| Abstract: |
T cell production by the thymus, thymic size, cellularity and output all decrease drastically after puberty. Among the candidates that may mediate this decrease are the sex steroids: hypersecretion or pharmacological administration of these hormones has long been known to induce thymic hypocellularity, and their depletion yields thymic hypercellularity. Here we show that a typical sex steroid, testosterone, specifically targets CD8+CD4+ double-positive (DP) thymocytes for apoptosis via TNF-α. Anti-TNF-α monoclonal antibodies abrogated testosterone-induced DP apoptosis, and TNF-α(-/-) DP thymocytes were largely resistant to testosterone-mediated apoptosis in vivo. Testosterone accomplished this effect by up-regulating TNF-α production and by simultaneously sensitizing DP thymocytes to TNF-α. Thus, TNF-α is the critical mediator of sex steroid-induced apoptosis in thymocytes, and its manipulation should provide a point of intervention to modulate T cell production in sex hormone disorders. |
| Keywords: |
controlled study; nonhuman; cd8 antigen; animal cell; mouse; animal; mice; animal tissue; apoptosis; mice, inbred c57bl; monoclonal antibody; tumor necrosis factor alpha; cytokine production; t-lymphocyte subsets; cd4 antigen; antigens, cd4; sex hormone; testosterone; thymocyte; tumor necrosis factor; antigens, cd8; dna fragment; sex steroids; tnf-α; priority journal; article; support, non-u.s. gov't; support, u.s. gov't, p.h.s.
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