title: Inhibition of endotoxin-induced TNF-alpha production in macrophages by 5Z-7-oxo-zeaenol and other fungal resorcylic acid lactones.
abstract: Resorcylic acid lactones are fungal metabolites that exhibit a wide range of biological properties which includes oestrogenic, antifungal, phytotoxic and anti-inflammatory activity. The capacity of 5Z-7-oxo-zeaenol, a resorcylic lactone of fungal origin and six naturally occurring analogues to inhibit lipopolysaccharide (LPS)-induced cytokine production in phorbol 12-myristate-13-acetate (PMA)-treated cultured myelomonocytic cells (U937) was compared. The activity of the natural analogues in the U937 assay varied over 10(4)-fold, with 5Z-7-oxo-zeaenol the most potent of those tested inhibiting tumour necrosis factor-alpha (TNF alpha) production in these cells with IC50 of 6 nM. The isomeric 7-oxo-zeaenol and structurally more distant monorden (radicicol) were the next most active compounds with IC50 approximately 500 nM, and zearalenone, the least active with IC50 > 400 microM. 5Z-7-oxo-zeaenol retained activity in LPS-stimulated peripheral blood mononuclear cells with an IC50 of 10-25 nM. This compound also inhibited LPS-induced TNF alpha production in whole blood experiments (IC50 100-1000 nM) and lowered serum levels of TNF alpha in mice when administered prior to LPS. 5Z-7-oxo-zeaenol was shown to inhibit the phosphorylation and activation of mitogen-activated protein kinase (MAPK) induced by LPS. These data are consistent with a mechanism of action at or upstream of MAPK with resultant downstream effects. This series of naturally occurring analogues represents an interesting group of compounds with diverse biological properties. Of this series, 5Z-7-oxo-zeanenol has exceptionally potent anti-inflammatory properties exhibited by its strong inhibition of cytokine production.
authors.affiliation: Xenova Ltd, Slough, Berkshire, UK.
authors.forename: P
authors.initials: P
authors.lastname: Rawlins
authors.forename: T
authors.initials: T
authors.lastname: Mander
authors.forename: R
authors.initials: R
authors.lastname: Sadeghi
authors.forename: S
authors.initials: S
authors.lastname: Hill
authors.forename: G
authors.initials: G
authors.lastname: Gammon
authors.forename: B
authors.initials: B
authors.lastname: Foxwell
authors.forename: S
authors.initials: S
authors.lastname: Wrigley
authors.forename: M
authors.initials: M
authors.lastname: Moore
mesh_terms: D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001203:Ascomycota / Q000737:chemistry; D006801:Humans; D062385:Hydroxybenzoates / Q000494:pharmacology; D007739:L Cells / Q000187:drug effects; D007783:Lactones / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018942:Macrolides; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D020298:U937 Cells / Q000187:drug effects; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000008:administration & dosage; D012118:Resorcinols
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D062385:Hydroxybenzoates; D007783:Lactones; D008070:Lipopolysaccharides; D018942:Macrolides; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha; D015025:Zearalenone; C505734:7-oxozeanol; D012118:Resorcinols; C035359:monorden