Fraxinellone inhibits lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 expression by negatively regulating nuclear factor-kappa B in RAW 264.7 macrophages cells

Jong-Hwan Kim, Young-Mi Park, Ji-Sun Shin, Seung Jae Park, Jung-Hye Choi, Hyun-Ju Jung, Hee-Juhn Park, Kyung-Tae Lee
Biological & Pharmaceutical Bulletin 2009, 32 (6): 1062-8
Fraxinellone is formed by the natural degradation of limonoids isolated from the root bark of Dictamnus dasycarpus. Fraxinellone has been reported to possess neuroprotective and vasorelaxing activities, but the effects and the mechanism of fraxinellone in inflammation have not been fully characterized. In the present study, the anti-inflammatory effect of fraxinellone was evaluated in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. Fraxinellone was found to inhibit LPS-induced nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production, and to reduce the LPS-induced expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in a dose-dependent manner. Furthermore, fraxinellone significantly attenuated LPS-induced DNA binding activity and the transcription activity of nuclear factor-kappa B (NF-kappaB). Consistent with these findings, pretreatment with fraxinellone significantly suppressed the LPS-stimulated phosphorylation of inhibitory kappa B-alpha (IkappaB-alpha) and the subsequent translocation of p65 to the nucleus. Fraxinellone also suppressed the IkappaB kinase (IKK) activity and the phosphorylation of extracellular-signal-related kinase (ERK1/2), whereas the phosphorylations of Jun N-terminal kinase (JNK1/2) and p38 were unaffected. These results suggest that the anti-inflammatory properties of fraxinellone are related to the down-regulations of iNOS and COX-2 due to NF-kappaB inhibition through the negative regulations of IKK and ERK1/2 phosphorylations in RAW 264.7 cells.

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