Interleukin-27 inhibits human osteoclastogenesis by abrogating RANKL-mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling.
Interleukin-27 inhibits human osteoclastogenesis by abrogating RANKL-mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling.
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DOI：
10.1002/art.27200
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发表时间：
2010-02
影响因子：
--
通讯作者：
Ivashkiv, Lionel B.
中科院分区：
文献类型：
--
作者：
Kalliolias, George D.;Zhao, Baohong;Triantafyllopoulou, Antigoni;Park-Min, Kyung-Hyun;Ivashkiv, Lionel B.
IL-27具有刺激和调节免疫功能，在类风湿关节炎滑膜中表达。我们研究了IL-27对人破骨细胞生成的影响，以确定IL-27是否可以刺激或减弱破骨细胞介导的骨吸收，这是类风湿性关节炎的标志。破骨细胞由血液来源的人CD 14+细胞产生。通过计数TRAP+多核细胞的数量和测量破骨细胞相关基因的表达来评估IL-27对破骨细胞形成的影响。通过免疫印迹法测定NFATc 1的诱导和RANK下游信号通路的激活。通过真实的时间RT-PCR测量涉及破骨细胞生成的关键分子（NFATc 1、RANK、共刺激受体、携带ITAM的衔接子）的表达。小鼠破骨细胞前体获自骨髓。还测试了来自RA患者的滑液巨噬细胞对IL-27的反应性。IL-27抑制人破骨细胞生成，抑制NFATc 1的诱导，下调RANK和TREM-2的表达，并抑制破骨细胞前体中RANKL介导的ERK、p38和NF-κB的活化。来自RA患者的滑液巨噬细胞对IL-27的作用是难治的。与人类相反，IL-27仅中度抑制鼠破骨细胞生成，可能是由于鼠破骨细胞前体上IL-27受体亚基WSX-1的低表达。IL-27通过抑制破骨细胞前体对RANKL的反应的直接机制抑制人破骨细胞生成。我们的研究结果表明，除了其众所周知的抗炎作用，IL-27在抑制骨侵蚀中发挥稳态作用。这种稳态功能在慢性炎症如RA滑膜炎的情况下受到损害。
IL-27 has stimulatory and regulatory immune functions and is expressed in rheumatoid arthritis synovium. We investigated the effects of IL-27 on human osteoclastogenesis to determine whether IL-27 can stimulate or attenuate osteoclast-mediated bone resorption that is a hallmark of rheumatoid arthritis. Osteoclasts were generated from blood-derived human CD14+ cells. The effects of IL-27 on osteoclast formation were evaluated by counting the number of TRAP+ multinucleated cells and measuring expression of osteoclast-related genes. The induction of NFATc1 and the activation of signaling pathways downstream of RANK were measured by immunoblotting. The expression of key molecules implicated in osteoclastogenesis (NFATc1, RANK, costimulatory receptors, ITAM-harboring adaptors) was measured by real time RT-PCR. Murine osteoclast precursors were obtained from bone marrow. Responsiveness to IL-27 of synovial fluid macrophages derived from RA patients was also tested. IL-27 inhibited human osteoclastogenesis, suppressed the induction of NFATc1, downregulated expression of RANK and TREM-2, and inhibited RANKL-mediated activation of ERK, p38 and NF-κB in osteoclast precursors. Synovial fluid macrophages derived from RA patients were refractory to the effects of IL-27. In contrast to humans, IL-27 only moderately suppressed murine osteoclastogenesis, likely due to low expression of the IL-27 receptor subunit WSX-1 on murine osteoclast precursors. IL-27 inhibits human osteoclastogenesis by a direct mechanism suppressing responses of osteoclast precursors to RANKL. Our findings suggest that in addition to its well-known anti-inflammatory effects, IL-27 plays a homeostatic role in restraining bone erosion. This homeostatic function is compromised under conditions of chronic inflammation such as RA synovitis.
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DOI：
10.1084/jem.20061775
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sato K;Suematsu A;Okamoto K;Yamaguchi A;Morishita Y;Kadono Y;Tanaka S;Kodama T;Akira S;Iwakura Y;Cua DJ;Takayanagi H
通讯作者：
Takayanagi H
影响因子：
32.4
作者：
Pflanz, S;Timans, JC;Kastelein, RA
通讯作者：
Kastelein, RA
影响因子：
5.4
作者：
Chen, Li;Wei, Xiao-Qing;Aeschlimann, Daniel
通讯作者：
Aeschlimann, Daniel
影响因子：
15.9
作者：
Aliprantis, Antonios O.;Ueki, Yasuyoshi;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
DOI：
10.1073/pnas.2536517100
发表时间：
2003-12-09
影响因子：
11.1
作者：
Lucas, S;Ghilardi, N;de Sauvage, FJ
通讯作者：
de Sauvage, FJ