T-614, a novel immunomodulator, attenuates joint inflammation and articular damage in collagen-induced arthritis

Du, Fukuan; Lu, Liangjing; Fu, Qiong; Dai, Min; Teng, Jialin; Fan, Wei; Chen, Shun‐le; Ye, Ping; Shen, Nan; Huang, Xinfang; Qian, Jie; Bao, Chunde

doi:10.1186/ar2554

Cited by 76 publications

(60 citation statements)

References 46 publications

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“…CIA was induced according to the method described previously with minor modification (Du et al, 2008). In brief, bovine type II collagen (Chondrex, Redmond, WA) was dissolved at 2 mg/ml in 0.05 M acetic acid by gently stirring overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory Effect of Baicalin on Collagen-Induced Arthritis in Rats through the Nuclear Factor–κB Pathway

Wang

Huang

et al. 2014

J Pharmacol Exp Ther

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This study focused on the potential therapeutic effect of baicalin on collagen-induced arthritis (CIA) in rats and the underlying mechanisms. The CIA rats were injected with baicalin (50, 100, or 200 mg/kg) once daily for 30 days. The rats were monitored for clinical severity of arthritis, and joint tissues were used for radiographic assessment and histologic examination. We quantified tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b) in experimental animals and used Western blots to assess levels of protein abundance, phosphorylation, and acetylation of nuclear factor (NF)-kB p65 and sirtuin 1 (sirt1) protein expression in joint tissues. Human fibroblast-like synoviocytes from rheumatoid arthritis (HFLS-RA) were adopted in further mechanistic investigations. Baicalin intraperitoneal injection for 30 days dose-dependently blocked clinical manifestations of CIA, such as functional impairment and swollen red paws. Meanwhile, it alleviated collageninduced joint inflammation injury and inhibited the secretion of TNF-a and IL-1b in both rat synovium and HFLS-RA. Further mechanistic investigations revealed that baicalin suppresses NF-kB p65 protein expression and phosphorylation in synovial tissue and human-derived synoviocytes. Moreover, the acetylation of NF-kB p65 was downregulated by baicalin, which negatively correlates with the baicalin-induced upregulation of sirt1 expression in the same conditions. The data indicate that CIA in rats can be alleviated by baicalin treatment via relieving joint inflammation, which is related to the suppression of synovial NF-kB p65 protein expression and the elevation of its deacetylation by sirt1.

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Section: Methodsmentioning

confidence: 99%

Inhibitory Effect of Baicalin on Collagen-Induced Arthritis in Rats through the Nuclear Factor–κB Pathway

Wang

Huang

et al. 2014

J Pharmacol Exp Ther

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“…In collagen-induced arthritis, T-614 can attenuate joint inflammation and articular damage [17]. Existing studies showed that T-614 suppressed inflammatory cytokine production in cultured human synovial cells and human THP-1 cells [18].…”

Section: Introductionmentioning

confidence: 99%

T-614 alters the production of matrix metalloproteinases (MMP-1 andMMP-3) and inhibits the migratory expansion of rheumatoid synovial fibroblasts, in vitro

Teng

et al. 2012

International Immunopharmacology

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“…Iguratimod is an anti-inflammatory and immunomodulatory compound that has been developed as a novel DMARD. Although previous research indicated that it yielded improvements in several autoimmune models, such as CIA (32)(33)(34), the unique antiarthritic mechanism of iguratimod has not been elucidated. In this study, we selected methotrexate and leflunomide as reference drugs and conducted a comparative analysis of the antiarthritic effects of these DMARDs and iguratimod.…”

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confidence: 99%

A Novel Disease-Modifying Antirheumatic Drug, Iguratimod, Ameliorates Murine Arthritis by Blocking IL-17 Signaling, Distinct from Methotrexate and Leflunomide

Luo

Sun

et al. 2013

The Journal of Immunology

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Iguratimod, a novel disease-modifying antirheumatic drug, which is now used in clinics in China and Japan, has been confirmed as a highly efficacious and safe drug for rheumatoid arthritis therapy. The antiarthritic mechanism of iguratimod, especially compared with that of the classical disease-modifying antirheumatic drugs, has not been elucidated. In this study, we conducted a comparative analysis of the antiarthritic effects of iguratimod and two reference drugs, methotrexate and leflunomide. We found that iguratimod dose dependently and potently inhibited arthritic inflammation of the synovium in collagen-induced arthritis and predominantly targeted IL-17 signaling. Consistent with its effects in vivo, iguratimod significantly suppressed the expression of various proinflammatory factors triggered by IL-17 in the cultured fibroblast-like synoviocytes. The inhibition of IL-17 signaling by iguratimod was further linked to a decrease in the mRNA stability of related genes and a reduction in phosphorylation of MAPKs. Iguratimod mainly targets Act1 to disrupt the interaction between Act1 and TRAF5 and IKKi in the IL-17 pathway of synoviocytes. Together, our results suggest that iguratimod yields a strong improvement in arthritis via its unique suppression of IL-17 signaling in fibroblast-like synoviocytes. This feature of iguratimod is different from those of methotrexate and leflunomide. This study may be helpful for further understanding the unique antiarthritic mechanism of iguratimod in patients with rheumatoid arthritis.

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T-614, a novel immunomodulator, attenuates joint inflammation and articular damage in collagen-induced arthritis

Abstract: Introduction T-614 is a novel oral antirheumatic agent for the treatment of rheumatoid arthritis. Whether it has immunomodulatory or disease-modifying properties and its mechanism of action are largely undetermined.

Cited by 76 publications

References 46 publications

Inhibitory Effect of Baicalin on Collagen-Induced Arthritis in Rats through the Nuclear Factor–κB Pathway

Inhibitory Effect of Baicalin on Collagen-Induced Arthritis in Rats through the Nuclear Factor–κB Pathway

T-614 alters the production of matrix metalloproteinases (MMP-1 andMMP-3) and inhibits the migratory expansion of rheumatoid synovial fibroblasts, in vitro

A Novel Disease-Modifying Antirheumatic Drug, Iguratimod, Ameliorates Murine Arthritis by Blocking IL-17 Signaling, Distinct from Methotrexate and Leflunomide

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