C5b-9 terminal complex protects oligodendrocytes from apoptotic cell death by inhibiting caspase-8 processing and up-regulating FLIP.
Activation of the terminal complement cascade involving C5 to C9 proteins has a beneficial role for oligodendrocytes (OLG) in experimental allergic encephalomyelitis, an animal model of multiple sclerosis, by protecting them from apoptotic cell death. We have previously shown that sublytic C5b-9 complexes, through posttranslational regulation of Bad, inhibit the mitochondrial pathway of apoptosis induced by serum deprivation. In the present study, we examined the possible involvement of the caspase-8 and Fas pathway in OLG apoptosis and the role of C5b-9 in this process. In a serum-free defined medium, OLG undergo apoptosis and differentiation concomitantly. Under this condition, we found that caspase-8 processing was increased in association with Bid cleavage and markedly reduced expression of cellular FLIP long isoform protein. The caspase-8 inhibitor Z-IETD-FMK inhibited cell death associated with differentiation in a dose-dependent manner. Exposure to C5b-9 induced an inhibition of caspase-8 activation, Bid cleavage, and a significant increase in expression of cellular FLIP long isoform. These C5b-9 effects were reversed by PI3K inhibitor LY294002. C5b-9 also down-regulated the expression of FasL and the Fas-induced apoptosis. These data suggest that C5b-9 through PI3K signaling can rescue OLG from Fas-mediated apoptosis by regulating caspase-8 processing.
Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Cornelia
C
Cudrici
Florin
F
Niculescu
Timothy
T
Jensen
Ekaterina
E
Zafranskaia
Matthew
M
Fosbrink
Violeta
V
Rus
Moon L
ML
Shin
Horea
H
Rus
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000276:immunology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D015938:Complement Membrane Attack Complex / Q000502:physiology*; D053418:Death Domain Receptor Signaling Adaptor Proteins; D015536:Down-Regulation / Q000502:physiology; D053222:Fas Ligand Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D009836:Oligodendroglia / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000276:immunology*
D051023:BH3 Interacting Domain Death Agonist Protein; C494816:Bid protein, rat; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D061945:Caspase Inhibitors; D015938:Complement Membrane Attack Complex; D053418:Death Domain Receptor Signaling Adaptor Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D048069:Tumor Necrosis Factors; C505530:CASP8 protein, human; C505528:Casp8 protein, rat; D053181:Caspase 8; D020169:Caspases