BMS-182123, A FUNGAL METABOLITE THAT INHIBITS THE PRODUCTION OF TNF-ALPHA BY MACROPHAGES AND MONOCYTES

A fungal metabolite, EMS-182173, which inhibited bacterial endotoxin-i nduced production of tumor necrosis factor (TNF-alpha) in murine macro phages and human peripheral blood monocytes (in vitro), was isolated f rom the culture broth of Penicillium chrysogenum strain V39673. The ef fective EMS-182123 concentration (IC50) resulting in 50% inhibition of lipopolysaccharide-induced TNF-alpha production in murine macrophages and human monocytes was 600 ng/ml and 4.0 mu g/ml, respectively. EMS- 182123 suppressed the lipopolysaccahride-induced TNF-alpha promoter ac tivity and did not affect the stability of posttranscriptional mRNA. A ddition of hydrophobic resin, Amberlite XAD-8 (1%), to the fermentatio n enhanced the production of EMS-182123 by 5.5 fold. A total of 577 mg pure EMS-182123 was recovered from a 250-liter fermentation supplemen ted with 1% Amberlite XAD-8.