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 CD# 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 some 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.
Baumann
C A
CA
Department of Biochemistry and Molecular Biology, George Washington University, School of Medicine and Health Sciences, Washington, D.C. 20037, USA.
Badamchian
M
M
Goldstein
A L
AL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D017252:CD3 Complex / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism*; D003907:Dexamethasone / Q000037:antagonists & inhibitors*; D005609:Free Radicals; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism*; D015290:Second Messenger Systems; D000077596:Thymalfasin; D013947:Thymosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D005609:Free Radicals; D013947:Thymosin; D003907:Dexamethasone; D006861:Hydrogen Peroxide; D000242:Cyclic AMP; D011493:Protein Kinase C; D000077596:Thymalfasin