1,8-Cineol inhibits nuclear translocation of NF-κB p65 and NF-κB-dependent transcriptional activity

• Published in: Biochimica et biophysica acta 2013-12, Vol.1833 (12), p.2866-2878
• Main Authors: Greiner, Johannes F.-W., Müller, Janine, Zeuner, Marie-Theres, Hauser, Stefan, Seidel, Thorsten, Klenke, Christin, Grunwald, Lena-Marie, Schomann, Timo, Widera, Darius, Sudhoff, Holger, Kaltschmidt, Barbara, Kaltschmidt, Christian
• Format: Article
• Language: English
• Subjects: 1,8-Cineol; Cell Nucleus - metabolism; Cell Proliferation - drug effects; Cyclohexanols - chemistry; Cyclohexanols - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Genes, Reporter; HeLa Cells; Human cell lines; Humans; I-kappa B Kinase - metabolism; I-kappa B Proteins - metabolism; Inflammation; Inflammatory diseases; JNK Mitogen-Activated Protein Kinases - metabolism; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - enzymology; Lipopolysaccharides - pharmacology; Models, Biological; Monoterpenes - chemistry; Monoterpenes - pharmacology; NF-KappaB Inhibitor alpha; NF-κB; PBMCs; Phosphorylation - drug effects; Protein Binding - drug effects; Protein Transport - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription Factor RelA - metabolism; Transcription, Genetic - drug effects
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2013.07.001

Natural plant-derived products are commonly applied to treat a broad range of human diseases, including cancer as well as chronic and acute airway inflammation. In this regard, the monoterpene oxide 1,8-cineol, the active ingredient of the clinically approved drug Soledum®, is well-established for the therapy of airway diseases, such as chronic sinusitis and bronchitis, chronic obstructive pulmonary disease and bronchial asthma. Although clinical trials underline the beneficial effects of 1,8-cineol in treating inflammatory diseases, the molecular mode of action still remains unclear. Here, we demonstrate for the first time a 1,8-cineol-depending reduction of NF-κB-activity in human cell lines U373 and HeLa upon stimulation using lipopolysaccharides (LPS). Immunocytochemistry further revealed a reduced nuclear translocation of NF-κB p65, while qPCR and western blot analyses showed strongly attenuated expression of NF-κB target genes. Treatment with 1,8-cineol further led to increased protein levels of IκBα in an IKK-independent matter, while FRET-analyses showed restoring of LPS-associated loss of interaction between NF-κB p65 and IκBα. We likewise observed reduced amounts of phosphorylated c-Jun N-terminal kinase 1/2 protein in U373 cells after exposure to 1,8-cineol. In addition, 1,8-cineol led to decreased amount of nuclear NF-κB p65 and reduction of its target gene IκBα at protein level in human peripheral blood mononuclear cells. Our findings suggest a novel mode of action of 1,8-cineol through inhibition of nuclear NF-κB p65 translocation via IκBα resulting in decreased levels of proinflammatory NF-κB target genes and may therefore broaden the field of clinical application of this natural drug for treating inflammatory diseases. [Display omitted] •A novel mode of action of 1,8-cineol via inhibition of NF-κB•1,8-Cineol-depending decrease of NF-κB-activity in human cell lines U373 and HeLa•1,8-Cineol treatment led to reduced amount of nuclear p65 in U373, HeLa and hPBMCs.•Reduced levels of NF-κB target genes and increased amount of IκBα by 1,8-cineol•Restoring of LPS-dependent loss of interaction between p65 and IκBα by 1,8-cineol