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.
Lee
Sang Hun
SH
Department of Veterinary Physiology, Biotherapy Human Resources Center (BK 21), College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Korea.
Lee
Yu Jin
YJ
Han
Ho Jae
HJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000975:Antioxidants; D018797:Cell Cycle Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D011480:Protease Inhibitors; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D016718:Arachidonic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse