THYMOSIN ALPHA(1) ANTAGONIZES DEXAMETHASONE AND CD3-INDUCED APOPTOSISOF CD4(-KINASE-C DEPENDENT 2ND-MESSENGER PATHWAYS()CD8(+) THYMOCYTES THROUGH THE ACTIVATION OF CAMP AND PROTEIN)

It is well established that glucocorticoid hormones and anti-CD3 monoc lonal antibodies induce apoptosis in immature developing thymocytes. T his process can be modulated by soluble factors, anti-oxidants and adh esion 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 th e mechanism of T alpha(1) action we determined a T alpha(1) sensitive thymocyte population and examined same of the molecular events associa ted with T alpha(1) anti-apoptotic activity. Phenotypic analysis of th e sub-populations of thymocytes, based on CD4 and CD8 expression, reve aled that T alpha(1) exerts its effect on CD4(+) CD8(+) immature thymo cytes. T alpha(1) treatment of thymocytes delays the production of fre e radicals and the subsequent consumption of glutathione, that is obse rved during both DEX and CD3 induced apoptosis. We further demonstrate that T alpha(1) stimulates the production of cAMP and activates PKC i n thymocytes. These data suggest that T alpha(1) exerts an influence o n the development of a population of immature T-cells in the thymus by effecting the sensitivity of thymocytes to apoptosis during the pre-s election stages of thymic development. Our studies also suggest that t he mechanism of T alpha(1) action involves the induction of both cAMP and PKC dependent second messenger pathways. (C) 1997 Elsevier Science Ireland Ltd.