Evidence that gliotoxin enhances lymphocyte activation and induces apoptosis by effects on cyclic AMP levels.
Gliotoxin is a secondary metabolite produced by several pathogenic fungi. It has potential clinical applications as an immunosuppressive agent in preventing allograft rejection. At low doses (< 30 nM) gliotoxin displays co-mitogenic activity, but at higher doses induces apoptosis in cells. Here we demonstrate that gliotoxin, although not mitogenic in its own right, enhances activation in preactivated splenocytes by a calcium-independent mechanism. The enhancement in activation correlates with a decrease in intracellular cyclic AMP levels. This property is inhibited by dibutyryl-cAMP. Increasing the concentration of gliotoxin to levels that caused apoptosis produced a dose-related increase in cAMP levels. Thus, the effects of gliotoxin on cell activation and the induction of apoptosis may both be mediated by changed levels of cAMP.
Sutton
P
P
Division of Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra ACT, Australia.
Beaver
J
J
Waring
P
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000032:analysis*; D004247:DNA / Q000096:biosynthesis; D005912:Gliotoxin / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008808:Mice, Inbred CBA; D013154:Spleen / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology; D013997:Time Factors
D007166:Immunosuppressive Agents; D005912:Gliotoxin; D004247:DNA; D013806:Theophylline; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium