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Infection and Immunity, December 2009, p. 5233-5244, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00665-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Bcl-2 Regulates the Onset of Shiga Toxin 1-Induced Apoptosis in THP-1 Cells {triangledown}

Moo-Seung Lee, Rama P. Cherla, Dinorah Leyva-Illades, and Vernon L. Tesh*

Department of Microbial and Molecular Pathogenesis, Texas A&M University System Health Science Center, College Station, Texas 77843-1114

Received 10 June 2009/ Returned for modification 7 July 2009/ Accepted 3 September 2009

Shiga toxins (Stxs), which are proteins expressed by the enteric pathogens Shigella dysenteriae serotype 1 and some serotypes of Escherichia coli, are potent protein synthesis inhibitors. Stx-producing organisms cause bloody diarrhea with the potential to progress to acute renal failure and central nervous system complications. Studies using animal models of these diseases have shown that Stxs are major virulence factors, and purified toxins have been shown to be capable of killing many types of cells in vitro. We showed that Stx type 1 (Stx1) rapidly induced apoptosis in undifferentiated, monocytic THP-1 cells through a mechanism involving the endoplasmic reticulum (ER) stress response. Rapid apoptosis correlated with increased expression of C/EBP homologous protein (CHOP), TRAIL, and DR5, while expression of the antiapoptotic factor Bcl-2 was downregulated. Stx1 treatment of differentiated, macrophage-like THP-1 cells was associated with cytokine production and delayed apoptosis. The mechanisms contributing to cell maturation-dependent differences in responses to Stx1 are unknown. We show here that in macrophage-like cells, Stx1 activated the proximal ER stress sensors RNA-dependent protein kinase-like ER kinase and inositol-requiring ER signal kinase 1{alpha} but did not activate activating transcription factor 6. Proapoptotic signaling pathways mediated by CHOP and by Bax and Bak were activated by Stx1. However, the toxin also activated prosurvival signaling through increased expression, mitochondrial translocation, and alternative phosphorylation of Bcl-2.

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

{triangledown} Published ahead of print on 14 September 2009.

Editor: B. A. McCormick

Infection and Immunity, December 2009, p. 5233-5244, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00665-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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