Glucocorticoids inhibit the induction of nitric oxide synthase and the related cell damage in adenocarcinoma cells.
Lipopolysaccharide (LPS) induced a time-dependent synthesis of nitric oxide (NO) in EMT6 adenocarcinoma cells, assayed by accumulation of NO-derived nitrite in the medium. The induction of NO synthesis was inhibited in a concentration-dependent manner by the glucocorticoids dexamethasone (IC50 = 5 nM) and hydrocortisone (IC50 = 20 nM) and this effect was partially antagonized by progesterone and cortexolone. If addition of dexamethasone was delayed 6 h or more, inhibition of nitrite accumulation over 24 h was substantially reduced, indicating a lack of direct effect of glucocorticoids on the NO synthase. Nitrite accumulation was accompanied by cell damage, which was increased by L-arginine and inhibited by NG-monomethyl-L-arginine (L-NMMA) and dexamethasone. These data show that NO is a primary cytotoxic mediator and that suppression of its formation by glucocorticoids explains some of their anti-inflammatory and cytoprotective effects.
O'Connor
K J
KJ
Wellcome Research Laboratories, Beckenham, Kent, U.K.
Moncada
S
S
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects*; D003350:Cortodoxone / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000032:analysis; D011374:Progesterone / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D019323:omega-N-Methylarginine
D008070:Lipopolysaccharides; D009573:Nitrites; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D011374:Progesterone; D003907:Dexamethasone; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D003350:Cortodoxone; D006854:Hydrocortisone