A cyclopentanediol analogue selectively suppresses the conserved innate immunity pathways, Drosophila IMD and TNF-alpha pathways.
Innate immunity comprises evolutionarily conserved self-defense mechanisms against microbial infections. In mammals, innate immunity interacts with adaptive immunity and has a key role in the regulated immune response. Therefore, innate immunity is a pharmaceutical target for the development of immune regulators. Using Drosophila ex vivo culture systems, we isolated a cyclopentanediol analogue from Aspergillus sp. as an immunosuppressive substance. This compound selectively suppressed activation of the IMD pathway in Drosophila in vivo and the target molecules of the compound lie between the Imd adaptor protein and dTAK1 kinase in the IMD pathway. In human cells, the compound suppressed TNF-alpha, but not IL-1beta, stimulation-induced activation of NF-kappaB, suggesting that its target molecules are upstream of TAK1 in mammalian innate immunity.
Sekiya
Mizuki
M
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Ueda
Kazunori
K
Okazaki
Kaori
K
Kikuchi
Haruhisa
H
Kurata
Shoichiro
S
Oshima
Yoshiteru
Y
D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D001230:Aspergillus / Q000737:chemistry; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins / Q000276:immunology / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000276:immunology* / Q000382:microbiology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D007814:Larva / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D000498:Allyl Compounds; D003517:Cyclopentanes; D029721:Drosophila Proteins; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C529440:4-(1-propenyl)cyclopentane-1,2-diol; C439909:imd protein, Drosophila