Mechanotransduction by integrin is essential for IL-6 secretion from endothelial cells in response to uniaxial continuous stretch.
Mechanotransduction by integrin is essential for IL-6 secretion from endothelial cells in response to uniaxial continuous stretch.
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DOI：
10.1152/ajpcell.00314.2004
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发表时间：
2005-05
期刊：
影响因子：
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通讯作者：
Akitoshi Sasamoto;M. Nagino;Satoshi Kobayashi;K. Naruse;Y. Nimura;M. Sokabe
中科院分区：
文献类型：
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作者：
Akitoshi Sasamoto;M. Nagino;Satoshi Kobayashi;K. Naruse;Y. Nimura;M. Sokabe
我们之前报道过，人脐静脉内皮细胞 (HUVEC) 的单轴连续拉伸通过 IkappaB 激酶 (IKK)/核因子-kappaB (NF-kappaB) 激活诱导白细胞介素 6 (IL-6) 分泌。本研究的目的是阐明造成这种现象的上游信号机制。使用 α(5)β(1) 整联蛋白抑制肽 (GRGDNP)、磷脂酰肌醇 3-激酶抑制剂 (LY-294002)、磷脂酶 C-γ 抑制剂 (U-73122) 或蛋白激酶 C 抑制剂 (H7) 可以抑制拉伸诱导的 IKK 激活和 IL-6 分泌。虽然分别使用毒胡萝卜素 (TG) 或 EGTA 消耗细胞内或细胞外 Ca(2+) 库几乎没有效果，但 TG-EGTA 混合物显着抑制拉伸诱导的 IKK 激活和 IL-6 分泌。即使在存在 TG、EGTA 或 GRGDNP 的情况下，也观察到连续拉伸时细胞内 Ca(2+) 浓度 ([Ca(2+)](i)) 增加，但在含有 TG-EGTA 混合物的溶液中观察不到，表明整合素激活和 [Ca(2+)](i) 升高是拉伸诱导的 IKK 激活和 HUVEC 中 IL-6 分泌后的关键因素。此外，虽然 TG-EGTA 混合物、GRGDNP、LY-294002 或 U-73122 抑制 PKC 活性，但 GRGDNP 或 LY-294002 延迟 PLC-gamma 活性。这些结果表明，HUVEC 中持续拉伸诱导的 IL-6 分泌取决于通过整合素的由外向内信号传导，然后是 PI3-K-PLC-gamma-PKC-IKK-NF-kappaB 信号级联。另一个关键因素，[Ca(2+)](i) 增加，可能至少需要激活 NF-kappaB 激活所需的 PKC。
We previously reported that uniaxial continuous stretch in human umbilical vein endothelial cells (HUVECs) induced interleukin-6 (IL-6) secretion via IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) activation. The aim of the present study was to clarify the upstream signaling mechanism responsible for this phenomenon. Stretch-induced IKK activation and IL-6 secretion were inhibited by application of alpha(5)beta(1) integrin-inhibitory peptide (GRGDNP), phosphatidylinositol 3-kinase inhibitor (LY-294002), phospholipase C-gamma inhibitor (U-73122), or protein kinase C inhibitor (H7). Although depletion of intra- or extracellular Ca(2+) pool using thapsigargin (TG) or EGTA, respectively, showed little effect, a TG-EGTA mixture significantly inhibited stretch-induced IKK activation and IL-6 secretion. An increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) upon continuous stretch was observed even in the presence of TG, EGTA, or GRGDNP, but not in a solution containing the TG-EGTA mixture, indicating that both integrin activation and [Ca(2+)](i) rise are crucial factors for stretch-induced IKK activation and after IL-6 secretion in HUVECs. Furthermore, while PKC activity was inhibited by the TG-EGTA mixture, GRGDNP, LY-294002, or U-73122, PLC-gamma activity was retarded by GRGDNP or LY-294002. These results indicate that continuous stretch-induced IL-6 secretion in HUVECs depends on outside-in signaling via integrins followed by a PI3-K-PLC-gamma-PKC-IKK-NF-kappaB signaling cascade. Another crucial factor, [Ca(2+)](i) increase, may at least be required to activate PKC needed for NF-kappaB activation.