Escherichia coli Shiga toxins induce apoptosis in epithelial cells that is regulated by the Bcl-2 family

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 278; no. 5; p. G811
• Main Authors: Jones, N L, Islur, A, Haq, R, Mascarenhas, M, Karmali, M A, Perdue, M H, Zanke, B W, Sherman, P M
• Format: Journal Article
• Language: English
• Published: United States 01-05-2000
• Subjects: Apoptosis - drug effects; Bacterial Toxins - toxicity; bcl-2-Associated X Protein; Cell Death - drug effects; Cysteine Proteinase Inhibitors - pharmacology; Enterotoxins - toxicity; Escherichia coli; Green Fluorescent Proteins; Humans; Intestinal Mucosa; Luminescent Proteins - analysis; Luminescent Proteins - genetics; Models, Biological; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Receptors, Cell Surface - physiology; Recombinant Proteins - biosynthesis; Shiga Toxins; Transfection; Trihexosylceramides - genetics; Trihexosylceramides - physiology; Tumor Cells, Cultured
• ISSN: 0193-1857
• DOI: 10.1152/ajpgi.2000.278.5.G811

Human intestinal cells lack globotriaosylceramide (Gb(3)), the receptor for Shiga toxin-1 (Stx1) and Shiga toxin-2 (Stx2). Therefore, the role of these toxins in mediating intestinal disease during infection with Shiga toxin-producing Escherichia coli is unclear. The aims of this study were to determine whether Stx1 and Stx2 induce apoptosis in epithelial cells expressing (HEp-2, Caco-2) or lacking (T84) Gb(3) and to characterize the role of the Bcl-2 family. Stx1 (12.5 ng/ml) induced apoptosis in both HEp-2 (21.9 +/- 7.9% vs. 0.8 +/- 0.3%, P = 0.01) and Caco-2 (10.1 +/- 1.2% vs. 3.1 +/- 0.4%, P = 0.006) cells but not in Gb(3)-deficient T84 cells. Toxin-mediated apoptosis of HEp-2 cells was associated with enhanced expression of the proapoptotic protein Bax. Inhibition of caspase activation prevented toxin-stimulated apoptosis. In addition, overexpression of Bcl-2 by transient transfection blocked Stx1-stimulated cell death. These findings indicate that Shiga toxins produced by E. coli signal Gb(3)-expressing epithelial cells to undergo apoptosis in association with enhanced Bax expression, thereby resulting in activation of the caspase cascade.