Androgens indirectly accelerate thymocyte apoptosis.
Apoptotic processes, or the disturbance of the natural regulation of these processes, may be involved in the pathogenesis of autoimmune diseases (AID). Women are, in general, more susceptible than men to develop AID like rheumatoid arthritis. Androgens and glucocorticoids, in contrast to oestrogens, have favourable effects in AID models as well as in human AID. It is known that glucocorticoids (GC), used for treatment of AID, increase apoptosis in the thymus resulting in decreased numbers of CD4+ CD8+ thymocytes. It was asked whether androgens, in contrast to oestrogens, exert their favourable effects in the treatment of AID by a mechanism comparable to that described for GC by eliminating the apoptosis prone CD4+ CD8+ population in the thymus. Although both androgens and oestrogens proved thymolytic, a significantly decreased percentage of CD4+ CD8+ thymocytes was observed by flow cytometry after treatment of mice with the androgen methyltestosterone, but not with the oestrogen ethinylestradiol. To investigate whether the observed thymolytic effects were due to the presence of hormone receptors on thymocytes, cells were isolated from the thymus and incubated with androgens or oestrogens to measure apoptosis. Several techniques were used to determine thymocyte apoptosis in vitro, but no enhanced apoptotic signal was observed. Using the very sensitive TUNEL assay, no direct effect of androgens on thymocytes in vitro could be observed. This is in sharp contrast to the high signal observed with GC. Therefore, upon in vivo androgen treatment, other cells containing androgen receptors than thymocytes are probably involved in inducing the increase in thymic apoptosis. To study the role of the androgen receptor on thymocyte apoptosis, androgen receptor mutant (Tfm/Y) mice were treated with androgens. No alterations of thymocyte subpopulations were seen, suggesting that changes in the percentage of CD4+ CD8+ thymocytes after administration of androgens depend on the presence of functional androgen receptors. Thus, it is concluded that androgens indirectly accelerate thymocyte apoptosis in vivo.
Dulos
G J
GJ
Department of Pharmacology, N.V. Organon, Oss, The Netherlands. G.Dulos@Organon.Oss.Akzonobel.nl
Bagchus
W M
WM
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D016130:Immunophenotyping; D051379:Mice; D011944:Receptors, Androgen / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
D000728:Androgens; D004967:Estrogens; D011944:Receptors, Androgen