Trichodimerol (BMS-182123) inhibits lipopolysaccharide-induced eicosanoid secretion in THP-1 human monocytic cells

• Published in: Journal of leukocyte biology 1996-08, Vol.60 (2), p.271-277
• Main Authors: Mazzucco, Charles E., Warr, Glenn
• Format: Article
• Language: English
• Subjects: Blotting, Northern; Blotting, Western; Bridged-Ring Compounds - pharmacology; Chromatography, High Pressure Liquid; cyclooxygenase; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - metabolism; Eicosanoids - metabolism; Humans; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Monocytes - drug effects; Monocytes - metabolism; Prostaglandin-Endoperoxide Synthases - biosynthesis; Prostaglandin-Endoperoxide Synthases - metabolism; prostaglandins; RNA - analysis; TNF‐α inhibitors
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1002/jlb.60.2.271

The fungal metabolite trichodimerol (BMS‐182123) has demonstrated inhibition of lipopolysaccharide (LPS) ‐stimulated tumor necrosis factor‐α (TNF‐α) 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 F2α (PGF2α). Studies directed at elucidating the mechanism of action of BMS‐182123 as a TNF‐α 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. J. Leukoc. Biol. 60: 271–277; 1996.