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Infection and Immunity, February 2004, p. 871-879, Vol. 72, No. 2
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.2.871-879.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Caspase-2 and Caspase-7 Are Involved in Cytolethal Distending Toxin-Induced Apoptosis in Jurkat and MOLT-4 T-Cell Lines

Masaru Ohara,1 Tomonori Hayashi,2 Yoichiro Kusunoki,2 Mutsumi Miyauchi,3 Takashi Takata,3 and Motoyuki Sugai1*

Departments of Bacteriology,1 Oral Maxillofacial Pathology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8553,3 Department of Radiobiology and Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan2

Received 20 May 2003/ Returned for modification 12 August 2003/ Accepted 22 October 2003

Cytolethal distending toxin (CDT) from Actinobacillus actinomycetemcomitans is a G2/M cell-cycle-specific growth-inhibitory toxin that leads to target cell distension followed by cell death. To determine the mechanisms by which A. actinomycetemcomitans CDT acts as an immunosuppressive factor, we examined the effects of highly purified CDT holotoxin on human T lymphocytes. Purified CDT was cytolethal toward normal peripheral T lymphocytes that were activated by in vitro stimulation with phytohemagglutinin. In addition, purified CDT showed cytolethal activity against Jurkat and MOLT-4 cells, which are known to be sensitive and resistant, respectively, to Fas-mediated apoptosis. Death in these cell lines was accompanied by the biochemical features of apoptosis, including membrane conformational changes, intranucleosomal DNA cleavage, and an increase in caspase activity in the cells. Pretreatment of Jurkat cells with the general caspase inhibitor z-VAD-fmk mostly suppressed CDT-induced apoptosis. Furthermore, specific inhibitors of caspase-2 and -7 showed significant inhibitory effects on CDT-induced apoptosis in Jurkat cells, and these inhibitory effects were fully associated with reduced activity of caspase-2 or -7 in the CDT-treated Jurkat cells. These results strongly suggest that CDT possesses the ability to induce human T-cell apoptosis through activation of caspase-2 and -7.

* 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 5635. Fax: (81) 82 257 5639. E-mail: sugai{at}hiroshima-u.ac.jp.

Editor: V. J. DiRita

Infection and Immunity, February 2004, p. 871-879, Vol. 72, No. 2
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.2.871-879.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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