title: The myxobacterial compounds spirangien a and spirangien M522 are potent inhibitors of IL-8 expression.
abstract: Elevated expression of interleukin-8 (IL-8) has been implicated in inflammatory diseases, in tumor growth, and in angiogenesis. The aim of this study was to identify natural or synthetic compounds that suppress IL-8 production in response to interleukin-1 (IL-1), the natural inflammatory stimulus of the IL-8 gene. We therefore developed an IL-1-inducible cell-based screening assay by stable integration of an IL-8 reporter gene into HeLa S3 cells. The screening of heterogeneous compound libraries revealed several compounds that displayed an inhibitory effect on the reporter gene expression. Following hit validation, we focused on the most efficient compound, spirangien A, and its chemical derivate spirangien M522. Detailed analysis shows that both compounds are potent inhibitors of the endogenous IL-8 gene transcription. Furthermore, both compounds decelerate the phosphorylation and degradation of IκBα, the key regulator of the IL-1-stimulated NF-κB signaling pathway. Our study has identified the two spirangiens A and M522 as potent inhibitors of IL-1/NF-κB-mediated IL-8 gene expression.
authors.affiliation: Department of Chemical Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Marc René
authors.initials: MR
authors.lastname: Reboll
authors.forename: Birgit
authors.initials: B
authors.lastname: Ritter
authors.forename: Florenz
authors.initials: F
authors.lastname: Sasse
authors.forename: Jutta
authors.initials: J
authors.lastname: Niggemann
authors.forename: Ronald
authors.initials: R
authors.lastname: Frank
authors.forename: Mahtab
authors.initials: M
authors.lastname: Nourbakhsh
mesh_terms: D000080:Acetals / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000235:genetics; D009231:Myxococcales / Q000737:chemistry*; D010766:Phosphorylation / Q000187:drug effects; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D000080:Acetals; D005231:Fatty Acids, Unsaturated; D020672:I-kappa B Proteins; D016209:Interleukin-8; D011714:Pyrans; D012333:RNA, Messenger; D013141:Spiro Compounds; C523683:spirangien A; C572725:spirangien M522