Ce. Mazzucco et G. Warr, TRICHODIMEROL (EMS-182123) INHIBITS LIPOPOLYSACCHARIDE-INDUCED EICOSANOID SECRETION IN THP-1 HUMAN MONOCYTIC CELLS, Journal of leukocyte biology, 60(2), 1996, pp. 271-277
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.