EVIDENCE THAT GLIOTOXIN ENHANCES LYMPHOCYTE-ACTIVATION AND INDUCES APOPTOSIS BY EFFECTS ON CYCLIC-AMP LEVELS

Gliotoxin is a secondary metabolite produced by several pathogenic fun gi. It has potential clinical applications as an immunosuppressive age nt 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 i n its own right, enhances activation in preactivated splenocytes by a calcium-independent mechanism. The enhancement in activation correlate s with a decrease in intracellular cyclic AMP levels. This property is inhibited by dibutyryl-cAMP. Increasing the concentration of gliotoxi n 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 .