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Infection and Immunity, March 2007, p. 1291-1302, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01700-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Simultaneous Induction of Apoptotic and Survival Signaling Pathways in Macrophage-Like THP-1 Cells by Shiga Toxin 1{triangledown}

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

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

Received 24 October 2006/ Returned for modification 28 November 2006/ Accepted 14 December 2006

Shiga toxins have been shown to induce apoptosis in many cell types. However, Shiga toxin 1 (Stx1) induced only limited apoptosis of macrophage-like THP-1 cells in vitro. The mechanisms regulating macrophage death or survival following toxin challenge are unknown. Differentiated THP-1 cells expressed tumor necrosis factor receptors and membrane-associated tumor necrosis factor alpha (TNF-{alpha}) and produced soluble TNF-{alpha} after exposure to Stx1. However, the cells were refractory to apoptosis induced by TNF-{alpha}, although the cytokine modestly increased apoptosis in the presence of Stx1. Despite the partial resistance of macrophage-like THP-1 cells to Stx1-mediated killing, treatment of these cells with Stx1 activated a broad array of caspases, disrupted the mitochondrial membrane potential ({Delta}{Psi}m), and released cytochrome c into the cytoplasm. The {Delta}{Psi}m values were greatest in cells that had detached from plastic surfaces. Specific caspase inhibitors revealed that caspase-3, caspase-6, caspase-8, and caspase-9 were primarily involved in apoptosis induction. The antiapoptotic factors involved in macrophage survival following toxin challenge include inhibitors of apoptosis proteins and X-linked inhibitor of apoptosis protein. NF-{kappa}B and JNK mitogen-activated protein kinases (MAPKs) appeared to activate survival pathways, while p38 MAPK was involved in proapoptotic signaling. The JNK and p38 MAPKs were shown to be upstream signaling pathways which may regulate caspase activation. Finally, the protein synthesis inhibitors Stx1 and anisomycin triggered limited apoptosis and prolonged JNK and p38 MAPK activation, while macrophage-like cells treated with cycloheximide remained viable and showed transient activation of MAPKs. Collectively, these data suggest that Stx1 activates both apoptotic and cell survival signaling pathways in macrophage-like THP-1 cells.

* Corresponding author. Mailing address: Department of Microbial and Molecular Pathogenesis, 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: tesh{at}medicine.tamhsc.edu.

{triangledown} Published ahead of print on 28 December 2006.

Editor: A. D. O'Brien

Infection and Immunity, March 2007, p. 1291-1302, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01700-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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