Effect of arachidonic acid on hypoxia-induced IL-6 production in mouse ES cells: Involvement of MAPKs, NF-kappaB, and HIF-1alpha.

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.