Control of fibroblast-like synoviocyte proliferation by macrophage migration inhibitory factor
Control of fibroblast-like synoviocyte proliferation by macrophage migration inhibitory factor
复制标题
DOI：
10.1002/art.10733
复制
发表时间：
2003-01-01
影响因子：
--
通讯作者：
Morand, E
中科院分区：
文献类型：
--
作者：
Lacey, D;Sampey, A;Morand, E
客观的。成纤维样滑膜细胞（FLS）的增生被认为对于类风湿性关节炎（RA）关节破坏的演变至关重要，但 FLS 增殖的机制仍知之甚少。巨噬细胞迁移抑制因子 (MIF) 是一种细胞因子，最近被证明对 RA FLS 具有促炎作用。本研究旨在确定MIF激活FLS的机制，并评估MIF对滑膜细胞增殖的影响。方法。用重组 MIF、白介素-1β (IL-1β)、肿瘤坏死因子 α (TNFα) 和/或抗 MIF 单克隆抗体 (mAb) 治疗人 RA FLS。用氚化胸苷掺入测量增殖。分别用免疫组织化学和蛋白质印迹法测量核因子 kappaB (NF-kappaB) 和丝裂原激活蛋白 (MAP) 激酶的激活。结果。 MIF 显着增加了 FLS 增殖。 IL-1β 和 TNFα 也诱导增殖，但这些效应可通过抗 MIF mAb 中和来阻止。 NF-κB 的激活由 IL-1beta 诱导，但不由 MIF 诱导。抗 MIF mAb 对 IL-1β 诱导的 NF-κB 核转位没有影响。相比之下，MIF 诱导细胞外信号调节激酶 (ERK) MAP 激酶的磷酸化。 ERK 拮抗作用而非 NF-kappaB 拮抗作用阻止了 MIF 对 FLS 增殖的影响。结论。这些数据表明，MIF 可能通过直接作用或参与 IL-1β 和 TNFα 的作用来调节 RA 滑膜增生。此外，MIF对FLS激活的影响不依赖于NF-kappaB，而是依赖于ERK MAP激酶。这些数据表明 MIF 拮抗作用在 RA 中具有重要的治疗潜力。
Objective. The hyperplasia of fibroblast-like synoviocytes (FLS) is considered essential to the evolution of joint destruction in rheumatoid arthritis (RA), but the mechanisms underlying FLS proliferation remain poorly understood. Macrophage migration inhibitory factor (MIF) is a cytokine that has recently been shown to exert proinflammatory effects on RA FLS. This study sought to identify the mechanisms of activation of FLS by MIF, and to assess the effects of MIF on synovial cell proliferation.Methods. Human RA FLS were treated with recombinant MIF, interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and/or anti-MIF monoclonal antibodies (mAb). Proliferation was measured with tritiated thymidine incorporation. Nuclear factor kappaB (NF-kappaB) and mitogen-activated protein (MAP) kinase activation were measured with immunohistochemistry and Western blotting, respectively.Results. FLS proliferation was significantly increased by MIF. IL-1beta and TNFalpha also induced proliferation, but these effects were prevented by neutralization with anti-MIF mAb. Activation of NF-kappaB was induced by IL-1beta, but not by MIF. Anti-MIF mAb had no effect on IL-1beta-induced NF-kappaB nuclear translocation. By contrast, MIF induced phosphorylation of extracellular signal-regulated kinase (ERK) MAP kinase. ERK antagonism, but not NF-kappaB antagonism, prevented the effect of MIF on FLS proliferation.Conclusion. These data suggest that MIF may regulate RA synovial hyperplasia by acting directly and via involvement in the effects of IL-1beta and TNFalpha. In addition, the effects of MIF on FLS activation are independent of NF-kappaB, and dependent on ERK MAP kinase. These data suggest an important therapeutic potential for MIF antagonism in RA.