Furukawa Mitsuru, Takaishi Hironari, Takito Jiro, Yoda Masaki, Sakai Sadaoki, Hikata Tomohiro, Hakozaki Akihiro, Uchikawa Shinichi, Matsumoto Morio, Chiba Kazuhiro, Kimura Tokuhiro, Okada Yasunori, Matsuo Koichi, Yoshida Hiroki, Toyama Yoshiaki
Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.
J Immunol. 2009 Aug 15;183(4):2397-406. doi: 10.4049/jimmunol.0802091. Epub 2009 Jul 20.
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-27Ralpha (WSX-1)/gp130 heterodimer. Cultivation in hM-CSF and human receptor activator of NF-kappaB 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-kappaB 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.
白细胞介素-27（IL-27）最初被发现是一种支持初始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作用，包括抑制某些免疫细胞、在造血干细胞分化中起调节作用以及抗肿瘤活性。然而，人IL（hIL）-27在人破骨细胞前体和炎性骨病中的作用尚不清楚。在此，我们研究了hIL-27对人破骨细胞生成的直接影响。在含有人类（h）粒细胞-巨噬细胞集落刺激因子（GM-CSF）、人干细胞因子和hIL-3的MethoCult培养基中培养的人骨髓细胞表达Mac-1、c-kit和c-Fms。这些细胞，称为hCFU-GM，也表达IL-27受体，即IL-27Rα（WSX-1）/gp130异二聚体。在hM-CSF和人核因子κB受体激活剂配体中培养可诱导hCFU-GM分化为抗酒石酸酸性磷酸酶阳性的多核细胞（破骨细胞），而hIL-27以剂量依赖的方式抑制这种破骨细胞生成。hIL-27还抑制破骨细胞在牙本质切片上的骨吸收。hIL-27导致信号转导和转录激活因子1（STAT1）磷酸化显著增加，并提高STAT1蛋白水平。它还抑制核因子κB受体激活剂配体诱导的c-Fos和细胞质钙调磷酸酶依赖性1活化T细胞核因子（NFATc1）的表达，这两种因子是破骨细胞生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作用。WSX-1缺陷在体内导致由大肠杆菌细胞壁裂解物引发的严重炎性骨破坏。因此，hIL-27可能通过STAT1依赖性下调转录因子c-Fos抑制hCFU-GM的破骨细胞生成，从而在人类骨破坏中作为一种抗炎细胞因子发挥作用。我们的结果表明，hIL-27可能被证明是炎性骨破坏的一个有用的治疗靶点。
