The membrane attack complex of complement induces caspase activation and apoptosis.
Activation of the terminal pathway of the complement system leads to insertion of terminal complement complexes (C5b-9) into the cell membrane, which may induce cytolysis. Recent data indicate that the terminal complement pathway can also result in apoptosis in vivo. To further define the cell death pathway induced by complement, we examined induction of apoptosis by complement in vitro. Rat mesangial cells opsonized with a complement-activating antibody and exposed to rat serum as a complement source underwent apoptotic cell death in a time- and dose-dependent fashion, as demonstrated by membrane exposure of phosphatidylserine and fragmentation of nuclei. No significant apoptosis was detected in either cultures treated with C6-deficient serum or in control cultures. The pan-caspase-inhibitor zVAD-fmk inhibited complement-induced apoptosis completely. In line with this observation, complement induced cleavage and activation of caspase 3. Importantly, cellular exposure to purified cytolytically inactive C5b-9, in the absence of antibody and early complement components, also resulted into caspase activation and apoptosis. Together, these results indicate that C5b-9 is involved in induction of apoptosis via a caspase-dependent pathway. Apoptosis as a consequence of complement-mediated cell damage may provide an explanation for the presence of apoptosis in inflammatory processes, for instance in hyperacute xenograft rejection.
Nauta
Alma J
AJ
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands. nauta@LUMC.nl
Daha
Mohamed R
MR
Tijsma
Odette
O
van de Water
Bob
B
Tedesco
Francesco
F
Roos
Anja
A
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D003167:Complement Activation; D015938:Complement Membrane Attack Complex / Q000494:pharmacology / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D004789:Enzyme Activation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology; D009895:Opsonin Proteins / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D015938:Complement Membrane Attack Complex; D015853:Cysteine Proteinase Inhibitors; D009895:Opsonin Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases