IL-6 counteracts the inhibitory effect of IL-4 on osteogenic differentiation of human adipose stem cells
IL-6 counteracts the inhibitory effect of IL-4 on osteogenic differentiation of human adipose stem cells
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DOI：
10.1002/jcp.28652
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发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Bakker, Astrid D.
中科院分区：
文献类型：
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作者：
Bastidas-Coral, Angela P.;Hogervorst, Jolanda M. A.;Bakker, Astrid D.
骨折修复的特点是细胞因子的产生和缺氧。为了更好地预测间充质干细胞（MSC）辅助骨愈合的细胞因子调节，我们研究了白细胞介素4（IL-4），IL-6及其组合，是否影响成骨分化，血管内皮生长因子（VEGF）的生产，和/或哺乳动物雷帕霉素复合物1（mTORC 1）的活化MSC在常氧或缺氧。将人脂肪干细胞（hASCs）与IL-4、IL-6或它们的组合在常氧（20%O（2））或缺氧（1%O（2））下培养3天，然后在不含细胞因子的常氧或缺氧下培养11天。缺氧不改变hASCs的IL-4或IL-6调节的基因或蛋白表达。IL-4单独降低正常氧和缺氧条件下hASCs的Runx相关转录因子2（RUNX 2）和胶原1型（COL 1）基因表达、碱性磷酸酶（ALP）活性和VEGF蛋白产生，并降低缺氧条件下hASCs的矿化。与此相反，IL-6在常氧下增加hASCs的矿化，并在常氧和缺氧下增强RUNX 2基因表达。IL-4和IL-6均不影响mTORC 1效应蛋白P70 S6 K的磷酸化。在常氧和缺氧条件下，IL-4联合IL-6可减弱IL-4对ALP活性、骨结节形成和VEGF产生的抑制作用，并降低RUNX 2和COL 1表达，与单独IL-4相似。总之，IL-4单独，但不与IL-6组合，抑制成骨分化和血管生成刺激潜力的hASC在常氧和缺氧下，可能通过mTORC 1以外的途径。这些结果表明，细胞因子可能差异影响骨愈合和再生时，单独或组合应用。
Fracture repair is characterized by cytokine production and hypoxia. To better predict cytokine modulation of mesenchymal stem cell (MSC)-aided bone healing, we investigated whether interleukin 4 (IL-4), IL-6, and their combination, affect osteogenic differentiation, vascular endothelial growth factor (VEGF) production, and/or mammalian target of rapamycin complex 1 (mTORC1) activation by MSCs under normoxia or hypoxia. Human adipose stem cells (hASCs) were cultured with IL-4, IL-6, or their combination for 3 days under normoxia (20% O (2)) or hypoxia (1% O (2)), followed by 11 days without cytokines under normoxia or hypoxia. Hypoxia did not alter IL-4 or IL-6-modulated gene or protein expression by hASCs. IL-4 alone decreased runt-related transcription factor 2 (RUNX2) and collagen type 1 (COL1) gene expression, alkaline phosphatase (ALP) activity, and VEGF protein production by hASCs under normoxia and hypoxia, and decreased mineralization of hASCs under hypoxia. In contrast, IL-6 increased mineralization of hASCs under normoxia, and enhanced RUNX2 gene expression under normoxia and hypoxia. Neither IL-4 nor IL-6 affected phosphorylation of the mTORC1 effector protein P70S6K. IL-4 combined with IL-6 diminished the inhibitory effect of IL-4 on ALP activity, bone nodule formation, and VEGF production, and decreased RUNX2 and COL1 expression, similar to IL-4 alone, under normoxia and hypoxia. In conclusion, IL-4 alone, but not in combination with IL-6, inhibits osteogenic differentiation and angiogenic stimulation potential of hASCs under normoxia and hypoxia, likely through pathways other than mTORC1. These results indicate that cytokines may differentially affect bone healing and regeneration when applied in isolation or in combination.