Abstract
Dehydroepiandrosterone (DHEA) mainly exerts indirect action via tissue-specific downstream conversion toward sex steroids within peripheral target cells including immune cells. In vitro DHEA has been shown to enhance IL-2 release from T lymphocytes while it inhibits IL-6 secretion. Vice versa, aging is associated with a decline in both DHEA and IL-2 while IL-6 increases. Here we sought to analyze the conversion of DHEA in human peripheral blood mononuclear cells (PBMCs) isolated from healthy young and elderly men (n=8 in each group; ages 23–29yrs and 52–66yrs). RT-PCR showed expression of 3β-HSD 1 and 2, 17β-HSD 4 and 5, and 5α-reductase 1. Thus PBMCs contain all enzymes required for the conversion of DHEA toward active androgens and to the immune-stimulatory metabolite androstenediol (5-diol). PBMCs were incubated with radiolabeled DHEA, androstenedione (A) and testosterone (T). Resulting steroids were separated and identified by TLC and subsequent phosphorimager analysis. Conversion of DHEA to 5-diol via 17β-HSD5 was significantly higher in elderly men (young vs. old: 3.48±0.26 vs. 4.79±0.36 pmol/10×106 cells/h, p<0.05). By contrast, conversion of DHEA to A via 3β-HSD occurred at a similar rate (young vs. old: 0.47±0.05 vs. 0.40±0.04 pmol/10×106 cells/h, n.s.). PBMCs from elderly men also exhibited a sginificantly higher activation of A to T via 17β-HSD5 (p<0.05) and of T to DHT via 5α-reductase 1 (p<0.05). Relative conversion did not differ between age groups except for DHEA conversion, which showed a significant shift toward 5-diol generation, and thus 17β-HSD5 activity, with aging (p<0.05). Accordingly, semiquantitative RT-PCR showed a significantly higher expression of 17β-HSD5 mRNA in elderly men (17β-HSD5/18S ratio young vs. old: 0.32±0.05 vs. 0.61±0.05, p<0.01). Our results provide evidence for significant changes in sex steroid metabolism by human PBMCs with aging. This may represent an endocrine link to immunesenescence.
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