Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages

Dehydroepiandrosterone (DHEA) is a ubiquitous adrenal hormone with immunomo dulatory effects such as inhibition of the production of monokines. Whether DHEA itself or the downstream steroids are the immunomodulatory effector h ormones in target cells is not known. In this study, we investigated the co nversion of DHEA to downstream steroid hormones in target macrophages. Within 1 day of culture with radiolabeled DHEA, monocyte-derived macrophage s converted DHEA to significant amounts of Delta 5-derivatives such as 160H -DHEA, 3 beta,17 beta-androstenediol (A'diol), and 3 beta,16 alpha,17 beta- androstenetriol (A'triol). However, the production of Delta 4-steroids (and rostenedione (A'dione), testosterone (T), and 16OH-T) and estrogens (estron e, estradiol, and estriol) was relatively low. Further cultivation of macro phages for 5 days with radiolabeled DHEA resulted in a significant (P<0.05) increase of the molar amounts of A'triol (P=0.012), 16OH-T (P=0.008), and estriol (P=0.003). In contrast to monocyte-derived macrophages, monocytes d id not express aromatase mRNA, which was demonstrated by RT-PCR (P<0.01). F urthermore, DHEA in macrophages significantly inhibited one of the downstre am converting enzymes, the aromatase, which was not demonstrated in the pre sence of the typical macrophage activator, lipopolysaccharide (LPS) (P<0.01 ). In conclusion, conversion of DHEA to physiologically relevant amounts of De lta 5- and Delta 4-steroids and estrogens was demonstrated in monocyte-deri ved macrophages. The conversion depends on maturation of monocytes and loca l factors such as the presence of LPS. The conversion of DHEA leads to an i ncrease of downstream effector hormones in target macrophages which may be an important factor for local immunomodulation.