Thymosin alpha(1) antagonizes dexamethasone and CD3-induced apoptosis of CD4(+)CD8(+) thymocytes through the activation of cAMP and protein kinase C dependent second messenger pathways

It is well established that glucocorticoid hormones and anti-CD3 monoclonal antibodies induce apoptosis in immature developing thymocytes. This process can be modulated by soluble factors, anti-oxidants and adhesion receptors. Previously we have demonstrated that thymosin alpha(1) (T alpha(1)), a 28-amino acid thymic peptide hormone, is a dose and time dependent antagonist of dexamethasone (DEX) and CD3 induced DNA. fragmentation of murine thymocytes in vitro. To further investigate the mechanism of T alpha(1) action we determined a T alpha(1) sensitive thymocyte population and examined same of the molecular events associated with T alpha(1) anti-apoptotic activity. Phenotypic analysis of the sub-populations of thymocytes, based on CD4 and CD8 expression, revealed that T alpha(1) exerts its effect on CD4(+) CD8(+) immature thymocytes. T alpha(1) treatment of thymocytes delays the production of free radicals and the subsequent consumption of glutathione, that is observed during both DEX and CD3 induced apoptosis. We further demonstrate that T alpha(1) stimulates the production of cAMP and activates PKC in thymocytes. These data suggest that T alpha(1) exerts an influence on the development of a population of immature T-cells in the thymus by effecting the sensitivity of thymocytes to apoptosis during the pre-selection stages of thymic development. Our studies also suggest that the mechanism of T alpha(1) action involves the induction of both cAMP and PKC dependent second messenger pathways. (C) 1997 Elsevier Science Ireland Ltd.