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.
Barger
S W
SW
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. bargerstevenw@exchange.uams.edu
Chavis
J A
JA
Drew
P D
PD
D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000378:metabolism* / Q000494:pharmacology*; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism / Q000494:pharmacology; D004660:Encephalitis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D009573:Nitrites; D009569:Nitric Oxide; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D019001:Nitric Oxide Synthase