Potent Inhibitory Effects of Quercetin on Inflammatory Responses of Collagen-Induced Arthritis in Mice

Author(s): Kiichiro Kawaguchi, Masahiro Kaneko*, Ryo Miyake, Hiroaki Takimoto, Yoshio Kumazawa.

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 19 , Issue 3 , 2019

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Graphical Abstract:


Background: Production of tumor necrosis factor (TNF)-α by inflammatory cells in lesions is the hallmark of the pathogenesis of rheumatoid arthritis (RA). Regulation of inflammatory responses in knee joints of patients with RA is critical for improving severe symptoms. Flavonoids have inhibitory effects on the acute and chronic inflammatory responses caused by TNF-α. The flavonoid quercetin (QUER) is one of the most prominent dietary antioxidants.

Objective: The present study investigated the preventive and therapeutic effects of QUER on inflammatory responses in collagen-induced arthritis (CIA) in mice.

Methods: Mice with CIA, a mouse model for RA, were treated with QUER orally three times a week either from the second immunization with collagen (day 21) or day 28 when symptoms of CIA had developed midway.

Results: In both cases, inflammation-related clinical scores of knee joints were significantly reduced by treatment with QUER. Histological analyses showed that the representative characteristics of RA, such as damage to interchondral joints, infiltration of inflammatory cells, and pannus formation, were significantly reduced by QUER treatment. Oral administration of QUER significantly decreases lipopolysaccharide (LPS)-induced TNF-α production in a dose-dependent manner. Expression of TNF- α mRNA in knee joints was decreased in QUER-treated mice, compared with those of CIA controls.

Conclusion: These results suggest that oral administration of QUER might effectively improve symptoms of RA.

Keywords: Quercetin, rheumatoid arthritis, inflammation, knee joints, tumor necrosis factor-α, lipopolysaccharide.

Kumazawa, Y.; Kawaguchi, K.; Takimoto, H. Immunomodulating effects of flavonoids on acute and chronic inflammatory responses caused by tumor necrosis factor-α. Curr. Pharm. Des., 2006, 12, 427-429.
Tracey, K.J.; Cerami, A. Cachectin/tumor necrosis factor and other cytokines in infectious disease. Curr. Opin. Immunol., 1989, 1(3), 454-461.
Dinarello, C.A. The proinflammatory cytokines interleukin-1 and tumor necrosis factor and treatment of the septic shock syndrome. J. Infect. Dis., 1991, 163(6), 1177-1184.
Feldmann, M.; Brennan, F.M.; Chantry, D.; Haworth, C.; Turner, M.; Abney, E.; Buchan, G.; Barrett, K.; Barkley, D.; Chu, A. Cytokine production in the rheumatoid joint: Implications for treatment. Ann. Rheum. Dis., 1990, 49(Suppl. 1), 480-486.
Brennan, F.M.; Maini, R.N.; Feldmann, M. TNF α--a pivotal role in rheumatoid arthritis? Br. J. Rheumatol., 1992, 31(5), 293-298.
Paska, W.; McDonald, K.J.; Croft, M. Studies on type II collagen induced arthritis in mice. Agents Actions, 1986, 18(3-4), 413-420.
Ellis, J.S.; Chain, B.M.; Cooke, A.; Ibrahim, M.A.; Katz, D.R. Adjuvant composition determines the induction of type II collagen-induced arthritis. Scand. J. Immunol., 1992, 36(1), 49-56.
Williams, R.O.; Feldmann, M.; Maini, R.N. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. USA, 1992, 89(20), 9784-9788.
Breedveld, F.C.; van der Lubbe, P.A. Monoclonal antibody therapy of inflammatory rheumatic diseases. Br. Med. Bull., 1995, 51(2), 493-502.
Feldmann, M.; Maini, R.N. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu. Rev. Immunol., 2001, 19, 1631-1696.
Padyukov, L.; Lampa, J.; Heimbürger, M.; Ernestam, S.; Cederholm, T.; Lundkvist, I.; Andersson, P.; Hermansson, Y.; Harju, A.; Klareskog, L.; Bratt, J. Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann. Rheum. Dis., 2003, 62(6), 526-529.
Ranganathan, P. Pharmacogenomics of tumor necrosis factor antagonists in rheumatoid arthritis. Pharmacogenomics, 2005, 6(5), 481-490.
Ueda, H.; Yamazaki, C.; Yamazaki, M. A hydroxyl group of flavonoids affects oral anti-inflammatory activity and inhibition of systemic tumor necrosis factor-alpha production. Biosci. Biotechnol. Biochem., 2004, 68(1), 119-125.
Wadsworth, T.L.; McDonald, T.L.; Koop, D.R. Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor-alpha. Biochem. Pharmacol., 2001, 62(7), 963-974.
Okoko, T.; Oruambo, I.F. Inhibitory activity of quercetin and its metabolite on lipopolysaccharide-induced activation of macrophage U937 cells. Food Chem. Toxicol., 2009, 47(4), 809-812.
Xagorari, A.; Papapetropoulos, A.; Mauromatis, A.; Economou, M.; Fotsis, T.; Roussos, C. Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages. J. Pharmacol. Exp. Ther., 2001, 296(1), 181-187.
Kotanidou, A.; Xagorari, A.; Bagli, E.; Kitsanta, P.; Fotsis, T.; Papapetropoulos, A.; Roussos, C. Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice. Am. J. Respir. Crit. Care Med., 2002, 165(6), 818-823.
Smolinski, A.T.; Pestka, J.J. Modulation of lipopolysaccharide-induced proinflammatory cytokine production in vitro and in vivo by the herbal constituents apigenin (chamomile), ginsenoside Rb(1) (ginseng) and parthenolide (feverfew). Food Chem. Toxicol., 2003, 41(10), 1381-1390.
Nicholas, C.; Batra, S.; Vargo, M.A.; Voss, O.H.; Gavrilin, M.A.; Wewers, M.D.; Guttridge, D.C.; Grotewold, E.; Doseff, A.I. Apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating NF-κB through the suppression of p65 phosphorylation. J. Immunol., 2007, 179(10), 7121-7127.
Rogers, J.; Perkins, I.; van Olphen, A.; Burdash, N.; Klein, T.W.; Friedman, H. Epigallocatechin gallate modulates cytokine production by bone marrow-derived dendritic cells stimulated with lipopolysaccharide or muramyldipeptide, or infected with Legionella pneumophila. Exp. Biol. Med., 2005, 230(9), 645-651.
Bae, H.B.; Li, M.; Kim, J.P.; Kim, S.J.; Jeong, C.W.; Lee, H.G.; Kim, W.M.; Kim, H.S.; Kwak, S.H. The effect of epigallocatechin gallate on lipopolysaccharide-induced acute lung injury in a murine model. Inflammation, 2010, 33(2), 82-91.
Liu, L.L.; Gong, L.K.; Wang, H.; Xiao, Y.; Wu, X.F.; Zhang, Y.H.; Xue, X.; Qi, X.M.; Ren, J. Baicalin inhibits macrophage activation by lipopolysaccharide and protects mice from endotoxin shock. Biochem. Pharmacol., 2008, 75(4), 914-922.
Wan, J.Y.; Gong, X.; Zhang, L.; Li, H.Z.; Zhou, Y.F.; Zhou, Q.X. Protective effect of baicalin against lipopolysaccharide/D-galactosamine-induced liver injury in mice by up-regulation of heme oxygenase-1. Eur. J. Pharmacol., 2008, 587(1-3), 302-308.
Kawaguchi, K.; Kikuchi, S.; Hasegawa, H.; Maruyama, H.; Morita, H.; Kumazawa, Y. Suppression of lipopolysaccharide-induced tumor necrosis factor-release and liver injury in mice by naringin. Eur. J. Pharmacol., 1999, 368, 245-250.
Kawaguchi, K.; Kikuchi, S.; Hasunuma, R.; Maruyama, H.; Ryll, R.; Kumazawa, Y. Suppression of infection-induced endotoxin shock in mice by a citrus flavanone naringin. Planta Med., 2004, 70, 17-22.
Kawaguchi, K.; Maruyama, H.; Kometani, T.; Kumazawa, Y. Suppression of collagen-induced arthritis by oral administration of the Citrus flavonoid hesperidin. Planta Med., 2006, 72, 477-479.
Kawaguchi, K.; Maruyama, H.; Hasunuma, R.; Kumazawa, Y. Suppression of inflammatory responses after onset of collagen-induced arthritis in mice by oral administration of the citrus flavanone naringin. Immunopharmacol. Immunotoxicol., 2011, 33, 723-729.
Terao, J. Dietary flavonoids as antioxidants in vivo: conjugated metabolites of (-)-epicatechin and quercetin participate in antioxidative defense in blood plasma. J. Med. Invest., 1999, 46(3-4), 159-168.
Terao, J.; Murota, K.; Kawai, Y. Conjugated quercetin glucuronides as bioactive metabolites and precursors of aglycone in vivo. Food Funct., 2011, 2(1), 11-17.
Kamada, C.; Mukai, R.; Kondo, A.; Sato, S.; Terao, J. Effect of quercetin and its metabolite on caveolin-1 expression induced by oxidized LDL and lysophosphatidylcholine in endothelial cells. J. Clin. Biochem. Nutr., 2016, 58(3), 193-201.
Conquer, J.A.; Maiani, G.; Azzini, E.; Raguzzini, A.; Holub, B.J. Supplementation with quercetin markedly increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects. J. Nutr., 1998, 128(3), 593-597.
Egert, S.; Bosy-Westphal, A.; Seiberl, J.; Kürbitz, C. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br. J. Nutr., 2009, 102(7), 1065-1074.
Heinz, S.A.; Henson, D.A.; Nieman, D.C.; Austin, M.D.; Jin, F. A 12-week supplementation with quercetin does not affect natural killer cell activity, granulocyte oxidative burst activity or granulocyte phagocytosis in female human subjects. Br. J. Nutr., 2010, 104(6), 849-857.
Bae, S.C.; Jung, W.J.; Lee, E.J.; Yu, R.; Sung, M.K. Effects of antioxidant supplements intervention on the level of plasma inflammatory molecules and disease severity of rheumatoid arthritis patients. J. Am. Coll. Nutr., 2009, 28(1), 56-62.
Lesser, S.; Cermak, R.; Wolffram, S. The fatty acid pattern of dietary fat influences the oral bioavailability of the flavonol quercetin in pigs. Br. J. Nutr., 2006, 96(6), 1047-1052.
Sugiyama, T.; Kawaguchi, K.; Dobashi, H.; Miyake, R.; Kaneko, M.; Kumazawa, Y. Quercetin but not luteolin suppresses the induction of lethal shock upon infection of mice with Salmonella typhimurium. FEMS Immunol. Med. Microbiol., 2008, 53(3), 306-313.

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Year: 2019
Page: [308 - 315]
Pages: 8
DOI: 10.2174/1871530319666190206225034
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