DHEAS inhibits TNF production in monocytes, astrocytes and microglial cells.
We previously reported that neurosteroids, including dehydroepiandrosterone sulfate (DHEAS), inhibit the production of TNF in vitro and in vivo. In this paper we evaluated the effect of DHEAS on TNF production by cultured rat astrocytes and murine glial cell clones, and compared it with the effect on monocytic THP-1 cells. We found that DHEAS at a concentration of 10(-4)-10(-7) M inhibits TNF production induced by lipopolysaccharide (LPS, 1 microgram/ml) in these cells. Since the inhibitory effect of DHEAS is not mediated by the glucocorticoid (GC) receptor and DHEAS is an allosteric antagonist of the GABAA receptor, we investigated the possible role of GABAA receptors in this effect. The results showed that the inhibitory effect of DHEAS (10(-6) M) on TNF production by THP-1 cells was completely reversed by addition of 10(-6) M GABA. However, a GABAA receptor antagonist (bicuculline) did not mimic the action of DHEAS. In conclusion, DHEAS can inhibit TNF production in astrocytic and microglial cells suggesting it could be an endogenous regulator of TNF production in the brain.
Di Santo
E
E
Istituto di Ricerche Farmacologiche, Mario Negri, Milan, Italy.
Foddi
M C
MC
Ricciardi-Castagnoli
P
P
Mennini
T
T
Ghezzi
P
P
D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D009000:Monocytes / Q000187:drug effects*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects*
D014409:Tumor Necrosis Factor-alpha; D003687:Dehydroepiandrosterone