A GLUCOCORTICOID RECEPTOR-INDEPENDENT MECHANISM FOR NEUROSTEROID INHIBITION OF TUMOR-NECROSIS-FACTOR PRODUCTION

We investigated the effect of two neurosteroids, pregnenolone and dehy droepiandrosterone sulfate on lipopolysaccharide-induced tumor necrosi s factor (TNF) production in vivo and in vitro, Dehydroepiandrosterone sulfate (0.3-30 mg/kg, i.p.) inhibited serum TNF induced by lipopolys accharide (2.5 mu g/mouse, i.p.), without affecting the induction of s erum corticosterone. Intracerebroventricular (i.c.v.) administration o f dehydroepiandrosterone sulfate (0.2-5 mu g/mouse) also inhibited bra in TNF induced by i.c.v. lipopolysaccharide (2.5 mu g/mouse). Dehydroe piandrosterone sulfate and pregnenolone (10(-6)-10(-4) M) inhibited TN F production in vitro by lipopolysaccharide-stimulated human periphera l blood mononuclear cells or by the human THP-1 cell line, suggesting that this action might also be relevant in humans. We obtained two lin es of evidence that neurosteroids do not inhibit THF via the glucocort icoid receptor. (1) Dehydroepiandrosterone sulfate and pregnenolone di d not activate the alpha(1)-acid glycoprotein promoter, a typical effe ct of glucocorticoids mediated by the glucocorticoid receptor, while s trong activation of this promoter was observed with dexamethasone. (2) The inhibitory effect of dehydroepiandrosterone sulfate and pregnenol one on TNF production was not reversed by the glucocorticoid receptor antagonist, mifepristone (RU38486). On the contrary the inhibitory eff ect of dexamethasone, a classical glucocorticoid and inhibitor of TNF synthesis, was completely reversed by RU38486.