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 ag e 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, DH EA and DHEA-S inhibited the production of nitrite and morphological changes stimulated by lipopolysaccharide. DHEA and DHEA-S also inhibited LPS induc tion of iNOS protein, but neither inhibited LPS-induced iNOS mRNA or the ac tivation of NF-KB. These data suggest that the hormone regulates nitrite pr oduction through a post-transcriptional mechanism. Interestingly, microglia l nitrite production in response to a secreted form of the beta -amyloid pr ecursor protein (sAPP) was unaffected by DHEA. Another Alzheimer-related fa ctor, amyloid beta -peptide, also stimulated microglial nitrite production but in a manner dependent on the co-stimulus interferon-gamma. DHEA was fou nd to inhibit only the interferon-gamma component of the microglial respons e. These data add to a growing body of evidence for differences in the prof iles of mononuclear phagocytes activated by distinct stimuli. (C) 2000 Wile y-Liss, Inc.