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.

1, 8-Cineol Protect Against Influenza-Virus-Induced Pneumonia in Mice

“…Overexpression of cytokines and chemokines induced by influenza virus infection is dependent on the NF-kB signaling pathway [47,48]. Previous study showed that 1,8-cineol can inhibit nuclear translocation of NF-kappaB p65 and NF-kappaBdependent transcriptional activity [20,22,49]. In present study, compared with the IFV-C group, the expression of NF-kB p65 (the major component of NF-kB) was significantly decreased in the lung after influenza virus challenge in cineol-treated mice.…”

“…1,8-cineol strongly inhibits tumor necrosis factor (TNF)-α and IL-1β level [12,21]. Likewise, 1,8-cineol is also known to inhibit directly signaling via NF-kB [22]. Previous studies have shown that proinflammatory cytokines are markedly elevated during influenza virus infection, and this Bcytokine storm^is hypothesized to be the main cause of mortality [23,24].…”

Transient Receptor Potential Cation Channel Subfamily M Member 8 channels mediate the anti‐inflammatory effects of eucalyptol

“…Eucalyptol interfered with arachidonic acid metabolism in blood monocytes of asthma patients, inhibited LPS‐induced IL‐1β production in human monocytes, suppressed LPS‐induced production of nitric oxide in a macrophage cell line and diminished LPS‐induced expression, translocation and transcriptional activities of early growth response factor 1 and NF‐κB in human cell lines (Juergens et al, ,b; Zhou et al, ; Kim et al, ). Finally, eucalyptol also has antioxidant and antimicrobial activity that may contribute to its anti‐inflammatory effects in some pathological conditions (Keinan et al, ; Hendry et al, ; Sadlon and Lamson, ; Greiner et al, ).…”

Inhibitory Effect of 1,8-Cineol on β-Catenin Regulation, WNT11 Expression, and Cellular Progression in HNSCC

“…Greiner et al have demonstrated that 1,8-cineol inhibits the nuclear import of the transcriptional activator protein NF-κB p65 and correspondingly its transcriptional activity (18) leading to decreased cell proliferation. Our findings of the suppressive influence of 1,8-cineol on relevant components in the WNT pathway-driven cancer progression, such as GSK-3 (Ser 9/21), β-catenin, and WNT11, describe a completely novel mode of action, which may lead to novel treatment approaches of this natural drug.…”

“…Various biological activities have been attributed to 1,8-cineol, which is commonly applied to treat various chronic and acute inflammatory airway diseases as well as patients with polyposis nasi. Recently, it has been shown that 1,8-cineol leads to decreased activity of the pro-inflammatory NF-κB-signaling by inhibiting its nuclear translocation (17, 18). …”