Dissociation of Phagocyte Recognition of Cells Undergoing Apoptosis from Other Features of the Apoptotic Program*
- Jianguo Zhuang‡,
- Yi Ren§,
- Roger T. Snowden‡,
- Huijun Zhu‡,
- Vladimir Gogvadze‡¶,
- John S. Savill§ and
- Gerald M. Cohen‡‖
- From the ‡Medical Research Council Toxicology Unit, Centre for Mechanisms of Human Toxicity, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LEI 9HN and the§Division of Renal and Inflammatory Disease, Department of Medicine, University Hospital, Nottingham NG7 2UH, United Kingdom
Abstract
Apoptosis is a programmed form of cell death characterized by biochemical and morphological changes affecting the nucleus, cytoplasm, and plasma membrane. These changes in various cellular compartments are widely regarded as mechanistically linked events in a single “program” in which activation of caspases and proteolysis of intracellular substrates represent a final common pathway leading to cell death. To date there has been very limited exploration of the linkage of this program to the plasma membrane changes, which bring about swift recognition, uptake, and safe degradation of apoptotic cells by phagocytes. Using the mitochondrial inhibitors antimycin A and oligomycin in human monocytic THP.1 cells triggered into apoptosis, we report the uncoupling of plasma membrane changes from other features of apoptosis. These inhibitors blocked increased plasma membrane permeability, externalization of phosphatidylserine, and recognition by two classes of phagocytes but not activation of caspase-3, cleavage of poly(ADP-ribose) polymerase and DNA fragmentation. Externalization of phosphatidylserine in apoptotic human leukemic U937 cells was also dissociated from caspase activation. Thus changes governing safe clearance of apoptotic cells may be regulated by an independent pathway to those bringing about caspase activation. This finding could have important consequences for attempts to manipulate cell death for therapeutic gainin vivo.
Footnotes
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↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵¶ Supported by the European Science Foundation Program in Toxicology. Present address: Inst. of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino 142292 Russia.
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↵‖ To whom correspondence should be addressed: MRC Toxicology Unit, Centre for Mechanisms of Human Toxicity, University of Leicester, Hodgkin Bldg., P.O. Box 138, Lancaster Road, Leicester LEI 9HN, UK. Tel.: 44-116-252-5589; Fax: 44-116-252-5616; E-mail: gmc2{at}le.ac.uk.
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↵1 The abbreviations used are: PARP, poly(ADP-ribose) polymerase; TPCK,N-tosyl-l-phenylalanyl chloromethyl ketone; Z-VAD.FMK, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone; PS, phosphatidylserine; TSP, thrombospondin; TNF-α, tumor necrosis factor-α; AIF, apoptosis-inducing factor.
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- Received October 29, 1997.
- Revision received February 28, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
