Department of Veterinary Physiology, Biotherapy Human Resources Center (BK 21), College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Korea.
J Cell Physiol. 2010 Mar;222(3):574-85. doi: 10.1002/jcp.21973.
This study examined the role of arachidonic acid (AA) in hypoxia-induced production of interleukin (IL)-6 and its related signaling pathways in mouse embryonic stem (ES) cells. Hypoxia with AA induced IL-6 production, which was mediated by reactive oxygen species (ROS). In addition, hypoxia increased the levels of p38 mitogen-activated protein kinases (MAPKs) and stress-activated protein kinase/c-jun NH(2)-terminal kinase (SAPK/JNK) phosphorylation, which were blocked by antioxidant (vitamin C). Inhibition of p38 MAPK and SAPK/JNK blocked hypoxia- or hypoxia with AA-induced nuclear factor-kappa B (NF-kappaB) activation. Furthermore, hypoxia-induced increase in hypoxia-inducible factor-1alpha (HIF-1alpha) expression was regulated by NF-kappaB activation. Consequently, the increased HIF-1alpha expression induced activation of matrix metalloproteinase (MMP)-2 and MMP-9. The expression of each signaling molecule stimulated an increase in IL-6 production that was greater in hypoxic conditions with AA than with hypoxia alone. Finally, inhibition of IL-6 production using IL-6 antibody or soluble IL-6 receptor attenuated the hypoxia-induced increases in DNA synthesis of mouse ES cells. In conclusion, AA potentiates hypoxia-induced IL-6 production through the MAPKs, NF-kappaB, and HIF-1alpha pathways in mouse ES cells.
本研究探讨了花生四烯酸（AA）在缺氧诱导的小鼠胚胎干细胞（ES 细胞）白细胞介素（IL）-6 产生及其相关信号通路中的作用。AA 诱导的缺氧诱导了 IL-6 的产生，这是由活性氧（ROS）介导的。此外，缺氧增加了丝裂原活化蛋白激酶（MAPKs）和应激激活蛋白激酶/c-Jun NH（2）-末端激酶（SAPK/JNK）磷酸化水平，抗氧化剂（维生素 C）可阻断这一过程。抑制 p38 MAPK 和 SAPK/JNK 阻断了缺氧或缺氧加 AA 诱导的核因子-κB（NF-κB）激活。此外，缺氧诱导的缺氧诱导因子-1α（HIF-1α）表达增加受 NF-κB 激活调节。因此，增加的 HIF-1α表达诱导基质金属蛋白酶（MMP）-2 和 MMP-9 的激活。每个信号分子的表达刺激 IL-6 产生增加，在缺氧加 AA 的条件下比单独缺氧时增加更多。最后，使用 IL-6 抗体或可溶性 IL-6 受体抑制 IL-6 产生可减弱缺氧诱导的小鼠 ES 细胞 DNA 合成增加。总之，AA 通过 MAPKs、NF-κB 和 HIF-1α 途径增强了缺氧诱导的小鼠 ES 细胞中 IL-6 的产生。
