Dehydrodiisoeugenol, an isoeugenol dimer, inhibits lipopolysaccharide-stimulated nuclear factor kappa B activation and cyclooxygenase-2 expression in macrophages

https://doi.org/10.1016/j.abb.2004.11.013Get rights and content

Abstract

o-Methoxyphenols such as eugenol and isoeugenol exhibit anti-oxidant and anti-inflammatory activities, but at higher concentrations act as oxidants and potent allergens. We recently demonstrated the eugenol dimer bis-eugenol to be an efficient inhibitor of lipopolysaccharide (LPS)-induced inflammatory cytokine expression in macrophages without cytotoxicity. This result suggested that dimer compound of o-methoxyphenols may possess anti-inflammatory activity. Thus, we further synthesized dehydrodiisoeugenol and α-diisoeugenol from isoeugenols, and investigated whether these dimers could inhibit LPS-stimulated nuclear factor kappa B (NF-κB) activation and cyclooxygenase (COX)-2 gene expression, both of which are closely involved in inflammation and mutagenesis. The expression of the COX-2 gene was strongly inhibited by dehydrodiisoeugenol in RAW264.7 murine macrophages stimulated with LPS. In contrast, isoeugenol and α-diisoeugenol did not inhibit it. Dehydrodiisoeugenol also significantly inhibited LPS-stimulated phosphorylation-dependent proteolysis of inhibitor κB-α and transcriptional activity of NF-κB in the cells. These findings suggest that dehydrodiisoeugenol acts as a potent anti-inflammatory agent.

Section snippets

Reagents

Isoeugenol and eugenol were purchased from Tokyo Kasei (Tokyo, Japan). Dehydrodiisoeugenol was synthesized from isoeugenol monomers by the FeCl3-catalyzed coupling reaction described previously [4]. α-Diisoeugenol was synthesized from isoeugenol monomers by use of the trifluoroacetic acid-catalyzed α-configurational coupling reaction described earlier [4]. bis-Eugenol was synthesized from eugenol monomers by the CuCl(OH)-catalyzed ortho coupling reaction described previously [3]. The chemical

Results and discussion

Many previous studies demonstrated that COX-2 plays important roles in inflammation and mutagenesis [11], [12], [13]. Recently, we demonstrated that bis-eugenol significantly inhibited LPS-stimulated NF-κB activation and expression of inflammatory cytokines in macrophages [5]. This result suggested that other dimer compounds of o-methoxyphenols might also have anti-inflammatory activity. Therefore, we first examined by using the Northern blot assay whether various o-methoxyphenol compounds (

Acknowledgment

This work was supported by a Grant-in-Aid for scientific research (No. 15592133) from the Ministry of Education, Science, and Culture of Japan.

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