The Flavonoid Quercetin Inhibits Proinflammatory Cytokine (Tumor Necrosis Factor Alpha) Gene Expression in Normal Peripheral Blood Mononuclear Cells via Modulation of the NF-κβ System

Madhavan Nair

Supriya Mahajan

Jessica Reynolds

Ravikumar Aalinkeel

Harikrishnan Nair

Stanley Schwartz

Chithan Kandaswami

Department of Medicine and Microbiology, Kaleida Health System, Buffalo General Hospital, State University of New York at Buffalo, Buffalo, New York 14203

^{Corresponding author. Mailing address: Department of Medicine, Division of Allergy, Immunology, and Rheumatology, 310 Multi Research Bldg., Buffalo General Hospital, 100 High Street, Buffalo, NY 14203. Phone: (716) 859-2985. Fax: (716) 859-2999. E-mail:}ude.olaffub.usca@rianm.

Received 2005 Jul 11; Revised 2005 Aug 11; Accepted 2006 Jan 4.

Abstract

The flavonoids comprise a large class of low-molecular-weight plant metabolites ubiquitously distributed in food plants. These dietary antioxidants exert significant antitumor, antiallergic, and anti-inflammatory effects. The molecular mechanisms of their biological effects remain to be clearly understood. We investigated the anti-inflammatory potentials of a safe, common dietary flavonoid component, quercetin, for its ability to modulate the production and gene expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) by human peripheral blood mononuclear cells (PBMC). Our results showed that quercetin significantly inhibited TNF-α production and gene expression in a dose-dependent manner. Our results provide direct evidence of the anti-inflammatory effects of quercetin by PBMC, which are mediated by the inhibition of the proinflammatory cytokine TNF-α via modulation of NF-κβ1 and Iκβ.

Abstract

The natural antioxidant flavonoids constitute significant components of the diet and display a diverse array of biological effects (16, 19, 21, 26). Polyphenolic compounds, including a large class of flavonoids, are enriched in certain vegetables, fruits, seeds, and beverages (e.g., tea and wine) and are regarded as a class of semiessential nutrients for humans. Dietary intake rich in these compounds has been suggested to improve the health of individuals and decrease the risk of cardiovascular disease. The beneficial effects of flavonoids have been attributed to their antioxidant and anti-inflammatory properties (18, 19, 31). The effects of flavonoids, including quercetin, on a variety of inflammatory processes and immune functions have been extensively reviewed (4, 6, 11, 17, 25, 27, 28, 40). Tumor necrosis factor alpha (TNF-α) is one of the major proinflammatory cytokines involved in the pathogenesis of chronic inflammatory diseases and is modulated by oxidative stress (5, 35). TNF-α is a multifunctional cytokine that regulates the growth, proliferation, differentiation, and viability of activated leukocytes. TNF-α also triggers the cellular release of other cytokines, chemokines, or inflammatory mediators and displays antiviral and antimicrobial effects (1, 2, 39).

Numerous signaling cascades have been elucidated in promotion of proinflammatory conditions by proinflammatory cytokines, such as TNF-α, which involves the activation of inducible transcriptional factors (1, 12, 13, 14, 29, 39). NF-κβ is one of the principal inducible transcription factors whose modulation triggers a cascade of signaling events involving an integrated sequence of protein-regulated steps, some of which are potential key targets for intervention in treating inflammatory conditions (3, 7, 20, 29, 33, 34). Previous studies have shown that quercetin inhibits lipopolysaccharide (LPS)-stimulated NF-κβ activation in RAW 264.7 macrophage (8, 37) and also inhibits LPS-induced Iκβ phosphorylation in bone marrow-derived macrophage (11). Although quercetin exhibits several biological effects, the molecular mechanisms of its anti-inflammatory effects by peripheral blood mononuclear cells (PBMCs) have not been clearly elucidated. We hypothesize that flavonoids exert anti-inflammatory effects by PBMCs by inhibiting the endogenous production of the proinflammatory cytokine TNF-α and that these effects are mediated through the regulation of NF-κβ and Iκβ. Therefore, the present study was undertaken to investigate the direct effect of quercetin on the gene expression and protein secretion of the proinflammatory cytokine TNF-α. We further investigated whether the transcription factor NF-κβ was involved in the regulation of TNF-α by quercetin by normal PBMCs.

Acknowledgments

This work was supported in part by NIH grants NIDA, RO1-DA15628, RO1-DA12366, and RO-DA14218; the Margaret Duffy and Robert Cameron Troup Memorial Fund for Cancer Research of the Kaleida Health System; Buffalo General Foundation; and the State University of New York.

Acknowledgments

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