PMID- 8901021
OWN - NLM
STAT- MEDLINE
DCOM- 19970123
LR  - 20240104
IS  - 0014-2999 (Print)
IS  - 0014-2999 (Linking)
VI  - 299
IP  - 1-3
DP  - 1996 Mar 28
TI  - A glucocorticoid receptor-independent mechanism for neurosteroid inhibition of 
      tumor necrosis factor production.
PG  - 179-86
AB  - We investigated the effect of two neurosteroids, pregnenolone and 
      dehydroepiandrosterone sulfate on lipopolysaccharide-induced tumor necrosis 
      factor (TNF) production in vivo and in vitro. Dehydroepiandrosterone sulfate 
      (0.3-30 mg/kg, i.p.) inhibited serum TNF induced by lipopolysaccharide (2.5 
      micrograms/mouse, i.p.), without affecting the induction of serum corticosterone. 
      Intracerebroventricular (i.c.v.) administration of dehydroepiandrosterone sulfate 
      (0.2-5 micrograms/mouse) also inhibited brain TNF induced by i.c.v. 
      lipopolysaccharide (2.5 micrograms/mouse). Dehydroepiandrosterone sulfate and 
      pregnenolone (10(-6)-10(-4) M) inhibited TNF production in vitro by 
      lipopolysaccharide-stimulated human peripheral blood mononuclear cells or by the 
      human THP-1 cell line, suggesting that this action might also be relevant in 
      humans. We obtained two lines of evidence that neurosteroids do not inhibit TNF 
      via the glucocorticoid receptor. (1) Dehydroepiandrosterone sulfate and 
      pregnenolone did not activate the alpha 1-acid glycoprotein promoter, a typical 
      effect of glucocorticoids mediated by the glucocorticoid receptor, while strong 
      activation of this promoter was observed with dexamethasone. (2) The inhibitory 
      effect of dehydroepiandrosterone sulfate and pregnenolone on TNF production was 
      not reversed by the glucocorticoid receptor antagonist, mifepristone (RU38486). 
      On the contrary the inhibitory effect of dexamethasone, a classical 
      glucocorticoid and inhibitor of TNF synthesis, was completely reversed by 
      RU38486.
FAU - Di Santo, E
AU  - Di Santo E
AD  - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
FAU - Sironi, M
AU  - Sironi M
FAU - Mennini, T
AU  - Mennini T
FAU - Zinetti, M
AU  - Zinetti M
FAU - Savoldi, G
AU  - Savoldi G
FAU - Di Lorenzo, D
AU  - Di Lorenzo D
FAU - Ghezzi, P
AU  - Ghezzi P
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Hormone Antagonists)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 320T6RNW1F (Mifepristone)
RN  - 57B09Q7FJR (Dehydroepiandrosterone Sulfate)
RN  - 73R90F7MQ8 (Pregnenolone)
SB  - IM
MH  - Animals
MH  - Brain/*drug effects/metabolism
MH  - Cell Line
MH  - Dehydroepiandrosterone Sulfate/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Escherichia coli
MH  - Hormone Antagonists/pharmacology
MH  - Lipopolysaccharides
MH  - Male
MH  - Mice
MH  - Mifepristone/pharmacology
MH  - Pregnenolone/*pharmacology
MH  - RNA, Messenger/analysis
MH  - Receptors, Glucocorticoid/*drug effects/metabolism
MH  - Tumor Necrosis Factor-alpha/genetics/*metabolism
EDAT- 1996/03/28 00:00
MHDA- 1996/03/28 00:01
CRDT- 1996/03/28 00:00
PHST- 1996/03/28 00:00 [pubmed]
PHST- 1996/03/28 00:01 [medline]
PHST- 1996/03/28 00:00 [entrez]
AID - 0014-2999(95)00840-3 [pii]
AID - 10.1016/0014-2999(95)00840-3 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 1996 Mar 28;299(1-3):179-86. doi: 10.1016/0014-2999(95)00840-3.