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CELLULAR AND MOLECULAR

Anti-Inflammatory Mechanisms of Isoflavone Metabolites in Lipopolysaccharide-Stimulated Microglial Cells

Department of Neuroscience and Medical Research Institute, College of Medicine (J.-S.P., M.-S.W., H.-S.K.) and Division of NanoScience (W.-K.K., J.-C.L.), Ewha Womans University, Seoul, Republic of Korea; Department of Microbial Chemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea (D.-H.K.); and Department of Biochemistry, College of Medicine, Cheju National University, Jeju, Republic of Korea (J.-W.H.)

The microglial activation plays an important role in neurodegenerative diseases by producing several proinflammatory cytokines and nitric oxide (NO). We found that three types of isoflavones and their metabolites that are transformed by the human intestinal microflora suppress lipopolysaccharide (LPS)-induced release of NO and tumor necrosis factor (TNF)- in primary cultured microglia and BV2 microglial cell lines. The inhibitory effect of the isoflavone metabolites (aglycon form) was more potent than that of isoflavones (glycoside form). The RNase protection assay showed that the isoflavone metabolites regulated inducible nitric oxide synthase (iNOS) and the cytokines at either the transcriptional or post-transcriptional level. A further molecular mechanism study was performed for irisolidone, a metabolite of kakkalide, which had the most potent anti-inflammatory effect among the six isoflavones tested. Irisolidone significantly inhibited the DNA binding and transcriptional activity of nuclear factor (NF)-B and activator protein-1. Moreover, it repressed the LPS-induced extracellular signal-regulated kinase (ERK) phosphorylation without affecting the activity of c-Jun N-terminal kinase or p38 mitogen-activated protein kinase. The level of NF-B inhibition by irisolidone correlated with the level of iNOS, TNF-, and interleukin (IL)-1 suppression in LPS-stimulated microglia, whereas the level of ERK inhibition correlated with the level of TNF- and IL-1 repression. Overall, the repression of proinflammatory cytokines and iNOS gene expression in activated microglia by isoflavones such as irisolidone might have therapeutic potential for various neurodegenerative diseases including ischemic cerebral disease.

Address correspondence to: Dr. Hee-Sun Kim, Department of Neuroscience, College of Medicine, Ewha Womans University, Mok-6-dong 911-1, Yangchun-Ku, Seoul 158-710, South Korea. E-mail: hskimp{at}ewha.ac.kr