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.
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