title: 1,8-Cineol inhibits nuclear translocation of NF-κB p65 and NF-κB-dependent transcriptional activity.
abstract: 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.
authors.affiliation: Department of Cell Biology, University of Bielefeld, D-33501 Bielefeld, Germany.
authors.forename: Johannes F-W
authors.initials: JF
authors.lastname: Greiner
authors.affiliation: AG Molecular Neurobiology, University of Bielefeld, D-33501 Bielefeld, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Müller
authors.affiliation: Department of Cell Biology, University of Bielefeld, D-33501 Bielefeld, Germany.
authors.forename: Marie-Theres
authors.initials: MT
authors.lastname: Zeuner
authors.affiliation: AG Molecular Neurobiology, University of Bielefeld, D-33501 Bielefeld, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hauser
authors.affiliation: Dynamic Cell Imaging, University of Bielefeld, D-33501 Bielefeld, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Seidel
authors.affiliation: Klinik für Hals-, Nasen- und Ohrenheilkunde, Kopf- und Halschirurgie, Klinikum Bielefeld, D-33604 Bielefeld, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Klenke
authors.affiliation: Department of Cell Biology, University of Bielefeld, D-33501 Bielefeld, Germany.
authors.forename: Lena-Marie
authors.initials: LM
authors.lastname: Grunwald
authors.affiliation: AG Molecular Neurobiology, University of Bielefeld, D-33501 Bielefeld, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Schomann
authors.affiliation: Department of Cell Biology, University of Bielefeld, D-33501 Bielefeld, Germany.
authors.forename: Darius
authors.initials: D
authors.lastname: Widera
authors.affiliation: Klinik für Hals-, Nasen- und Ohrenheilkunde, Kopf- und Halschirurgie, Klinikum Bielefeld, D-33604 Bielefeld, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Sudhoff
authors.affiliation: AG Molecular Neurobiology, University of Bielefeld, D-33501 Bielefeld, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kaltschmidt
authors.affiliation: Department of Cell Biology, University of Bielefeld, D-33501 Bielefeld, Germany. Electronic address: c.kaltschmidt@uni-bielefeld.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Kaltschmidt
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D003511:Cyclohexanols / Q000737:chemistry / Q000494:pharmacology*; D000077591:Eucalyptol; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008954:Models, Biological; D039821:Monoterpenes / Q000737:chemistry / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D003511:Cyclohexanols; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D039821:Monoterpenes; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D000077591:Eucalyptol
keywords: 1,8-Cineol; Human cell lines; Inflammation; Inflammatory diseases; NF-κB; PBMCs