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Inhibition of c-Jun N-Terminal Kinase Pathway Improves Cell Viability in Response to Oxidant Injury

The CardioPulmonary Research Institute, Winthrop-University Hospital, SUNY at Stony Brook School of Medicine, Mineola, New York

Address correspondence to: Yuchi Li, Ph.D., The CardioPulmonary Research Institute, Winthrop-University Hospital, Suite 505, 222 Station Plaza N, Mineola, NY 11501. E-mail: liyuchi{at}hotmail.com

Oxidant insults can lead to apoptotic and nonapoptotic cell death. Lung epithelial cells exposed to high levels of oxygen do not die via apoptosis, but through a much slower, morphologically distinct process involving cell and nuclear swelling. In contrast, H₂O₂ induces a rapid apoptotic cell death. We first assessed the effect of oxidant exposure on activator protein-1 (c-Jun and Fos) and c-Jun N-terminal kinase (JNK) regulation in MLE12 cells. Both oxidants induced c-Jun and Fos expression, albeit with a different pattern of regulation—hyperoxia (95% O₂) induced a biphasic response, whereas H₂O₂ (500 µM) induced a sustained response. We then examined the role of JNK by Western blot, JNK activity assay, and a pull-down assay and observed an identical pattern of regulation. To assess whether JNK functions in a pro-death or pro-survival capacity, we generated stable cell lines that constitutively express a dominant-negative mutation of JNK resulting in significant inhibition of JNK activity. Inhibition of the JNK pathway in this manner prevented hyperoxic and H₂O₂-induced cell death. These results demonstrate that hyperoxic cell death is pathway-driven and that both modes of death involve the JNK signaling pathway.

Abbreviations: activator protein-1, AP-1 • digoxigenin-11-dUTP, DIG • c-Jun N-terminal kinase, JNK • murine lung epithelial cells, MLE12 cells • nuclear factor-B, NF-B • sodium dodecyl sulfate, SDS

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