Induction of programmed cell death and immunosuppression by exogenous sphingolipids are separate processes.
Gangliosides are highly immunosuppressive molecules but the mechanism(s) by which they act upon cells remains to be fully defined. Several metabolic products of exogenous gangliosides, including ceramide, have recently been suggested as second messengers in programmed cell death (PCD). Therefore, we have probed the role of gangliosides and ceramides in the induction of PCD and in the inhibition of in vitro lymphoproliferation. PCD was caused only by exogenous ceramides with short fatty acyl groups-d18:1-C2:0 (C2-ceramide, where d18:1 is sphingosine and C2:O is an acetyl group) and d18:1-C6:0 (C6-ceramide, where C6:O is a hexanoyl group). None of the gangliosides studied induced PCD, including naturally occurring GM3, synthetic d18:1-C18:0 GM3 (C18-Cer GM3, where C18:0 is a stearoyl group), or even d18:1-C2:0 GM3 (C2-Cer GM3), which itself contains a PCD-causing ceramide. However, these gangliosides were highly immunosuppressive, inhibiting antigen-induced lymphoproliferation at micromolar concentrations. We conclude that exogenous sphingolipids cause inhibition of lymphoproliferation and PCD by two separate and distinct mechanisms of action.
Center for Cancer and Transplantation Biology, Children's National Medical Center, George Washington University School of Medicine, Washington, DC 20010-2970, USA.
R
R
Olshefski
B
B
Taylor
A
A
Heitger
A
A
Hasegawa
S
S
Ladisch
D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002518:Ceramides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004587:Electrophoresis, Agar Gel; D005434:Flow Cytometry; D005732:Gangliosides / Q000494:pharmacology; D006801:Humans; D007165:Immunosuppression Therapy; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism / Q000494:pharmacology*; D013745:Tetanus Toxoid / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D002518:Ceramides; D005732:Gangliosides; D013107:Sphingolipids; D013745:Tetanus Toxoid