Regulation of the immune response by dehydroepiandrosterone and its metabolites.
Dehydroepiandrosterone (5-androsten-3 beta-ol-17-one, DHEA) has been shown to protect mice from a variety of lethal infections. This includes, but is not limited to, infection with viruses (herpes virus type 2, coxsackie virus B4 (CB4)), bacteria (Enterococcus faecalis, Pseudomonas aeruginosa), and a parasite (Cryptosporidium parvum). We have previously reported that androstenediol (5-androstene-3 beta, 17 beta-diol, AED), derived from DHEA, is at least 100 x more effective in up-regulating systemic resistance against CB4 infection than its precursor. Furthermore, androstenetriol (5-androstene-3 beta,7 beta, 17 beta-triol, AET) which is formed by 7 beta hydroxylation of AED, was more effective against CB4 infection than its precursor, AED. Neither steroid, however, has shown any significant direct antiviral effects. The in vitro influences of DHEA, AED and AET on a mitogen-induced mixed splenocyte proliferation assay were determined. The results showed that DHEA suppressed the proliferation of concanavalin A (ConA)- or lipopolysaccharide-activated cultures in a dose-dependent manner. AED had little influence on the activation response. However, AET potentiated the response to both mitogens significantly above the control level. The regulation of interleukin (IL)-2 and IL-3 secretion from ConA-activated lymphocytes was analogous to these observations. These functions were depressed by DHEA, unaffected by AED, and potently increased by AET. Moreover, the classic immunosuppressive effects of hydrocortisone on ConA-induced lymphocyte proliferation, as well as IL-2 and IL-3 production, were unaffected by co-culture with DHEA and only minimally counteracted by AED. In contrast. AET significantly counteracted the effect of hydrocortisone when co-cultured together. These data show that while DHEA, AED and AET each function in a similar manner in vivo, in vitro their effects are dramatically different from one another with only AET potentiating the cellular response by increasing lymphocyte activation and counteracting the immunosuppressive activity of hydrocortisone.
Loria
R M
RM
Department of Microbiology, Virginia Commonwealth University, Medical College of Virginia, Richmond 23298-09678, USA.
Padgett
D A
DA
Huynh
P N
PN
D015113:Androstane-3,17-diol / Q000031:analogs & derivatives / Q000378:metabolism; D015114:Androstenediol / Q000378:metabolism*; D000818:Animals; D001424:Bacterial Infections / Q000276:immunology; D003687:Dehydroepiandrosterone / Q000378:metabolism*; D006801:Humans; D007109:Immunity / Q000502:physiology*; D007376:Interleukin-2 / Q000096:biosynthesis; D007377:Interleukin-3 / Q000096:biosynthesis; D051379:Mice; D008815:Mice, Inbred Strains; D010272:Parasitic Diseases / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism; D014777:Virus Diseases / Q000276:immunology
D007376:Interleukin-2; D007377:Interleukin-3; C015680:androstane-3,7,17-triol; D015113:Androstane-3,17-diol; D003687:Dehydroepiandrosterone; D015114:Androstenediol