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

Snigdha Samarpita,Mahaboob Khan Rasool,Kyoung Soo Kim,Joo Young Kim

doi:10.1186/s13075-020-2097-2

Abstract

BackgroundProper 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.MethodsThe 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.ResultsTAK-242 dose dependently inhibited the increased expression of IL-6, IL-8, MMP-1, and VEGF in LPS-stimulated 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.ConclusionsBased 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.

Highlights

Tissue and cells are injured during chronic and persistent inflammation of rheumatoid arthritis (RA)
TAK-242 inhibits the increased expression of IL-6, IL-8, MMP-1, and VEGF in LPS-stimulated fibroblast-like synoviocytes in vitro First, to estimate if LPS stimulates pro-inflammatory mediators in human FLS, MH7A cells were treated with LPS at 2 μg/ml for 24 h
TAK-242 treatment showed the trend of inhibiting the increased expression of IL-6 and IL-8 caused by LPS or poly(I:C), but did not alter IL-1βstimulated FLS. These findings suggest that TAK-242 treatment effectively inhibited the signaling pathway through TLR4 and TLR3 activation, but not through the IL-1β receptor

Summary

Introduction

Tissue and cells are injured during chronic and persistent inflammation of rheumatoid arthritis (RA). Endogenous molecules such as nuclear proteins, RNA, and DNA may be released into synovial fluid and activate inflammatory responses through the signaling pathway of toll-like receptors (TLRs) expressed in cells such as macrophages, synovial cells, and preosteoclasts located in joints [1]. TLRs are the front line of innate. Proper blocking of TLR4 activation during disease progression may help control RA. 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 TAK242 had potential as a remedy for rheumatoid arthritis

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