Bone marrow stromal cells mediate androgenic suppression of B lymphocyte development

Castration of normal male mice induces expansion of the bone marrow B cell population, an effect that can be reversed by androgen replacement. We empl oyed in vitro cultures and two in vivo models to investigate whether androg ens exert these effects directly on marrow lymphoid precursors or whether a ctions on marrow stromal elements are required. Immature B cells from norma l mouse bone marrow were not responsive to the suppressive effect of androg ens unless they were cocultured with marrow stromal. cells or with supernat ants from androgen-treated stromal cells, suggesting that the androgen effe cts are exerted through marrow stromal elements by production of a diffusib le mediator. Further experiments revealed that bone marrow stromal cells pr oduced TGF-beta in response to dihydrotestosterone (DHT), and neutralizatio n of TGF-beta in the DHT-treated stromal cells reversed the suppressive eff ects, The stromal cell requirement for androgen-mediated effects was confir med in vivo by experiments using chimeric animals created by bone marrow tr ansplantation in which androgen receptor expression was restricted to eithe r the stromal or lymphoid cells of the bone marrow. Androgens only affected B cell development in chimeric mice with androgen-sensitive stromal cells. These experiments suggest that effects of androgens on developing B cells are mediated through androgen receptors in bone marrow stromal cells. TGF-b eta is a candidate mediator for these hormonal effects.