TRICHODIMEROL (EMS-182123) INHIBITS LIPOPOLYSACCHARIDE-INDUCED EICOSANOID SECRETION IN THP-1 HUMAN MONOCYTIC CELLS

The fungal metabolite trichodimerol (BMS-182123) has demonstrated inhi bition of lipopolysaccharide (LPS)-stimulated tumor necrosis factor-al pha (TNF-alpha) secretion in various in vitro macrophage models (human and murine) including primary and tumor cell Lines, When challenged w ith LPS, differentiated THP-1 monocytic cells secrete elevated levels of the cyclooxygenase products prostaglandin E(2) (PGE(2)), thromboxan e B-2, and prostaglandin F-2 alpha (PGF(2) alpha), Studies directed at elucidating the mechanism of action of BMS-182123 as a TNF-alpha inhi bitor revealed that the compound has a profound inhibitory effect on p rostanoid secretion in response to LPS challenge, The key enzymes in p rostaglandin synthesis are the constitutive cyclooxygenase, prostaglan din H synthase-1 (PGHS-1), and the mitogen-induced cyclooxygenase (PGH S-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 fr om THP-1 cells stimulated with LPS (with or without BMS-182123 pretrea tment) provided convincing evidence that the inhibition of prostagland in synthesis is a result of suppressed synthesis of PGHS-2 enzyme, Nor thern blot analysis of THP-1 RNA demonstrated that BMS-182123 inhibits the induction of PGHS-2 at the level of transcription.