Interleukin-1 beta and reactive oxygen species mediate activation of c-Jun NH2-terminal kinases, in human epithelial cells, by two independent pathways.
The c-Jun N terminal kinases (JNKs) are members of the mitogen activated protein kinases family, which have been shown to be preferentially activated either by cytokines or stress stimuli. In this study we identify a selective and potent antisense oligonucleotide to RhoA (ISIS 17131) and investigate its effect on JNK activation induced by IL-1beta and H2O2 in A549 cells. The RhoA antisense oligonucleotide was able to inhibit JNK activation when A549 cells were stimulated by H2O2, but did not have any effect on IL-1beta induced JNK activation. Consistent with the idea that the phosphatidylinositol 3-kinase (PI 3-kinase) activates the small G protein exchange factors, H2O2 activated the PI 3-kinase. Additionally, Wortmannin, a potent inhibitor of the PI 3-kinase and phospholipase A2 (PLA2), and AACOCF3, also a PLA2 inhibitor, were able to inhibit JNK activation induced by H2O2, but they had no effect on JNK activation when stimulated by IL-1beta. These results suggest that, in A549, IL-1beta and H2O2 induce JNK activation by two independent pathways.
Roberts
M L
ML
Department of Molecular Pharmacology, ISIS Pharmaceuticals, 2280 Faraday Avenue, Carlsbad, California, 92008, USA.
Cowsert
L M
LM
D000730:Androstadienes / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002277:Carcinoma; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D008175:Lung Neoplasms; D020928:Mitogen-Activated Protein Kinases; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D000077191:Wortmannin; D020742:rhoA GTP-Binding Protein
D000730:Androstadienes; D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C081565:arachidonyltrifluoromethane; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000077191:Wortmannin