Inhibitors of membrane lipid metabolism enhance complement-mediated nucleated cell killing through distinct mechanisms.
The ability of nucleated cells to survive limited complement attack has been attributed to metabolic processes unique to these cells, such as rapid elimination of terminal complement complexes (TCC) from their surfaces. The biochemical processes activated by complement channels responsible for cell defense remain poorly defined. Metabolic inhibitors affecting membrane lipid turnover have been shown to increase the complement-mediated cell death. Whether these metabolic inhibitors increase lytic susceptibility of target cells by reducing the rate of TCC elimination has not been previously evaluated. In the present study, inhibitors of membrane lipid transmethylation and lysolecithin reacylation were evaluated in view of the observations that TCC concurrently increase lipid transmethylation and inhibit lysolecithin reacylation, and the inhibition of lipid transmethylation correlates with increased complement-mediated cell death. We have measured the formation as well as the elimination of C5b-9 on the target membrane that affect the outcome of cell death. Our results in the present communication indicated that inhibitors of transmethylation and lysolecithin reacylation increased TCC-mediated cell death through distinct pathways, the former by allowing more efficient deposition of TCC, and the latter by impairing TCC elimination.
Papadimitriou
J C
JC
Department of Pathology, University of Maryland, School of Medicine, Baltimore.
Carney
D F
DF
Shin
M L
ML
D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000187:drug effects; D000215:Acylation / Q000187:drug effects; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000276:immunology; D003186:Complement C9 / Q000378:metabolism; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins / Q000187:drug effects / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D006710:Homocysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis; D008563:Membrane Lipids / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D051379:Mice; D013849:Thimerosal / Q000494:pharmacology
D003186:Complement C9; D015938:Complement Membrane Attack Complex; D007166:Immunosuppressive Agents; D008563:Membrane Lipids; C042295:complement C5b-8 complex; D006710:Homocysteine; D013849:Thimerosal; C010192:9-(2-hydroxy-3-nonyl)adenine; D000255:Adenosine Triphosphate; D003165:Complement System Proteins; C007957:homocysteine thiolactone; D007770:L-Lactate Dehydrogenase; D008243:1-Acylglycerophosphocholine O-Acyltransferase; D000225:Adenine; D000241:Adenosine