Dexamethasone inhibits lipopolysaccharide-induced  hydrogen sulphide biosynthesis in intact cells  and in an animal model of endotoxic shock.
Dexamethasone (1 mg/kg, i.p.) administered either 1 hr before or 1 hr after E. coli lipopolysaccharide (LPS, 4 mg/kg, i.p.) in conscious rats inhibited the subsequent (4 hrs) rise in plasma cytokine (interleukin [IL]-1beta, tumour necrosis factor [TNF]-alpha), nitrate/nitrite (NO(x)), soluble intercellular adhesion molecule-1 (sICAM-1) concentration and lung/liver myeloperoxidase activity indicative of an anti-inflammatory effect. Dexamethasone also reduced the LPS-evoked rise in plasma hydrogen sulphide (H(2)S) concentration, liver H(2)S synthesizing activity and expression of cystathionine gamma lyase (CSE) and inducible nitric oxide synthase (iNOS). Mifepristone (RU-486) inhibited these effects. Dexamethasone (1-10 microM) reduced the LPS-evoked release of IL-1beta, TNF-alpha and L-selectin, decreased expression of CSE and iNOS and diminished nuclear factor kappaB (NF-kappaB)-DNA binding in isolated rat neutrophils. In contrast, NaHS (100 microM) increased L-selectin release from rat neutrophils. Dexamethasone also reduced LPS-induced up-regulation of CSE in foetal liver cells. 6-amino-4-(4-phenoxyphenylethylamino) quinazoline (QNZ, 10 nM), a selective inhibitor of transcription via the NF-kappaB pathway, abolished LPS-induced up-regulation of CSE expression. We propose that inhibition of CSE expression and reduction in formation of the pro-inflammatory component of H(2)S activity contributes to the anti-inflammatory effect of dexamethasone in endotoxic shock. Whether H(2)S plays a part in the anti-inflammatory effect of this steroid in other forms of inflammation such as arthritis or asthma warrants further study.
Li
Ling
L
Pharmaceutical Science Research Division, King's College, University of London, Franklin Wilkins Building, London, UK.
Whiteman
Matthew
M
Institute of Biomedical & Clinical Science, Peninsula Medical School, Universities of Exeter & Plymouth, Exeter, UK.
Moore
Philip K
PK
Pharmaceutical Science Research Division, King's College, University of London, Franklin Wilkins Building, London, UK.
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051381:Rats; D012772:Shock, Septic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D008070:Lipopolysaccharides; D003907:Dexamethasone; D006862:Hydrogen Sulfide