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Infect. Immun. doi:10.1128/IAI.01612-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Cytolethal distending toxin induces caspase-dependent and -independent cell death in MOLT-4 cells

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

^* To whom correspondence should be addressed. Email: mohara{at}hiroshima-u.ac.jp.

	Abstract

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 (PI) showed 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 an opposite characteristic of caspase-dependent apoptosis. Over-expression of bcl2 almost completely inhibited cell death using CDT treatment in the presence of z-VAD-fmk. The data suggests there are at least two different pathways used in CDT-induced cell death: the conventional caspase–dependent (early) apoptotic cell death and a caspase-independent (late) one, both are through the mitochondrial membrane disruption pathway.