Interleukin 29 inhibits RANKL-induced osteoclastogenesis via activation of JNK and STAT, and inhibition of NF-kappa B and NFATc1
Interleukin 29 inhibits RANKL-induced osteoclastogenesis via activation of JNK and STAT, and inhibition of NF-kappa B and NFATc1
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Interleukin 29 通过激活 JNK 和 STAT 以及抑制 NF-kappa B 和 NFATc1 抑制 RANKL 诱导的破骨细胞生成
DOI：
10.1016/j.cyto.2018.06.032
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发表时间：
2019
期刊：
影响因子：
3.8
通讯作者：
Wang Fang
中科院分区：
文献类型：
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作者：
Peng Qiuyue;Luo Aishu;Zhou Zihao;Xuan Wenhua;Qiu Ming;Wu Qin;Xu Lingxiao;Kong Xiangqing;Zhang Miaojia;Tan Wenfeng;Xue Meilang;Wang Fang
已知白细胞介素 (IL)-29 可以调节单核细胞或巨噬细胞的免疫功能。在本研究中，我们利用小鼠巨噬细胞系RAW264.7细胞、骨髓源性单核/巨噬细胞前体细胞（BMM）和人外周血单核细胞（PBMC）研究了IL-29对核因子κB配体受体激活剂（RANKL）诱导的破骨细胞生成的影响及其潜在机制。针对人重组 IL-29，通过 Cell Counting Kit-8 和流式细胞术评估细胞活力和凋亡；分别通过抗酒石酸酸性磷酸酶（TRAP）染色和凹坑形成测定来观察破骨细胞的形成和活性；通过实时 PCR、免疫印迹或免疫荧光分析来检测与破骨细胞生成相关的分子的表达和激活。 IL-28受体α（IL-28Rα）是IL-29的特异性受体，在RAW264.7细胞上表达。虽然IL-29不影响RAW264.7细胞的活力和凋亡，但它抑制多核细胞破骨细胞分化、成熟破骨细胞的骨吸收活性和破骨细胞特异性基因的表达，包括TRAP、组织蛋白酶K（CTSK）、活化T细胞核因子、细胞质1（NFATc1）、C-Fos和基质金属肽酶9（MMP-9）。 IL-29 的这种抑制作用在 BMM 和 PBMC 上得到证实，并通过 IL-28Rα 通过激活 Stat1 和 3 以及抑制 RAW264.7 细胞中的核因子 kappa B (NF-κB) 和 NFATc1 核转位来介导。总之，IL-29通过激活STAT信号通路、阻止NF-κB激活和NFATc1易位以及抑制下游破骨细胞基因表达来抑制破骨细胞生成。
Interleukin (IL)-29 is known to modulate immune functions of monocytes or macrophages. In this study, we investigated the effect and its underlying mechanism of IL-29 on receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis using murine macrophage cell line RAW264.7 cells and bone-marrow-derived monocyte/macrophage precursor cells (BMMs), and human peripheral blood mononuclear cells (PBMCs). In response to human recombinant IL-29, cell viability and apoptosis were assessed by Cell Counting Kit-8 and flow cytometry; the osteoclast formation and activity by tartrate-resistant acid phosphatase (TRAP) staining and pit formation assay, respectively; the expression and activation of molecules that associated with osteoclastogenesis by real time-PCR, immunoblotting or immunofluorescent analysis. IL-28 receptor α (IL-28Rα), a specific receptor of IL-29 was expressed on RAW264.7 cells. Although IL-29 did not affect the viability and apoptosis of RAW264.7 cells, it inhibited multinucleated cells in the differentiation of osteoclastogenesis, the bone-resorbing activity of mature osteoclasts and osteoclastic specific genes expression including TRAP, cathepsin K (CTSK), nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), C-Fos and matrix metallopeptidase 9 (MMP-9). This inhibitory effect of IL-29 was confirmed on BMMs and PBMCs and mediated via IL-28Rα through the activation of Stat1 and 3 and the suppression of nuclear factor kappa B (NF-κB) and NFATc1 nuclear translocation in RAW264.7 cells. In conclusion, IL-29 inhibited osteoclastogenesis via activation of STAT signaling pathway, prevention of NF-κB activation and NFATc1 translocation, and suppression of downstream osteoclastogenic genes expression.