The effect of a ceramide analog, N-acetylsphingosine on the induction of proliferation and IL-2 synthesis in T cells from young and old F344 rats.
Ceramide is a physiological mediator of extracellular signals that control various cellular functions, including proliferation and apoptosis. In the present study, we examined the effects of cell-permeable ceramide analog, N-acetyl-sphingosine (C(2)-ceramide) on the induction of proliferation and interleukin-2 (IL-2) synthesis in T cells from young and old rats. Splenic T cells from 6- and 24-month-old Fischer 344 rats were treated with C(2)-ceramide and then incubated with anti-CD3 antibody for 24 or 48 h. The induction of proliferation and IL-2 production by anti-CD3 was significantly (P<0.001) lower in T cells from old rats compared to T cells from young rats. C(2)-ceramide treatment resulted in suppression of proliferation and IL-2 production in a concentration-dependent manner. The suppressive effect of C(2)-ceramide on proliferation and IL-2 production was greater in T cells from old rats than T cells from young rats. We investigated whether this decreased responsiveness was due to induction of program cell death (apoptosis) and found that there was a significant increase in DNA fragmentation in C(2)-ceramide treated and anti-CD3 stimulated T cells from both young and old rats. The increase in DNA fragmentation was paralleled with an increase in caspase-3 activation. C(2)-ceramide-induced caspase-3 activation and DNA fragmentation was significantly (P<0.5) higher in stimulated T cells from old rats compared to stimulated T cells from young rats. These results suggest that the sphingomyelin-ceramide signaling pathway may play an important regulatory role in the well-documented age-related decline in immune function.
Pahlavani
M A
MA
Geriatric Research, Education, and Clinical Center (GRECC) 182, South Texas Veterans Health Care System, Audie L. Murphy Veterans Hospital, 7400 Merton Minter Blvd., San Antonio, TX 78284, USA. pahlavani@uthscsa.edu
Vargas
D M
DM
D000375:Aging / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; C064769:N-acetylsphingosine; D013110:Sphingosine