Dissociation of phagocyte recognition of cells undergoing apoptosis from other features of the apoptotic program.
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 gain in vivo.
Zhuang
J
J
Medical Research Council Toxicology Unit, Centre for Mechanisms of Human Toxicity, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LEI 9HN, United Kingdom.
Ren
Y
Y
Snowden
R T
RT
Zhu
H
H
Gogvadze
V
V
Savill
J S
JS
Cohen
G M
GM
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009840:Oligomycins / Q000494:pharmacology; D010586:Phagocytes / Q000187:drug effects / Q000276:immunology*; D010718:Phosphatidylserines / Q000378:metabolism; D013499:Surface Properties; D014407:Tumor Cells, Cultured
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D009840:Oligomycins; D010718:Phosphatidylserines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000968:Antimycin A; D003546:Cysteine Endopeptidases