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1 Division of Cell Biology and Biochemistry, Department of Basic Medical Sciences, The Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
2 Division of Bacterial Infection, Department of Microbiology and Immunology, The Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Correspondence
Takashi Nonaka
Shinobu Imajoh-Ohmi
nonakat{at}prit.go.jp
ohmi{at}ims.u-tokyo.ac.jp
It is currently unclear whether Shigella kills its phagocytic host cells by apoptosis or necrosis. This study shows that rapid necrosis ensues in macrophage-like cell lines (U937 cells differentiated by all-trans-retinoic acid and J774 cells) infected with the Shigella flexneri strain YSH6000. The infected cells rapidly lose membrane integrity, a typical feature of necrosis, as indicated by the release of the cytoplasmic lactate dehydrogenase and the exposure of phosphatidylserine (PS) associated with the rapid uptake of propidium iodide (PI). The infected cells exhibit DNA fragmentation without nuclear condensation, and substantial involvement of either caspase-3/-7 or caspase-1 was not detected, which is also contrary to what is normally observed in apoptosis. Cytochalasin D potently inhibited Shigella-induced cell death, indicating that only internalized Shigella can cause necrosis. Osmoprotectants such as polyethylene glycols could suppress cell death, suggesting that insertion of a pore by Shigella into the host cell membrane induces the necrosis. The pore was estimated to be 2·87±0·4 nm in diameter. Shigella was also found to be able to induce apoptosis but only in one of the lines tested and under specific conditions, namely U937 cells differentiated with interferon-
(U937IFN). Caspase-3/-7 but not caspase-1 activation was observed in these infected cells and the exposure of PS occurred without the uptake of PI. An avirulent Shigella strain, wild-type Shigella killed with gentamicin, and even Escherichia coli strain JM109, could also induce apoptosis in U937IFN cells, and cytochalasin D could not prevent apoptosis. It appears therefore that Shigella-induced apoptosis of U937IFN cells is unrelated to Shigella pathogenicity and does not require bacterial internalization. Thus, Shigella can induce rapid necrosis of macrophage-like cells in a virulence-related manner by forming pores in the host cell membrane while some cells can be killed through apoptosis in a virulence-independent fashion.
; PARP, poly(ADP-ribose) polymerase; PI, propidium iodide; PS, phosphatidylserine; RA, all-trans retinoic acid; RBC, red blood cell; stsp, staurosporine; TBS, Tris-buffered saline; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling; Z-VAD-fmk, carbobenzoxy-Val-Ala-Asp-fluoromethylketone
Present address: Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2-1-8, Kamikitazawa, Setagaya-ku, Tokyo, 156-8585, Japan.
Present address: Laboratory of Bacterial Infection, Kitasato Institute for Life Sciences, Kitasato University and the Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan.
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