Anti-inflammatory mechanisms of isoflavone metabolites in lipopolysaccharide-stimulated microglial cells

Jin Sun Park, Moon Sook Woo, Dong Hyun Kim, Jin Won Hyun, Won-Ki Kim, Jae Chul Lee, Hee Sun Kim

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

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)-α 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)-κB 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-κB inhibition by irisolidone correlated with the level of iNOS, TNF-α, and interleukin (IL)-1β suppression in LPS-stimulated microglia, whereas the level of ERK inhibition correlated with the level of TNF-α and IL-1β 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.

Original languageEnglish
Pages (from-to)1237-1245
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume320
Issue number3
DOIs
Publication statusPublished - 2007 Mar 1
Externally publishedYes

Fingerprint

Isoflavones
Lipopolysaccharides
Anti-Inflammatory Agents
Microglia
Nitric Oxide Synthase Type II
Tumor Necrosis Factor-alpha
Extracellular Signal-Regulated MAP Kinases
Cytokines
Interleukin-1
Neurodegenerative Diseases
Nitric Oxide
JNK Mitogen-Activated Protein Kinases
Transcription Factor AP-1
p38 Mitogen-Activated Protein Kinases
Ribonucleases
Glycosides
Phosphorylation
Gene Expression
Cell Line
irisolidone

ASJC Scopus subject areas

  • Pharmacology

Cite this

Anti-inflammatory mechanisms of isoflavone metabolites in lipopolysaccharide-stimulated microglial cells. / Park, Jin Sun; Woo, Moon Sook; Kim, Dong Hyun; Hyun, Jin Won; Kim, Won-Ki; Lee, Jae Chul; Kim, Hee Sun.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 320, No. 3, 01.03.2007, p. 1237-1245.

Research output: Contribution to journalArticle

Park, Jin Sun ; Woo, Moon Sook ; Kim, Dong Hyun ; Hyun, Jin Won ; Kim, Won-Ki ; Lee, Jae Chul ; Kim, Hee Sun. / Anti-inflammatory mechanisms of isoflavone metabolites in lipopolysaccharide-stimulated microglial cells. In: Journal of Pharmacology and Experimental Therapeutics. 2007 ; Vol. 320, No. 3. pp. 1237-1245.
@article{38a6330d820e4d639e5be7ad8533a118,
title = "Anti-inflammatory mechanisms of isoflavone metabolites in lipopolysaccharide-stimulated microglial cells",
abstract = "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)-α 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)-κB 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-κB inhibition by irisolidone correlated with the level of iNOS, TNF-α, and interleukin (IL)-1β suppression in LPS-stimulated microglia, whereas the level of ERK inhibition correlated with the level of TNF-α and IL-1β 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.",
author = "Park, {Jin Sun} and Woo, {Moon Sook} and Kim, {Dong Hyun} and Hyun, {Jin Won} and Won-Ki Kim and Lee, {Jae Chul} and Kim, {Hee Sun}",
year = "2007",
month = "3",
day = "1",
doi = "10.1124/jpet.106.114322",
language = "English",
volume = "320",
pages = "1237--1245",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Anti-inflammatory mechanisms of isoflavone metabolites in lipopolysaccharide-stimulated microglial cells

AU - Park, Jin Sun

AU - Woo, Moon Sook

AU - Kim, Dong Hyun

AU - Hyun, Jin Won

AU - Kim, Won-Ki

AU - Lee, Jae Chul

AU - Kim, Hee Sun

PY - 2007/3/1

Y1 - 2007/3/1

N2 - 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)-α 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)-κB 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-κB inhibition by irisolidone correlated with the level of iNOS, TNF-α, and interleukin (IL)-1β suppression in LPS-stimulated microglia, whereas the level of ERK inhibition correlated with the level of TNF-α and IL-1β 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.

AB - 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)-α 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)-κB 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-κB inhibition by irisolidone correlated with the level of iNOS, TNF-α, and interleukin (IL)-1β suppression in LPS-stimulated microglia, whereas the level of ERK inhibition correlated with the level of TNF-α and IL-1β 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.

UR - http://www.scopus.com/inward/record.url?scp=33847091290&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33847091290&partnerID=8YFLogxK

U2 - 10.1124/jpet.106.114322

DO - 10.1124/jpet.106.114322

M3 - Article

C2 - 17194798

AN - SCOPUS:33847091290

VL - 320

SP - 1237

EP - 1245

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -