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Infection and Immunity, October 2008, p. 4783-4791, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.01612-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cytolethal Distending Toxin Induces Caspase-Dependent and -Independent Cell Death in MOLT-4 Cells {triangledown}

Masaru Ohara,1* Tomonori Hayashi,2 Yoichiro Kusunoki,2 Kei Nakachi,2 Tamaki Fujiwara,1 Hitoshi Komatsuzawa,1 and Motoyuki Sugai1

Department of Bacteriology, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan,1 Department of Radiobiology and Molecular Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima, Hiroshima 732-0815, Japan2

Received 6 December 2007/ Returned for modification 28 April 2008/ Accepted 7 July 2008

Cytolethal distending toxin (CDT) induces apoptosis using the caspase-dependent classical pathway in the majority of human leukemic T cells (MOLT-4). However, we found the process to cell death is only partially inhibited by pretreatment of the cells with a general caspase inhibitor, z-VAD-fmk. Flow cytometric analysis using annexin V and propidium iodide showed that a 48-h CDT treatment decreased the living cell population by 35% even in the presence of z-VAD-fmk. z-VAD-fmk completely inhibited caspase activity in 24 h CDT-intoxicated cells. Further, CDT with z-VAD-fmk treatment clearly increased the cell population that had a low level of intracellular reactive oxygen. This is a characteristic opposite to that of caspase-dependent apoptosis. Overexpression of bcl2 almost completely inhibited cell death using CDT treatment in the presence of z-VAD-fmk. The data suggest there are at least two different pathways used in CDT-induced cell death: conventional caspase-dependent (early) apoptotic cell death and caspase-independent (late) death. Both occur via the mitochondrial membrane disruption pathway.

* Corresponding author. Mailing address: Department of Bacteriology, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Minami-ku, Hiroshima, Hiroshima 734-8553, Japan. Phone: (81) 82 257 5636. Fax: (81) 82 257 5639. E-mail: mohara{at}hiroshima-u.ac.jp

{triangledown} Published ahead of print on 21 July 2008.

Editor: V. J. DiRita

Infection and Immunity, October 2008, p. 4783-4791, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.01612-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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