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

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 (R), 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-kappa B-activity in human cell lines U373 and HeLa upon stimulation using lipopolysaccharides (LPS). Immunocytochemistry further revealed a reduced nuclear translocation of NF-kappa B p65, while qPCR and western blot analyses showed strongly attenuated expression of NF-kappa B target genes. Treatment with 1,8-cineol further led to increased protein levels of lact in an IKK-independent matter, while FRET-analyses showed restoring of LPS-associated loss of interaction between NF-kappa B p65 and I kappa B alpha. 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-kappa B p65 and reduction of its target gene I kappa B alpha 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-kappa B p65 translocation via I kappa B alpha resulting in decreased levels of proinflammatory NF-kappa B target genes and may therefore broaden the field of clinical application of this natural drug for treating inflammatory diseases. (C) 2013 Elsevier B.V. All rights reserved.