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Arthritis Rheum:抑制核受体RORγ显著改善类风湿关节炎症状

  1. 核受体RORγ
  2. 类风湿关节炎

来源:生物谷 2013-12-11 21:06

2013年12月12日讯 /生物谷BIOON/--近日,由斯克里普斯研究所(TSRI)科学家合成及开发的新化合物在类风湿关节炎动物模型中显示出能显著减少关节炎症症状。类风湿关节炎是一种自身免疫性疾病,影响超过200万美国人。

这项研究发表在Arthritis & Rheumatism杂志上。研究表明该化合物SR2211,在第一个八至十天的治疗期间内,能阻断小鼠类风湿关节炎几乎所有症状的发展。

较未接受治疗的动物相比,治疗小鼠也显著表现出骨和软骨侵蚀程度降低。这一实验性化合物靶向核受体RORγ,核受体RORγ是调节TH 17细胞的关键因子。TH 17细胞是白细胞家族一员,其在免疫系统中发挥作用。

TH17细胞参与众多自身免疫性疾病,包括多发性硬化症,类风湿性关节炎,炎症性肠病和狼疮发病过程。这种化合物及其前体化合物,能阻止Th17细胞释放特异性炎性介质的能力,化学家Patrick R. Griffin说:所以我们有信心,SR2211将在自身免疫性疾病啮齿动物模型中展示出很好的疗效。

最新的研究强烈支持,通过靶向RORγ受体,可以治疗抑制类风湿关节炎相关的炎症和关节破坏。这项研究表明,抑制RORγ受体活性的SR2211,可以减轻关节糜烂和关节炎症。(生物谷Bioon.com)


 

Pharmacological repression of RORγ is therapeutic in the collagen-induced arthritis experimental model

Mi Ra Chang, Brent Lyda, Theodore M. Kamenecka, Patrick R. Griffin

Objective: The nuclear receptor RORγ (RAR-related orphan receptor gamma; T cell specific isoform is RORγt) is a key regulator of TH17 cell differentiation controlling the production of the inflammatory cytokine IL17. Further it has been shown that LPS stimulation of monocytes leads to induction of RORγ. Previously we have shown that the potent and selective inverse agonist of RORγ, SR2211 was effective at suppressing IL17 production in EL4 cells. Further, we demonstrate here that SR2211 treatment blocks proinflammatory cytokine expression in LPS stimulated RAW264.7 cells. Based on these findings SR2211 was administered to collagen-induced arthritis (CIA) mice to evaluate the ability of the compound to reduce joint inflammation.

Methods: Collagen was injected into the tail of DBA mice followed by a second boost inoculation 21 days later. Three days prior to the boost inoculation, SR2211 was administered into these mice twice daily for 15 days. Thymus, spleen and lymph node (DLN) were harvested and TH17 cell differentiation and DLN stimulation were performed.

Results: Treatment of TH17 cells with SR2211 suppressed the expression and production of inflammatory cytokines. Likewise, SR2211 reduced inflammatory cytokine production in LPS stimulated RAW264.7 cells. CIA mice administered SR2211 twice daily for 15 days exhibited statistically significant reduction in joint inflammation as compared to mice receiving only vehicle. Interestingly, systemic TH1 cell activation was detected in SR2211 treated CIA mice as indicated by an increase in IFNγ.

Conclusions: These findings support targeting RORγ to therapeutically repress inflammatory T cell function and macrophage activation in rheumatoid arthritis. Compounds such as SR2211 have potential utility for the treatment of inflammatory disease. ? 2013 American College of Rheumatology.

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