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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Luteolin Inhibits an Endotoxin-Stimulated Phosphorylation Cascade and Proinflammatory Cytokine Production in Macrophages

Angeliki Xagorari, Andreas Papapetropoulos, Antonis Mauromatis, Michalis Economou, Theodore Fotsis and Charis Roussos
Journal of Pharmacology and Experimental Therapeutics January 2001, 296 (1) 181-187;
Angeliki Xagorari
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Andreas Papapetropoulos
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Antonis Mauromatis
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Michalis Economou
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Theodore Fotsis
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Charis Roussos
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Abstract

Flavonoids are naturally occurring polyphenolic compounds with a wide distribution throughout the plant kingdom. In the present study, we compared the ability of several flavonoids to modulate the production of proinflammatory molecules from lipopolysaccharide (LPS)-stimulated macrophages and investigated their mechanism(s) of action. Pretreatment of RAW 264.7 with luteolin, luteolin-7-glucoside, quercetin, and the isoflavonoid genistein inhibited both the LPS-stimulated TNF-α and interleukin-6 release, whereas eriodictyol and hesperetin only inhibited TNF-α release. From the compounds tested luteolin and quercetin were the most potent in inhibiting cytokine production with an IC50 of less than 1 and 5 μM for TNF-α release, respectively. To determine the mechanisms by which flavonoids inhibit LPS signaling, we used luteolin and determined its ability to interfere with total protein tyrosine phosphorylation as well as Akt phosphorylation and nuclear factor-κB activation. Pretreatment of the cells with luteolin attenuated LPS-induced tyrosine phosphorylation of many discrete proteins. Moreover, luteolin inhibited LPS-induced phosphorylation of Akt. Treatment of macrophages with LPS resulted in increased IκB-α phosphorylation and reduced the levels of IκB-α. Pretreatment of cells with luteolin abolished the effects of LPS on IκB-α. To determine the functional relevance of the phosphorylation events observed with IκB-α, macrophages were transfected either with a control vector or a vector coding for the luciferase reporter gene under the control of κBcis-acting elements. Incubation of transfected RAW 264.7 cells with LPS increased luciferase activity in a luteolin-sensitive manner. We conclude that luteolin inhibits protein tyrosine phosphorylation, nuclear factor-κB-mediated gene expression and proinflammatory cytokine production in murine macrophages.

Footnotes

  • Send reprint requests to: Andreas Papapetropoulos, Ph.D., “George P Livanos” Laboratory, University of Athens, Ploutarchou 3, Athens, Greece 10675. E-mail:andreaspap{at}altavista.net

  • This study was supported by a grant by the Greek Secretariat of Research and Technology and by the Thorax Foundation.

  • Abbreviations:
    LPS
    lipopolysaccharide
    TNF-α
    tumor necrosis factor-α
    IL-6
    interleukin-6
    NO
    nitric oxide
    iNOS
    inducible nitric-oxide synthase
    NF-κB
    nuclear factor-κB
    EtOH
    ethanol
    DMSO
    dimethyl sulfoxide
    DMEM
    Dulbecco's modified Eagle's medium
    TTBS
    Tween 20 in Tris-buffered saline
    PAGE
    polyacrylamide gel electrophoresis
    Ab
    antibody
    • Received May 31, 2000.
    • Accepted August 30, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 296 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 296, Issue 1
1 Jan 2001
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Luteolin Inhibits an Endotoxin-Stimulated Phosphorylation Cascade and Proinflammatory Cytokine Production in Macrophages

Angeliki Xagorari, Andreas Papapetropoulos, Antonis Mauromatis, Michalis Economou, Theodore Fotsis and Charis Roussos
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 181-187;

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Luteolin Inhibits an Endotoxin-Stimulated Phosphorylation Cascade and Proinflammatory Cytokine Production in Macrophages

Angeliki Xagorari, Andreas Papapetropoulos, Antonis Mauromatis, Michalis Economou, Theodore Fotsis and Charis Roussos
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 181-187;
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