Profiling drugs for rheumatoid arthritis that inhibit synovial fibroblast activation.
Profiling drugs for rheumatoid arthritis that inhibit synovial fibroblast activation.
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DOI：
10.1038/nchembio.2211
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发表时间：
2017-01
影响因子：
14.8
通讯作者：
Sorger PK
中科院分区：
文献类型：
--
作者：
Jones DS;Jenney AP;Swantek JL;Burke JM;Lauffenburger DA;Sorger PK
滑膜成纤维细胞（SF）的活化通过破坏滑膜并产生炎性细胞因子将免疫细胞募集到关节来促成类风湿性关节炎（RA）。在本文中，我们分析了正常和RA供体的原代人SF的细胞因子分泌，并表明TNFα、IL-1α和Poly（I：C）激活的SF可导致RA滑液中高水平的多种细胞因子分泌。我们使用相互作用多元线性回归来量化激活剂和患者供体之间的治疗和反治疗药物作用，并发现药物阻断SF激活的能力强烈依赖于激活细胞因子的身份。（5 z）-7-oxozeaenol（5 ZO）是一种临床前药物，其主要靶点是转化生长因子β相关激酶1（TAK 1），在所有情况下都比批准的药物托法替尼更有效地阻断SF激活，因此有理由开发类似于5 ZO的分子作为RA治疗药物。
Activation of synovial fibroblasts (SF) contributes to rheumatoid arthritis (RA) by damaging synovial membranes and generating inflammatory cytokines that recruit immune cells to the joint. In this paper we profile cytokine secretion by primary human SF from normal and RA donors and show that SF activation by TNFα, IL–1α, and Poly(I:C) causes secretion of multiple cytokines found at high levels in RA synovial fluids. We use interaction multi-linear regression to quantify therapeutic and counter–therapeutic drug effects across activators and patient donors and find that the ability of drugs to block SF activation is strongly dependent on the identity of the activating cytokine. (5z)–7–oxozeaenol (5ZO), a pre–clinical drug whose primary target is transforming growth factor β–associated kinase 1 (TAK1), is more effective at blocking SF activation across all contexts than the approved drug tofacitinib, arguing for development of molecules similar to 5ZO as RA therapeutics.