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Evidence that gliotoxin enhances lymphocyte activation and induces apoptosis by effects on cyclic AMP levels
1Division of Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra ACT, Australia.
Abstract:
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.
Insights
Gliotoxin enhances immune cell activation by reducing cyclic AMP (cAMP) levels, a mechanism potentially linked to its ability to induce apoptosis at higher concentrations. This finding offers insights into gliotoxin
Area of Science:
- Immunology
- Mycology
- Cell Biology
Background:
- Gliotoxin, a fungal metabolite, has immunosuppressive potential for preventing allograft rejection.
- At low doses, gliotoxin is co-mitogenic, while higher doses induce apoptosis.
- The precise mechanisms underlying gliotoxin's immunomodulatory effects are not fully understood.
Purpose of the Study:
- To investigate the mechanism by which gliotoxin enhances splenocyte activation.
- To explore the role of intracellular cyclic AMP (cAMP) in gliotoxin's effects on immune cells.
- To determine if cAMP levels mediate both gliotoxin-induced cell activation and apoptosis.
Main Methods:
- Treatment of preactivated splenocytes with varying concentrations of gliotoxin.
- Assessment of splenocyte activation and intracellular cAMP levels.
- Evaluation of the effect of dibutyryl-cAMP on gliotoxin-induced activation.
Main Results:
- Gliotoxin enhanced activation in preactivated splenocytes via a calcium-independent pathway.
- This enhancement correlated with a decrease in intracellular cAMP levels.
- Higher gliotoxin concentrations, inducing apoptosis, showed a dose-related increase in cAMP.
Conclusions:
- Gliotoxin modulates immune cell activation through a mechanism involving changes in cAMP levels.
- Altered cAMP levels may be a common mediator for both gliotoxin's co-mitogenic and apoptotic effects.
- Further research into cAMP signaling could elucidate gliotoxin's therapeutic potential in transplantation.