A novel therapy of murine collagen-induced arthritis with soluble T1/ST2
A novel therapy of murine collagen-induced arthritis with soluble T1/ST2
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DOI：
10.4049/jimmunol.173.1.145
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发表时间：
2004-07-01
影响因子：
4.4
通讯作者：
Liew, FY
中科院分区：
文献类型：
--
作者：
Leung, BP;Xu, D;Liew, FY
风湿性关节炎的特征是滑膜的慢性炎症浸润，导致最终的软骨和骨破坏。以前，我们已经报道了可溶性T1/ST 2（sST 2），IL-1 R基因家族的成员，抑制LPS诱导的巨噬细胞促炎细胞因子的产生。在这项研究中，我们报告了sST 2-Fe在胶原诱导的关节炎小鼠模型中的治疗作用。与用正常IgG处理的对照相比，短期施用sST 2-Fc融合蛋白显著减弱疾病严重程度。组织学检查显示，虽然对照IgG处理的小鼠在关节中出现严重的细胞浸润、滑膜增生和关节侵蚀，但这种病理在sST 2-Fe处理的动物中显著减少。sST 2-FC治疗还下调了IL-6、IL-12和TNF-α的血清水平。当与胶原蛋白体外培养时，与对照小鼠的细胞相比，sST 2-Fc处理小鼠的脾细胞产生的IFN-γ、TNF-α、IL-6和IL-12显著减少。最后，当与来自类风湿患者的外周血T细胞共培养时，用ST 2-Fc预处理显著抑制人单核细胞THP 1细胞释放TNF-α的能力。总之，这些结果表明，sST 2-Fc可以提供一种新的方法，通过抑制促炎细胞因子的释放治疗慢性自身免疫性疾病。
Rheumatoid arthritis is characterized by chronic inflammatory infiltration of the synovium, leading to eventual cartilage and bone destruction. Previously, we have reported that soluble T1/ST2 (sST2), a member of the IL-1R gene family, inhibits LPS-induced macrophage proinflammatory cytokine production. In this study, we report the therapeutic effect of sST2-Fe in the murine model of collagen-induced arthritis. A short term administration of sST2-Fc fusion protein significantly attenuated disease severity compared with controls treated with normal IgG. Histological examination revealed that while control IgG-treated mice developed severe cellular infiltration in the joints, synovial hyperplasia, and joint erosion, this pathology was profoundly reduced in sST2-Fe-treated animals. Treatment of sST2-Fc also down-regulated serum levels of IL-6, IL-12, and TNF-alpha. Spleen cells from the sST2-Fc-treated mice produced significantly less IFN-gamma, TNF-alpha, IL-6, and IL-12 compared with cells from the control mice when cultured with collagen in vitro. Finally, pretreatment with ST2-Fc markedly inhibited the ability of human monocytic THP1 cells to release TNF-alpha when cocultured with peripheral blood T cells from rheumatoid patients. Together these results demonstrate that sST2-Fc may provide a novel approach in treating chronic autoimmune conditions by inhibiting the release of proinflammatory cytokines.