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

Biochimica et biophysica acta (2013-07-23)
Johannes F-W Greiner, Janine Müller, Marie-Theres Zeuner, Stefan Hauser, Thorsten Seidel, Christin Klenke, Lena-Marie Grunwald, Timo Schomann, Darius Widera, Holger Sudhoff, Barbara Kaltschmidt, Christian Kaltschmidt
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Eucalyptol, 99%
Supelco
Eucalyptol, analytical standard
Sigma-Aldrich
Eucalyptol, natural, ≥99%, FCC, FG
Supelco
1,8-Cineole, primary reference standard
Sigma-Aldrich
Lipopolysaccharides (rough strains) from Salmonella enterica serotype minnesota Re 595 (Re mutant)
Cineole, European Pharmacopoeia (EP) Reference Standard
Supelco
Eucalyptol, certified reference material, TraceCERT®