S-adenosylhomocysteine as a physiological modulator of Apo-1-mediated apoptosis.
APO-1/Fas (CD95) is a member of the tumor necrosis factor/nerve growth factor receptor superfamily and mediates apoptosis in various cell types. Here we show that L929 cells, expressing human APO-1 treated with agonistic antibodies (anti-APO-1), elicit an early and transient increase of S-adenosylhomocysteine (AdoHcy), a potent inhibitor of S-adenosylmethionine (AdoMet)-dependent methylation reactions. In contrast, anti-APO-1 did not induce an AdoHcy increase in L929-APO-1 Delta4 cells expressing a C-terminally truncated APO-1 lacking part of the 'death domain' known to be required for the transduction of apoptotic signals. Addition of adenosine and D, L-homocysteine also led to an increase of cellular AdoHcy thus enhancing anti-APO-1-induced killing of L929-APO-1 cells. Treatment with anti-APO-1 also induced release of arachidonic acid from phospholipids: this effect was augmented by elevated levels of AdoHcy. In contrast, AdoHcy had only a minor effect on anti-APO-1-mediated DNA fragmentation. These findings suggest that AdoHcy functions as a physiological modulator of APO-1-mediated cell death in L929 cells and enhances anti-APO-1-induced cell killing at least partially by acting via the phospholipase A2 pathway.
Ratter
F
F
Division of Immunochemistry, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany.
Germer
M
M
Fischbach
T
T
Schulze-Osthoff
K
K
Peter
M E
ME
Dröge
W
W
Krammer
P H
PH
Lehmann
V
V
D000241:Adenosine / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D007739:L Cells; D051379:Mice; D010741:Phospholipases A / Q000502:physiology; D054467:Phospholipases A2; D012435:S-Adenosylhomocysteine / Q000276:immunology*; D012436:S-Adenosylmethionine / Q000037:antagonists & inhibitors; D014162:Transfection / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000502:physiology*
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D019014:fas Receptor; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D010741:Phospholipases A; D054467:Phospholipases A2; D000241:Adenosine