Inhibition of LPS-stimulated pathways in macrophages by the flavonoid luteolin

Angeliki Xagorari, Charis Roussos, Andreas Papapetropoulos

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

1. We have previously shown that the flavonoid luteolin inhibits the expression of pro-inflammatory molecules induced by LPS. In the present study we tested the ability of luteolin to block signalling pathways implicated in LPS-induced inflammatory gene expression in macrophages. 2. Exposure of the murine macrophage cell line RAW 264.7 to LPS increased phosphorylation of the mitogen-activated protein kinase family members ERK1/2, p38 and JNK1/2 in a time-dependent manner. Pretreatment of RAW 264.7 with luteolin inhibited the LPS-induced ERK1/2 and p38, but not JNK1/2, phosphorylation, and blocked the LPS-induced TNF-α release. 3. To investigate which of these pathways contribute to the inhibitory effects of luteolin on TNF-α release, cells were pretreated with pharmacological inhibitors of these pathways; PD98059 and SB203580 when used alone failed to inhibit TNF-α release, whereas pretreatment with both agents attenuated TNF-α release. 4. We have previously shown that luteolin blocks Akt phosphorylation in response to LPS in RAW 264.7 macrophages. To determine the role of Akt in TNF-α release, cells were transiently transfected with a dominant negative form of Akt (K179M). Overexpression of K179M Akt did not alter LPS-induced TNF-α release, suggesting that inhibition of this kinase does not mediate the inhibitory action of luteolin. 5. In addition, DRB (a pharmacological inhibitor of CK2) blocked TNF-α release in a concentration-dependent manner, whereas co-treatment of cells with luteolin and DRB did not have an additive effect. 6. We conclude that luteolin interferes with LPS signalling by reducing the activation of several MAPK family members and that its inhibitory action on TNF-α release correlates with inhibition of ERK, p38 and CK2 activation.

Original languageEnglish (US)
Pages (from-to)1058-1064
Number of pages7
JournalBritish Journal of Pharmacology
Volume136
Issue number7
DOIs
StatePublished - Aug 26 2002
Externally publishedYes

Fingerprint

Luteolin
Flavonoids
Macrophages
Dichlororibofuranosylbenzimidazole
Phosphorylation
Pharmacology
Aptitude
Inhibition (Psychology)
Mitogen-Activated Protein Kinases
Phosphotransferases
Gene Expression

Keywords

  • Casein kinase 2
  • Lipopolysaccharide
  • Luteolin
  • MAPK
  • Tumour necrosis factor-α

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibition of LPS-stimulated pathways in macrophages by the flavonoid luteolin. / Xagorari, Angeliki; Roussos, Charis; Papapetropoulos, Andreas.

In: British Journal of Pharmacology, Vol. 136, No. 7, 26.08.2002, p. 1058-1064.

Research output: Contribution to journalArticle

@article{432e5db600624ef7805de92e06f71728,
title = "Inhibition of LPS-stimulated pathways in macrophages by the flavonoid luteolin",
abstract = "1. We have previously shown that the flavonoid luteolin inhibits the expression of pro-inflammatory molecules induced by LPS. In the present study we tested the ability of luteolin to block signalling pathways implicated in LPS-induced inflammatory gene expression in macrophages. 2. Exposure of the murine macrophage cell line RAW 264.7 to LPS increased phosphorylation of the mitogen-activated protein kinase family members ERK1/2, p38 and JNK1/2 in a time-dependent manner. Pretreatment of RAW 264.7 with luteolin inhibited the LPS-induced ERK1/2 and p38, but not JNK1/2, phosphorylation, and blocked the LPS-induced TNF-α release. 3. To investigate which of these pathways contribute to the inhibitory effects of luteolin on TNF-α release, cells were pretreated with pharmacological inhibitors of these pathways; PD98059 and SB203580 when used alone failed to inhibit TNF-α release, whereas pretreatment with both agents attenuated TNF-α release. 4. We have previously shown that luteolin blocks Akt phosphorylation in response to LPS in RAW 264.7 macrophages. To determine the role of Akt in TNF-α release, cells were transiently transfected with a dominant negative form of Akt (K179M). Overexpression of K179M Akt did not alter LPS-induced TNF-α release, suggesting that inhibition of this kinase does not mediate the inhibitory action of luteolin. 5. In addition, DRB (a pharmacological inhibitor of CK2) blocked TNF-α release in a concentration-dependent manner, whereas co-treatment of cells with luteolin and DRB did not have an additive effect. 6. We conclude that luteolin interferes with LPS signalling by reducing the activation of several MAPK family members and that its inhibitory action on TNF-α release correlates with inhibition of ERK, p38 and CK2 activation.",
keywords = "Casein kinase 2, Lipopolysaccharide, Luteolin, MAPK, Tumour necrosis factor-α",
author = "Angeliki Xagorari and Charis Roussos and Andreas Papapetropoulos",
year = "2002",
month = "8",
day = "26",
doi = "10.1038/sj.bjp.0704803",
language = "English (US)",
volume = "136",
pages = "1058--1064",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "7",

}

TY - JOUR

T1 - Inhibition of LPS-stimulated pathways in macrophages by the flavonoid luteolin

AU - Xagorari, Angeliki

AU - Roussos, Charis

AU - Papapetropoulos, Andreas

PY - 2002/8/26

Y1 - 2002/8/26

N2 - 1. We have previously shown that the flavonoid luteolin inhibits the expression of pro-inflammatory molecules induced by LPS. In the present study we tested the ability of luteolin to block signalling pathways implicated in LPS-induced inflammatory gene expression in macrophages. 2. Exposure of the murine macrophage cell line RAW 264.7 to LPS increased phosphorylation of the mitogen-activated protein kinase family members ERK1/2, p38 and JNK1/2 in a time-dependent manner. Pretreatment of RAW 264.7 with luteolin inhibited the LPS-induced ERK1/2 and p38, but not JNK1/2, phosphorylation, and blocked the LPS-induced TNF-α release. 3. To investigate which of these pathways contribute to the inhibitory effects of luteolin on TNF-α release, cells were pretreated with pharmacological inhibitors of these pathways; PD98059 and SB203580 when used alone failed to inhibit TNF-α release, whereas pretreatment with both agents attenuated TNF-α release. 4. We have previously shown that luteolin blocks Akt phosphorylation in response to LPS in RAW 264.7 macrophages. To determine the role of Akt in TNF-α release, cells were transiently transfected with a dominant negative form of Akt (K179M). Overexpression of K179M Akt did not alter LPS-induced TNF-α release, suggesting that inhibition of this kinase does not mediate the inhibitory action of luteolin. 5. In addition, DRB (a pharmacological inhibitor of CK2) blocked TNF-α release in a concentration-dependent manner, whereas co-treatment of cells with luteolin and DRB did not have an additive effect. 6. We conclude that luteolin interferes with LPS signalling by reducing the activation of several MAPK family members and that its inhibitory action on TNF-α release correlates with inhibition of ERK, p38 and CK2 activation.

AB - 1. We have previously shown that the flavonoid luteolin inhibits the expression of pro-inflammatory molecules induced by LPS. In the present study we tested the ability of luteolin to block signalling pathways implicated in LPS-induced inflammatory gene expression in macrophages. 2. Exposure of the murine macrophage cell line RAW 264.7 to LPS increased phosphorylation of the mitogen-activated protein kinase family members ERK1/2, p38 and JNK1/2 in a time-dependent manner. Pretreatment of RAW 264.7 with luteolin inhibited the LPS-induced ERK1/2 and p38, but not JNK1/2, phosphorylation, and blocked the LPS-induced TNF-α release. 3. To investigate which of these pathways contribute to the inhibitory effects of luteolin on TNF-α release, cells were pretreated with pharmacological inhibitors of these pathways; PD98059 and SB203580 when used alone failed to inhibit TNF-α release, whereas pretreatment with both agents attenuated TNF-α release. 4. We have previously shown that luteolin blocks Akt phosphorylation in response to LPS in RAW 264.7 macrophages. To determine the role of Akt in TNF-α release, cells were transiently transfected with a dominant negative form of Akt (K179M). Overexpression of K179M Akt did not alter LPS-induced TNF-α release, suggesting that inhibition of this kinase does not mediate the inhibitory action of luteolin. 5. In addition, DRB (a pharmacological inhibitor of CK2) blocked TNF-α release in a concentration-dependent manner, whereas co-treatment of cells with luteolin and DRB did not have an additive effect. 6. We conclude that luteolin interferes with LPS signalling by reducing the activation of several MAPK family members and that its inhibitory action on TNF-α release correlates with inhibition of ERK, p38 and CK2 activation.

KW - Casein kinase 2

KW - Lipopolysaccharide

KW - Luteolin

KW - MAPK

KW - Tumour necrosis factor-α

UR - http://www.scopus.com/inward/record.url?scp=0036024242&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036024242&partnerID=8YFLogxK

U2 - 10.1038/sj.bjp.0704803

DO - 10.1038/sj.bjp.0704803

M3 - Article

C2 - 12145106

AN - SCOPUS:0036024242

VL - 136

SP - 1058

EP - 1064

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 7

ER -