Browse > Article
http://dx.doi.org/10.3904/kjim.2016.053

Grape seed proanthocyanidin extract ameliorates murine autoimmune arthritis through regulation of TLR4/MyD88/NF-κB signaling pathway  

Kim, Sang-Hyon (Division of Rheumatology, Department of Internal Medicine, Keimyung University Dongsan Medical Center)
Bang, Jihye (Keimyung University School of Medicine)
Son, Chang-Nam (Division of Rheumatology, Department of Internal Medicine, Keimyung University Dongsan Medical Center)
Baek, Won-Ki (Department of Microbiology, Keimyung University School of Medicine)
Kim, Ji-Min (Division of Rheumatology, Department of Internal Medicine, Keimyung University Dongsan Medical Center)
Publication Information
The Korean journal of internal medicine / v.33, no.3, 2018 , pp. 612-621 More about this Journal
Abstract
Background/Aims: Grape seed proanthocyanidin extract (GSPE) has been reported to have a beneficial effect on regulating inf lammation. However, the anti-inflammatory mechanism of GSPE remains unclear. The aim of this study was to verify the influence of GSPE on the Toll-like receptor 4 (TLR4)-mediated signaling pathway in the regulation of murine autoimmune arthritis. Methods: Collagen-induced arthritis (CIA) was induced in dilute brown non-agouti (DBA)/1J mice. The mice were treated with GSPE (0 or 100 mg/kg) intraperitoneally. The severity of arthritis was assessed clinically, biochemically, and histologically. Immunostaining for TLR4 was performed. The expressions of TLR4 and downstream signaling molecules were analyzed by Western blot. The effect of GSPE on lipopolysaccharide (LPS)-induced TLR4 activation was also evaluated using RAW264.7 cells and fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis and from those with osteoarthritis. Results: GSPE attenuated the clinical severity of arthritis and decreased histological damage. GSPE treatment reduced the number of TLR4-stained cells in the synovium of mice with CIA. GSPE also downregulated the expression of TLR4, myeloid differentiation factor 88 (MyD88) and phosphorylated $I{\kappa}B{\alpha}$ synovial protein in CIA mice. Concurrently, GSPE inhibited the nuclear translocation of nuclear $factor-{\kappa}B$ ($NF-{\kappa}B$) subunits (p65 and p50). LPS-induced TLR4 activation was suppressed by GSPE in human FLS as well as in murine macrophages in vitro. Conclusions: Our results demonstrated that GSPE ameliorated CIA by regulating the $TLR4-MyD88-NF-{\kappa}B$ signaling pathway.
Keywords
Grape seed proanthocyanidin extract; Arthritis; experimental; Toll-like receptor 4; Arthritis; rheumatoid;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Lorenz W, Buhrmann C, Mobasheri A, Lueders C, Shakibaei M. Bacterial lipopolysaccharides form procollagen-endotoxin complexes that trigger cartilage inflammation and degeneration: implications for the development of rheumatoid arthritis. Arthritis Res Ther 2013;15:R111.   DOI
2 Radstake TR, Franke B, Hanssen S, et al. The Toll-like receptor 4 Asp299Gly functional variant is associated with decreased rheumatoid arthritis disease susceptibility but does not influence disease severity and/or outcome. Arthritis Rheum 2004;50:999-1001.   DOI
3 Yang H, Wei C, Li Q, et al. Association of TLR4 gene non-missense single nucleotide polymorphisms with rheumatoid arthritis in Chinese Han population. Rheumatol Int 2013;33:1283-1288.   DOI
4 Palsson-McDermott EM, O'Neill LA. Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology 2004;113:153-162.   DOI
5 Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 2010;233:233-255.   DOI
6 Huang QQ, Pope RM. The role of toll-like receptors in rheumatoid arthritis. Curr Rheumatol Rep 2009;11:357-364.   DOI
7 Davignon JL, Hayder M, Baron M, et al. Targeting monocytes/macrophages in the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2013;52:590-598.   DOI
8 Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. Type 17 T helper cells-origins, features and possible roles in rheumatic disease. Nat Rev Rheumatol 2009;5:325-331.   DOI
9 Pasare C, Medzhitov R. Toll-like receptors: linking innate and adaptive immunity. Adv Exp Med Biol 2005;560:11-18.
10 Radstake TR, Roelofs MF, Jenniskens YM, et al. Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma. Arthritis Rheum 2004;50:3856-3865.   DOI
11 Ospelt C, Brentano F, Rengel Y, et al. Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: toll-like receptor expression in early and longstanding arthritis. Arthritis Rheum 2008;58:3684-3692.   DOI
12 Li WG, Zhang XY, Wu YJ, Tian X. Anti-inflammatory effect and mechanism of proanthocyanidins from grape seeds. Acta Pharmacol Sin 2001;22:1117-1120.
13 Davis ML, LeVan TD, Yu F, et al. Associations of toll-like receptor (TLR)-4 single nucleotide polymorphisms and rheumatoid arthritis disease progression: an observational cohort study. Int Immunopharmacol 2015;24:346-352.   DOI
14 Bagchi D, Bagchi M, Stohs SJ, et al. Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention. Toxicology 2000;148:187-197.   DOI
15 Gabetta B, Fuzzati N, Griffini A, et al. Characterization of proanthocyanidins from grape seeds. Fitoterapia 2000;71:162-175.   DOI
16 Fine AM. Oligomeric proanthocyanidin complexes: history, structure, and phytopharmaceutical applications. Altern Med Rev 2000;5:144-151.
17 Zhang XY, Li WG, Wu YJ, Bai DC, Liu NF. Proanthocyanidin from grape seeds enhances doxorubicin-induced antitumor effect and reverses drug resistance in doxorubicin-resistant K562/DOX cells. Can J Physiol Pharmacol 2005;83:309-318.   DOI
18 Li XL, Cai YQ, Qin H, Wu YJ. Therapeutic effect and mechanism of proanthocyanidins from grape seeds in rats with TNBS-induced ulcerative colitis. Can J Physiol Pharmacol 2008;86:841-849.   DOI
19 Meeran SM, Vaid M, Punathil T, Katiyar SK. Dietary grape seed proanthocyanidins inhibit 12-O-tetradecanoyl phorbol-13-acetate-caused skin tumor promotion in 7,12-dimethylbenz[a]anthracene-initiated mouse skin, which is associated with the inhibition of inflammatory responses. Carcinogenesis 2009;30:520-528.   DOI
20 Cho ML, Heo YJ, Park MK, et al. Grape seed proanthocyanidin extract (GSPE) attenuates collagen-induced arthritis. Immunol Lett 2009;124:102-110.   DOI
21 Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-2581.   DOI
22 Pierer M, Wagner U, Rossol M, Ibrahim S. Toll-like receptor 4 is involved in inflammatory and joint destructive pathways in collagen-induced arthritis in DBA1J mice. PLoS One 2011;6:e23539.   DOI
23 Abdollahi-Roodsaz S, Joosten LA, Roelofs MF, et al. Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum 2007;56:2957-2967.   DOI
24 Kim H, Kim JY, Song HS, Park KU, Mun KC, Ha E. Grape seed proanthocyanidin extract inhibits interleukin-17-induced interleukin-6 production via MAPK pathway in human pulmonary epithelial cells. Naunyn Schmiedebergs Arch Pharmacol 2011;383:555-562.   DOI
25 Bravo L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev 1998;56:317-333.
26 Bagchi D, Garg A, Krohn RL, Bagchi M, Tran MX, Stohs SJ. Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro. Res Commun Mol Pathol Pharmacol 1997;95:179-189.
27 Chacon MR, Ceperuelo-Mallafre V, Maymo-Masip E, et al. Grape-seed procyanidins modulate inflammation on human differentiated adipocytes in vitro. Cytokine 2009;47:137-142.   DOI
28 Park JS, Park MK, Oh HJ, et al. Grape-seed proanthocyanidin extract as suppressors of bone destruction in inflammatory autoimmune arthritis. PLoS One 2012;7:e51377.   DOI
29 Jhun JY, Moon SJ, Yoon BY, et al. Grape seed proanthocyanidin extract-mediated regulation of STAT3 proteins contributes to Treg differentiation and attenuates inflammation in a murine model of obesity-associated arthritis. PLoS One 2013;8:e78843.   DOI
30 Choi EM. Oxidative status of DBA/1J mice with type II collagen-induced arthritis. J Appl Toxicol 2007;27:472-481.   DOI
31 McCubbin MD, Hou G, Abrams GD, Dick R, Zhang Z, Brewer GJ. Tetrathiomolybdate is effective in a mouse model of arthritis. J Rheumatol 2006;33:2501-2506.
32 Gelderman KA, Hultqvist M, Pizzolla A, et al. Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species. J Clin Invest 2007;117:3020-3028.   DOI
33 Park MK, Park JS, Cho ML, et al. Grape seed proanthocyanidin extract (GSPE) differentially regulates Foxp3(+) regulatory and IL-17(+) pathogenic T cell in autoimmune arthritis. Immunol Lett 2011;135:50-58.   DOI
34 Ahmad SF, Zoheir KM, Abdel-Hamied HE, et al. Grape seed proanthocyanidin extract has potent anti-arthritic effects on collagen-induced arthritis by modifying the T cell balance. Int Immunopharmacol 2013;17:79-87.   DOI
35 Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997;388:394-397.   DOI
36 Sadanaga A, Nakashima H, Akahoshi M, et al. Protection against autoimmune nephritis in MyD88-deficient MRL/lpr mice. Arthritis Rheum 2007;56:1618-1628.   DOI
37 Kowalski ML, Wolska A, Grzegorczyk J, et al. Increased responsiveness to toll-like receptor 4 stimulation in peripheral blood mononuclear cells from patients with recent onset rheumatoid arthritis. Mediators Inflamm 2008;2008:132732.
38 Chovanova L, Vlcek M, Krskova K, et al. Increased production of IL-6 and IL-17 in lipopolysaccharide-stimulated peripheral mononuclears from patients with rheumatoid arthritis. Gen Physiol Biophys 2013;32:395-404.
39 Tang CH, Hsu CJ, Yang WH, Fong YC. Lipoteichoic acid enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, PKCdelta and c-Src dependent pathways. Biochem Pharmacol 2010;79:1648-1657.   DOI