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Infection and Immunity, August 2005, p. 5115-5126, Vol. 73, No. 8
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.8.5115-5126.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Shiga Toxin 1 Induces Apoptosis in the Human Myelogenous Leukemia Cell Line THP-1 by a Caspase-8-Dependent, Tumor Necrosis Factor Receptor-Independent Mechanism

Sang-Yun Lee,* Rama P. Cherla, Isa Caliskan, and Vernon L. Tesh

Department of Medical Microbiology and Immunology, Texas A&M University System Health Science Center, College Station, Texas

Received 7 February 2005/ Returned for modification 21 March 2005/ Accepted 6 April 2005

Shiga toxins (Stxs) induce apoptosis in a variety of cell types. Here, we show that Stx1 induces apoptosis in the undifferentiated myelogenous leukemia cell line THP-1 in the absence of tumor necrosis factor alpha (TNF-{alpha}) or death receptor (TNF receptor or Fas) expression. Caspase-8 and -3 inhibitors blocked, and caspase-6 and -9 inhibitors partially blocked, Stx1-induced apoptosis. Stx1 induced the mitochondrial pathway of apoptosis, as activation of caspase-8 triggered the (i) cleavage of Bid, (ii) disruption of mitochondrial membrane potential, and (iii) release of cytochrome c into the cytoplasm. Caspase-8, -9, and -3 cleavage and functional activities began 4 h after toxin exposure and peaked after 8 h of treatment. Caspase-6 may also contribute to Stx1-induced apoptosis by directly acting on caspase-8. It appears that functional Stx1 holotoxins must be transported to the endoplasmic reticulum to initiate apoptotic signaling through the ribotoxic stress response. These data suggest that Stxs may activate monocyte apoptosis via a novel caspase-8-dependent, death receptor-independent mechanism.

* Corresponding author. Mailing address: Department of Medical Microbiology and Immunology, Room 407, Reynolds Medical Building, Texas A&M University System Health Science Center, College Station, TX 77843-1114. Phone: (979) 845-1313. Fax: (979) 845-3479. E-mail: syunlee{at}medicine.tamu.edu.

Editor: A. D. O'Brien

Infection and Immunity, August 2005, p. 5115-5126, Vol. 73, No. 8
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.8.5115-5126.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Matsuura, G., Morinaga, N., Yahiro, K., Komine, R., Moss, J., Yoshida, H., Noda, M. (2009). Novel Subtilase Cytotoxin Produced by Shiga-Toxigenic Escherichia coli Induces Apoptosis in Vero Cells via Mitochondrial Membrane Damage. Infect. Immun. 77: 2919-2924 [Abstract] [Full Text]  
  • Jin, D., Ojcius, D. M., Sun, D., Dong, H., Luo, Y., Mao, Y., Yan, J. (2009). Leptospira interrogans Induces Apoptosis in Macrophages via Caspase-8- and Caspase-3-Dependent Pathways. Infect. Immun. 77: 799-809 [Abstract] [Full Text]  
  • Lee, S.-Y., Cherla, R. P., Tesh, V. L. (2007). Simultaneous Induction of Apoptotic and Survival Signaling Pathways in Macrophage-Like THP-1 Cells by Shiga Toxin 1. Infect. Immun. 75: 1291-1302 [Abstract] [Full Text]  


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