‐κB p65 phosphorylation in RA rat synovial tissues. The TLRs–NF‐κB signalling pathways have been recognized to participate in RA pathogenesis, among which the roles of TLR4 have been largely investigated (Kim, Bang, Son, Baek, & Kim, 2018; Samarpita, Kim, Rasool, & Kim, 2020). Likewise, TLR3 up‐regulation and NF‐κB activation have been evidenced in synovial fibroblasts in a mouse model with RA (Yu, Xie, Jiang, Sun, & Huang, 2018).…”

Soluble CD14 Induces Pro-inflammatory Cytokines in Rheumatoid Arthritis Fibroblast-Like Synovial Cells via Toll-Like Receptor 4

“…Biological disease-modifying antirheumatic drugs, such as anti-TNF-α antibodies, have shown considerable efficacy in clinical practice, but many patients continue to have active disease [ 32 ]. TLR-4 inhibitor therapy for RA is considered one further promising candidate [ 33 ], and several TLR-4 inhibitors have demonstrated some therapeutic effect in vitro and in vivo [ 34 ]. In fact, an anti-TLR-4 monoclonal antibody has now advanced to a phase II clinical trial [ 35 ].…”

Drug Repositioning: New Approaches and Future Prospects for Life-Debilitating Diseases and the COVID-19 Pandemic Outbreak

“…Also, multiple omics analysis mapped to significant pathways allows for the simultaneous detection of target genes and human proteins for their potential in specific diseases. For instance, drug candidates and human protein targets have been identified for several diseases such as dengue haemorrhagic fever [27], head and neck squamous cell carcinoma [28] and rheumatoid arthritis [29] amongst many others, using this approach. However, there are also downsides to this approach.…”