A novel caspase dependent pathway is involved in apoptosis of human endothelial cells by Shiga toxins.
Shiga toxins have been shown to induce apoptosis on primary cultures, but not passaged ones, of human umbilical vein endothelial cells, independent of cytokine pre-treatment. Here, a peculiar pattern of caspase activation was observed; caspase-3 and -2, but not conventional upstream caspases, were activated at the initial phase of 6 hr, whereas a broad range inhibitor of caspases, VAD-fmk, but not mono-specific ones, suppressed DNA fragmentation and cell death. These results suggest additional analogous molecules, which have yet to be delineated, are involved. The requirement of retrograde uptake of toxins was also proved by the intervening effect of brefeldin A.
Yoshida
Tomoaki
T
Department of Microbiology and Immunology, Aichi Medical University, Aichi 480-1195, Japan. Tomo@aichi-med-u.ac.jp
Koide
Naoki
N
Sugiyama
Tsuyoshi
T
Mori
Isamu
I
Yokochi
Takashi
T
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020126:Brefeldin A / Q000494:pharmacology; D053143:Caspase 2; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D022603:Shiga Toxins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D011500:Protein Synthesis Inhibitors; D022603:Shiga Toxins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020126:Brefeldin A; C505407:CASP3 protein, human; D053143:Caspase 2; D053148:Caspase 3; D020169:Caspases