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(Journal of Leukocyte Biology. 2000;68:87-96.)
© 2000 by Society for Leukocyte Biology

Oxidative stress as a necessary factor in room temperature-induced apoptosis of HL-60 cells

Mari Shimura^*, Yutaka Osawa, Akira Yuo, Kiyohiko Hatake, Fumimaro Takaku and Yukihito Ishizaka^*

Departments of
^* Intractable Diseases and
Hematology, International Medical Center of Japan, Tokyo;
Department of Neurology, Neurological Institute, Tokyo Women’s Medical University, Tokyo; and
Jichi Medical School, Tochigi, Japan

Correspondence: Yukihito Ishizaka, Dept. of Intractable Diseases, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. E-mail: zakay{at}ri.imcj.go.jp

HL-60 cells undergo apoptosis when placed at room temperature (RT) [Shimura et al. (1997) FEBS Lett. 417, 379–384]. We report that superoxide anion radical, one of the reactive oxygen species (ROS), was produced after RT treatment. Affinity blot analysis with a biotinylated YVAD-CHO detected the generation of processed peptides with molecular masses of 15–25 kDa. Activation of such an ICE-like protease was completely abolished by N-acetylcysteine and exogenously expressed Bcl-2, known as antioxidants. We concluded that oxidative stress was a critical factor in the signal cascade of the apoptosis. Western blot analysis and experiments using tetrapeptide inhibitors suggested that caspases-1, -3, -4, -6, and -9 did not have an essential role in the apoptotic cascade. It is interesting that cyclosporin A (CsA) blocked RT-induced apoptosis with an inhibition of cytochrome c release from mitochondria. CsA, however, generated a significant amount of ROS with considerable reduction of mitochondrial membrane potential, implying that oxidative stress was one necessary factor for RT-induced apoptosis. It is also likely that mitochondrial membrane potential and the release of apoptotic factors from cytoplasm are differently regulated. Taken together with the reports that some Burkitt lymphoma cells showed apoptosis when exposed at low temperature followed by rewarming, and that hepatocytes or liver endothelial cells are susceptible to cold-induced apoptosis through the ROS function, we propose that studying the mechanism of RT-induced apoptosis of HL-60 cells may provide a therapeutic strategy for pathological conditions involving ROS, such as neurodegenerative diseases and ischemia.

Key Words: reactive oxygen species • YVAD-tagged peptide • permeability transition

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