IL-27 Abrogates Receptor Activator of NF-κB Ligand-Mediated Osteoclastogenesis of Human Granulocyte-Macrophage Colony-Forming Unit Cells through STAT1-Dependent Inhibition of c-Fos
IL-27 Abrogates Receptor Activator of NF-κB Ligand-Mediated Osteoclastogenesis of Human Granulocyte-Macrophage Colony-Forming Unit Cells through STAT1-Dependent Inhibition of c-Fos
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DOI：
10.4049/jimmunol.0802091
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发表时间：
2009-08-15
影响因子：
4.4
通讯作者：
Toyama, Yoshiaki
中科院分区：
文献类型：
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作者：
Furukawa, Mitsuru;Takaishi, Hironari;Toyama, Yoshiaki
IL-27最先被发现是作为一种支持初始Th1免疫反应的因子。随后的研究表明，这种细胞因子具有多效性，包括对某些免疫细胞的抑制，对造血干细胞分化的调节作用，以及抗肿瘤活性。然而，人类IL(HIL)-27在人类破骨细胞前体和炎症性骨病中的作用尚不清楚。在这里，我们研究了hIL-27对人类破骨细胞形成的直接影响。在含人(H)GM-CSF、人干细胞因子和hIL-3的MethoCult培养液中培养的人骨髓细胞表达Mac-1、c-kit和c-FMS。这些细胞被称为hCFU-GM，也表达IL-27受体，一种IL-27Rα(WSX-1)/gp130异源二聚体。人巨噬细胞集落刺激因子和人核因子-kappaB受体激活剂诱导hCFU-GM向酒石酸酸性磷酸酶阳性的多核细胞(破骨细胞)分化，hIL-27以剂量依赖的方式抑制这种破骨细胞的形成。HIL-27还抑制牙本质片上破骨细胞的骨吸收。HIL-27可显著增加STAT1的磷酸化，提高STAT1的蛋白水平。它还能抑制核因子-kappa B受体激活物c-Fos和胞浆钙调神经磷酸酶依赖的1 NFAT(NFATc1)的表达，而NFATc1是破骨细胞形成所必需的转录因子。STAT1抑制剂氟达拉滨和STAT1小干扰RNA部分挽救了IL-27对破骨细胞生成的抑制。WSX-1缺乏可导致体内由大肠杆菌细胞壁裂解物引发的严重炎症性骨破坏。因此，hIL-27可能通过STAT1依赖的转录因子c-Fos下调抑制hCFU-GM的破骨细胞生成，从而在人类骨质破坏中发挥抗炎细胞因子的作用。我们的结果表明，hIL-27可能被证明是治疗炎症性骨破坏的有效靶点。免疫学杂志，2009,183：2397-2406。
IL-27 was first discovered as a factor supporting initial Th1 immune responses. Subsequent studies revealed that this cytokine has pleiotropic effects, including inhibition of certain immune cells, a regulatory role in hemopoietic stem cell differentiation, and antitumor activities. However, the role of human IL (hIL)-27 in human osteoclast precursors and inflammatory bone disease is unclear. Here, we examined the direct effect of hIL-27 on human osteoclastogenesis. Human bone marrow cells cultured in MethoCult medium containing human (h) GM-CSF, human stem cell factor, and hIL-3 expressed Mac-1, c-kit, and c-Fms. These cells, called hCFU-GMs, also expressed the IL-27 receptor, an IL-27R alpha (WSX-1)/gp130 heterodimer. Cultivation in hM-CSF and human receptor activator of NF-kappa B ligand induced the differentiation of tartrate-resistant acid phosphatase-positive multinucleated cells (osteoclasts) from hCFU-GMs, and hIL-27 inhibited this osteoclastogenesis in a dose-dependent manner. hIL-27 also repressed bone resorption by osteoclasts on a dentine slice. hIL-27 caused a remarkable increase in STAT1 phosphorylation and enhanced the STAT1 protein level. It also inhibited the expression of receptor activator of NF-kappa B ligand-induced c-Fos and cytoplasmic, calcineurin-dependent 1 NFAT (NFATc1), which are indispensable transcription factors for osteoclastogenesis. Fludarabine, a STAT1 inhibitor, and STAT1 small interfering RNA partially rescued the inhibition of osteoclastogenesis by IL-27. A WSX-1 deficiency caused severe inflammatory bone destruction primed by Escherichia coli cell wall lysate in vivo. Therefore, hIL-27 may act as an anti-inflammatory cytokine in human bone destruction, by inhibiting osteoclastogenesis from hCFU-GMs via STAT1-dependent down-regulation of the transcription factor c-Fos. Our results suggest that hIL-27 may prove useful as a therapeutic target for inflammatory bone destruction. The Journal of Immunology, 2009, 183: 2397-2406.