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-Mangostin Inhibits Inhibitor-B Kinase Activity and Decreases Lipopolysaccharide-Induced Cyclooxygenase-2 Gene Expression in C6 Rat Glioma Cells

Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (K.N., T.Y., N.K., Y.O.); Central Laboratory, Lotte Co., Ltd., Saitama, Japan (T.A., K.O., S.S.); and Department of Pharmacology, National Cardiovascular Center Research Institute, Osaka, Japan (H.I.)

We investigated the effect of -mangostin purified from the fruit hull of the medicinal plant Garcinia mangostana on spontaneous prostaglandin E₂ (PGE₂) genase release and inducible cyclooxy-2 (COX-2) gene expression in C6 rat glioma cells. An 18-h treatment with -mangostin potently inhibited spontaneous PGE₂ release in a concentration-dependent manner with the IC₅₀ value of approximately 2 µM, without affecting the cell viability even at 30 µM. By immunoblotting and reverse-transcription polymerase chain reaction, we showed that -mangostin concentration-dependently inhibited lipopolysaccharide (LPS)-induced expression of COX-2 protein and its mRNA, but not those of constitutive COX-1 cyclooxygenase. Because LPS is known to stimulate inhibitor B (IB) kinase (IKK)-mediated phosphorylation of IB followed by its degradation, which in turn induces nuclear factor (NF)-B nuclear translocation leading to transcriptional activation of COX-2 gene, the effect of -mangostin on the IKK/IB cascade controlling the NF-B activation was examined. An in vitro IKK assay using IKK protein immunoprecipitated from C6 cell extract showed that this compound inhibited IKK activity in a concentration-dependent manner, with the IC₅₀ value of approximately 10 µM. Consistently -mangostin was also observed to decrease the LPS-induced IB degradation and phosphorylation in a concentration-dependent manner, as assayed by immunoblotting. Furthermore, luciferase reporter assays showed that -mangostin reduced the LPS-inducible activation of NF-B–and human COX-2 gene promoter region-dependent transcription. -Mangostin also inhibited rat carrageenan-induced paw edema. These results suggest that -mangostin directly inhibits IKK activity and thereby prevents COX-2 gene transcription, an NF-B target gene, probably to decrease the inflammatory agent-stimulated PGE₂ production in vivo, and is a new useful lead compound for anti-inflammatory drug development.

Address correspondence to: Dr. Tohru Yamakuni, Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. E-mail: yamakuni{at}mail.pharm.tohoku.ac.jp

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