title: Trichodimerol (BMS-182123) inhibits lipopolysaccharide-induced eicosanoid secretion in THP-1 human monocytic cells.
abstract: The fungal metabolite trichodimerol (BMS-182123) has demonstrated inhibition of lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF-alpha) secretion in various in vitro macrophage models (human and murine) including primary and tumor cell lines. When challenged with LPS, differentiated THP-1 monocytic cells secrete elevated levels of the cyclooxygenase products prostaglandin E2 (PGE2), thromboxane B2, and prostaglandin F2alpha (PGF2alpha). Studies directed at elucidating the mechanism of action of BMS-182123 as a TNF-alpha inhibitor revealed that the compound has a profound inhibitory effect on prostanoid secretion in response to LPS challenge. The key enzymes in prostaglandin synthesis are the constitutive cyclooxygenase, prostaglandin H synthase-1 (PGHS-1), and the mitogen-induced cyclooxygenase (PGHS-2), which is induced upon LPS stimulation in THP-1 cells. BMS-182123 did not inhibit the cyclooxygenase activity of PGHS-1 in an in vitro assay, suggesting that inhibition is due to a blockade in synthesis of cyclooxygenase enzyme. Western blot analysis of microsomal pellets from THP-1 cells stimulated with LPS (with or without BMS-182123 pretreatment) provided convincing evidence that the inhibition of prostaglandin synthesis is a result of suppressed synthesis of PGHS-2 enzyme. Northern blot analysis of THP-1 RNA demonstrated that BMS-182123 inhibits the induction of PGHS-2 at the level of transcription.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492-7660, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Mazzucco
authors.forename: G
authors.initials: G
authors.lastname: Warr
mesh_terms: D015152:Blotting, Northern; D015153:Blotting, Western; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism; D012313:RNA / Q000032:analysis
chemical_list: D001952:Bridged-Ring Compounds; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D008070:Lipopolysaccharides; C099299:trichodimerol; D012313:RNA; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone