IL-6 AND TGF-α COSTIMULATE MESENCHYMAL STEM CELL VASCULAR ENDOTHELIAL GROWTH FACTOR PRODUCTION BY ERK-, JNK-, AND PI3K-MEDIATED MECHANISMS
IL-6 AND TGF-α COSTIMULATE MESENCHYMAL STEM CELL VASCULAR ENDOTHELIAL GROWTH FACTOR PRODUCTION BY ERK-, JNK-, AND PI3K-MEDIATED MECHANISMS
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DOI：
10.1097/shk.0b013e31820b2fb9
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发表时间：
2011-05-01
期刊：
影响因子：
3.1
通讯作者：
Meldrum, Daniel R.
中科院分区：
文献类型：
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作者：
Herrmann, Jeremy L.;Weil, Brent R.;Meldrum, Daniel R.
间充质干细胞（MSC）部分通过旁分泌生长因子的产生来保护缺血组织。 IL-6 在缺血期间在心脏中表达上调，已被证明可以增强干细胞的增殖和迁移。然而，IL-6 对 MSC 旁分泌功能的影响仍不清楚。此外，TGF-α 可增加 MSC 血管内皮生长因子 (VEGF) 的产生，并可能与 IL-6 共享涉及 ERK、JNK 和 PI3K 的下游信号通路。我们假设通过这些信号通路，IL-6 和 TGF-α 联合治疗将比单独治疗产生更多的 MSC VEGF 产量。用 IL-6 (0.05 ng/mL) 联合或不联合 TGF-α (250 ng/mL) 联合 ERKI/II、JNK 和 PI3K 抑制剂处理小鼠 MSC 24 小时。使用酶联免疫吸附测定法测量上清液中的血管内皮生长因子浓度。使用蛋白质印迹分析测量 ERK、JNK 和 PI3K 的磷酸化。 IL-6 在 0.05 ng/mL 的剂量下增加 MSC VEGF 的产生，IL-6 和 TGF-α 的组合 (250 ng/mL) 比单独使用 IL-6 或 TGF-α 更大程度地增加 VEGF 的产生。 IL-6 诱导 ERK、JNK 和 PI3K 磷酸化，抑制每种磷酸化可抑制 IL-6 诱导的 VEGF 产生。 TGF-α 联合治疗克服了 ERK2 抑制后的 VEGF 抑制，但不能克服 ERK1、JNK 或 PI3K。这些数据表明，IL-6 单独刺激 MSC VEGF 产生，并通过 ERK、JNK 和 PI3K 介导的机制与 TGF-α 相加。 IL-6 和 TGF-α 联合治疗可能是增强 MSC VEGF 产生和心肌缺血期间心脏保护的有用策略。
Mesenchymal stem cells (MSCs) protect ischemic tissues in part through paracrine growth factor production. IL-6, which is upregulated in the heart during ischemia, has been shown to enhance stem cell proliferation and migration. The effect of IL-6 on MSC paracrine function, however, remains unknown. In addition, TGF-alpha increases MSC vascular endothelial growth factor (VEGF) production and may share downstream signaling pathways with IL-6 involving ERK, JNK, and PI3K. We hypothesize that cotreatment with IL-6 and TGF-alpha will result in greater MSC VEGF production than by either treatment alone via these signaling pathways. Murine MSCs were treated with IL-6 (0.05 ng/mL) with or without TGF-alpha (250 ng/mL) and in combination with inhibitors of ERKI/II, JNK, and PI3K for 24 h. Vascular endothelial growth factor concentrations in the supernatants were measured using enzyme-linked immunosorbent assay. Phosphorylation of ERK, JNK, and PI3K was measured using Western blot analysis. IL-6 increased MSC VEGF production at a dose of 0.05 ng/mL, and the combination of IL-6 and TGF-alpha (250 ng/mL) increased VEGF production to a greater extent than IL-6 or TGF-alpha alone. IL-6 induced phosphorylation of ERK, JNK, and PI3K, and inhibition of each suppressed IL-6-induced VEGF production. TGF-alpha cotreatment overcame VEGF suppression after ERK2 inhibition but not ERK1, JNK, or PI3K. These data suggest that IL-6 stimulates MSC VEGF production alone and additively with TGF-alpha via ERK-, JNK-, and PI3K-mediated mechanisms. IL-6 and TGF-alpha cotreatment may be a useful strategy for enhancing MSC VEGF production and cardioprotection during myocardial ischemia.