Inhibition of inducible TNF-alpha expression by oxaspirodion, a novel spiro-compound from the ascomycete Chaetomium subspirale.
In a search for compounds inhibiting the inducible TNF-alpha promoter activity in T cells, a new spiro-compound, designated oxaspirodion, was isolated from fermentations of the ascomycete Chaetomium subspirale. Oxaspirodion inhibited TNF-alpha promoter-driven luciferase reporter gene expression with an IC50 value of 2.5 microg/ml (10 microM) in TPA/ionomycin-stimulated Jurkat T cells. Studies on the mode of action of the compound revealed that the inhibition of the TNF-alpha promoter activity is caused by an inhibition of the phosphorylation of the ERK1/2 kinases. In addition, oxaspirodion inhibited the activation of the transcription factor NF-kappaB, which is involved in the inducible expression of many proinflammatory genes.
Rether
Jan
J
Institut für Biotechnologie und Wirkstoff-Forschung e.V., Erwin-Schrödinger-Str. 56, D-67663 Kaiserslautern, Germany.
Erkel
Gerhard
G
Anke
Timm
T
Sterner
Olov
O
D000818:Animals; D001203:Ascomycota / Q000302:isolation & purification; D002597:Chaetomium / Q000302:isolation & purification; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D020298:U937 Cells
D005663:Furans; D013141:Spiro Compounds; D014409:Tumor Necrosis Factor-alpha; C493110:oxaspirodion