Interleukin-1β 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-1β and H2O2in 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-1β induced JNK activation. Consistent with the idea that the phosphatidylinositol 3-kinase (PI 3-kinase) activates the small G protein exchange factors, H2O2activated the PI 3-kinase. Additionally, Wortmannin, a potent inhibitor of the PI 3-kinase and phospholipase A2(PLA2), and AACOCF3, also a PLA2inhibitor, were able to inhibit JNK activation induced by H2O2, but they had no effect on JNK activation when stimulated by IL-1β. These results suggest that, in A549, IL-1β and H2O2induce JNK activation by two independent pathways.