Dehydroepiandrosterone inhibits microglial nitric oxide production in a stimulus-specific manner

Dehydroepiandrosterone (DHEA) is a steroid that circulates in abundance in the form of a sulfated reserve (DHEA-S). The levels of DHEA decline with age and further in age-related neuropathologies, including Alzheimer disease. Because of their reported anti-inflammatory effects, we tested the actions of these compounds on microglia. At concentrations of 3(-9) to 1(-6) M, DHEA and DHEA-S inhibited the production of nitrite and morphological changes stimulated by lipopolysaccharide. DHEA and DHEA-S also inhibited LPS induction of iNOS protein, but neither inhibited LPS-induced iNOS mRNA or the activation of NF-kappaB. These data suggest that the hormone regulates nitrite production through a post-transcriptional mechanism. Interestingly, microglial nitrite production in response to a secreted form of the beta-amyloid precursor protein (sAPP) was unaffected by DHEA. Another Alzheimer-related factor, amyloid beta-peptide, also stimulated microglial nitrite production but in a manner dependent on the co-stimulus interferon-gamma. DHEA was found to inhibit only the interferon-gamma component of the microglial response. These data add to a growing body of evidence for differences in the profiles of mononuclear phagocytes activated by distinct stimuli.