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Grape seed proanthocyanidin extract inhibits interleukin-17-induced interleukin-6 production via MAPK pathway in human pulmonary epithelial cells

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Abstract

This study was aimed to investigate the effect of grape seed proanthocyanidin extract (GSPE) on interleukin-17 (IL-17)-induced interleukin-6 (IL-6) production in A549 human pulmonary epithelial cells. Cells were treated with IL-17 (10 ng/ml) or GSPE (50 μg/ml), or both. The effects of GSPE on cell viability and apoptosis were evaluated. The mRNA and protein levels of IL-6 were determined by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Expressions of inhibitory factor κB-α (IκB-α) and ERK 1/2, p38, and JNK mitogen-activated protein kinase (MAPK) were examined by Western blot analysis. GSPE significantly inhibited both GSPE treatment only and IL-17-induced mRNA expressions and protein productions of IL-6 in pulmonary epithelial cells (p < 0.01). GSPE decreased the IL-17-induced phosphorylation of IκB-α. The IL-17 stimulated ERK 1/2, p38, and JNK MAPK activities and GSPE decreased IL-17-stimulated ERK 1/2, p38, and JNK MAPK activities. GSPE also attenuated TNF-α and IL-1β-induced IL-6 productions (p < 0.05). Our results show that GSPE may inhibit IL-17-stimulated IL-6 productions in human pulmonary epithelial cells by inhibiting MAPK and nuclear factor-κB-mediated signaling pathway.

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References

  • Akhtar S, Meeran SM, Katiyar N, Katiyar SK (2009) Grape seed proanthocyanidins inhibit the growth of human non-small cell lung cancer xenografts by targeting insulin-like growth factor binding protein-3, tumor cell proliferation, and angiogenic factors. Clin Cancer Res 15:821–831

    Article  PubMed  CAS  Google Scholar 

  • Awane M, Andres PG, Li DJ, Reinecker HC (1999) NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells. J Immunol 162:5337–5344

    PubMed  CAS  Google Scholar 

  • Bagchi D, Das DK, Engelman RM, Prasad MR, Subramanian R (1990) Polymorphonuclear leucocytes as potential source of free radicals in the ischaemic-reperfused myocardium. Eur Heart J 11:800–813

    PubMed  CAS  Google Scholar 

  • Bagchi D, Garg A, Krohn RL, Bagchi M, Tran MX, Stohs SJ (1997) Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro. Res Commun Mol Pathol Pharmacol 95:179–189

    PubMed  CAS  Google Scholar 

  • Bagchi D, Bagchi M, Stohs SJ, Das DK, Ray SD, Kuszynski CA et al (2000) Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention. Toxicology 148:187–197

    Article  PubMed  CAS  Google Scholar 

  • Bagchi D, Sen CK, Ray SD, Das DK, Bagchi M, Preuss HG et al (2003) Molecular mechanisms of cardioprotection by a novel grape seed proanthocyanidin extract. Mutat Res 523–524:87–97

    PubMed  Google Scholar 

  • Chacon MR, Ceperuelo-Mallafre V, Maymo-Masip E, Mateo-Sanz JM, Arola L, Guitierrez C et al (2009) Grape-seed procyanidins modulate inflammation on human differentiated adipocytes in vitro. Cytokine 47:137–142

    Article  PubMed  CAS  Google Scholar 

  • Cho ML, Heo YJ, Park MK, Oh HJ, Park JS, Woo YJ et al (2009) Grape seed proanthocyanidin extract (GSPE) attenuates collagen-induced arthritis. Immunol Lett 124:102–110

    Article  PubMed  CAS  Google Scholar 

  • Crowe CR, Chen K, Pociask DA, Alcorn JF, Krivich C, Enelow RI et al (2009) Critical role of IL-17RA in immunopathology of influenza infection. J Immunol 183:5301–5310

    Article  PubMed  CAS  Google Scholar 

  • Hacievliyagil SS, Gunen H, Mutlu LC, Karabulut AB, Temel I (2006) Association between cytokines in induced sputum and severity of chronic obstructive pulmonary disease. Respir Med 100:846–854

    Article  PubMed  Google Scholar 

  • Halliwell B, Gutteridge JM, Cross CE (1992) Free radicals, antioxidants, and human disease: where are we now? J Lab Clin Med 119:598–620

    PubMed  CAS  Google Scholar 

  • Hashimoto T, Akiyama K, Kobayashi N, Mori A (2005) Comparison of IL-17 production by helper T cells among atopic and nonatopic asthmatics and control subjects. Int Arch Allergy Immunol 137(Suppl 1):51–54

    Article  PubMed  CAS  Google Scholar 

  • Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producting CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132

    Article  PubMed  CAS  Google Scholar 

  • Johnson-Varghese L, Brodsky N, Bhandari V (2004) Effect of antioxidants on apoptosis and cytokine release in fetal rat Type II pneumocytes exposed to hyperoxia and nitric oxide. Cytokine 28:10–16

    Article  PubMed  CAS  Google Scholar 

  • Kawaguchi M, Kokubu F, Kuga H, Matsukura S, Hoshino H, Ieki K et al (2001) Modulation of bronchial epithelial cells by IL-17. J Allergy Clin Immunol 108:804–809

    Article  PubMed  CAS  Google Scholar 

  • Kolls JK, Kanaly ST, Ramsay AJ (2003) Interleukin-17: an emerging role in lung inflammation. Am J Respir Cell Mol Biol 28:9–11

    Article  PubMed  CAS  Google Scholar 

  • Laan M, Cui ZH, Hoshino H, Lotvall J, Sjostrand M, Gruenert DC et al (1999) Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J Immunol 162:2347–2352

    PubMed  CAS  Google Scholar 

  • Laan M, Lotvall J, Chung KF, Linden A (2001) IL-17-induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen-activated protein (MAP) kinases. Br J Pharmacol 133:200–206

    Article  PubMed  CAS  Google Scholar 

  • Li H, Witte K, August M, Brausch I, Godtel-Armbrust U, Habermeier A et al (2006) Reversal of endothelial nitric oxide synthase uncoupling and up-regulation of endothelial nitric oxide synthase expression lowers blood pressure in hypertensive rats. J Am Coll Cardiol 47:2536–2544

    Article  PubMed  CAS  Google Scholar 

  • Linden A (2001) Role of interleukin-17 and the neutrophil in asthma. Int Arch Allergy Immunol 126:179–184

    Article  PubMed  CAS  Google Scholar 

  • Linden A, Hoshino H, Laan M (2000) Airway neutrophis and interleukin-17. Eur Respir J 15:973–977

    Article  PubMed  CAS  Google Scholar 

  • Linden A, Laan M, Anderson GP (2005) Neutrophils, interleukin-17A and lung disease. Eur Respir J 25:159–172

    Article  PubMed  CAS  Google Scholar 

  • Lippi G, Franchini M, Favaloro EJ, Targher G (2010) Moderate red wine consumption and cardiovascular disease risk: beyond the “French paradox”. Semin Thromb Hemost 36:59–70

    Article  PubMed  CAS  Google Scholar 

  • Liu HT, He JL, Li WM, Yang Z, Wang YX, Yin J et al (2010) Geniposide inhibits interleukin-6 and interleukin-8 production in lipopolysaccharide-induced human umbilical vein endothelial cells by blocking p38 and ERK1/2 signaling pathways. Inflamm Res 59:451–461

    Article  PubMed  CAS  Google Scholar 

  • Ma L, Gao HQ, Li BY, Ma YB, You BA, Zhang FL (2007) Grape seed proanthocyanidin extracts inhibit vascular cell adhesion molecule expression induced by advanced glycation end products through activation of peroxisome proliferators-activated receptor gamma. J Cardiovasc Pharmacol 49:293–298

    Article  PubMed  CAS  Google Scholar 

  • Ma X, Reynolds SL, Baker BJ, Li X, Benveniste EN, Qin H (2010) IL-17 enhancement of the IL-6 signaling cascade in astrocytes. J Immunol 184:4898–4906

    Article  PubMed  CAS  Google Scholar 

  • Marini M, Vittori E, Hollemborg J, Mattoli S (1992) Expression of the potent inflammatory cytokines, granulocyte-macrophage-colony-stimulating factor and interleukin-6 and interleukin-8, in bronchial epithelial cells of patients with asthma. J Allergy Clin Immunol 89:1001–1009

    Article  PubMed  CAS  Google Scholar 

  • Miljkovic D, Cvetkovic I, Vuckovic O, Stosic-Grujicic S, Mostarica Stojkovic M, Trajkovic V (2003) The role of interleukin-17 in inducible nitric oxide synthase-mediated nitric oxide production in endothelial cells. Cell Mol Life Sci 60:518–525

    Article  PubMed  CAS  Google Scholar 

  • Molet S, Hamid Q, Davoine F, Nutku E, Taha R, Page N et al (2001) IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol 108:430–438

    Article  PubMed  CAS  Google Scholar 

  • Ning W, Choi AM, Li C (2005) Carbon monoxide inhibits IL-17-induced IL-6 production through the MAPK pathway in human pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol 289:L268–L273

    Article  PubMed  CAS  Google Scholar 

  • Prause O, Laan M, Lotvall J, Linden A (2003) Pharmacological modulation of interleukin-17-induced GCP-2-, GRO-alpha- and interleukin-8 release in human bronchial epithelial cells. Eur J Pharmacol 462:193–198

    Article  PubMed  CAS  Google Scholar 

  • Renaud S, de Lorgeril M (1992) Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339:1523–1526

    Article  PubMed  CAS  Google Scholar 

  • Roussel L, Houle F, Chan C, Yao Y, Berube J, Olivenstein R et al (2010) IL-17 promotes p38 MAPK-dependent endothelial activation enhancing neutrophil recruitment to sites of inflammation. J Immunol 184:4531–4537

    Article  PubMed  CAS  Google Scholar 

  • Sen CK, Bagchi D (2001) Regulation of inducible adhesion molecule expression in human endothelial cells by grape seed proanthocyanidin extract. Mol Cell Biochem 216:1–7

    Article  PubMed  CAS  Google Scholar 

  • Shalom-Barak T, Quach J, Lotz M (1998) Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF-kappaB. J Biol Chem 273:27467–27473

    Article  PubMed  CAS  Google Scholar 

  • Sharma SD, Katiyar SK (2010) Dietary grape seed proanthocyanidins inhibit UVB-induced cyclooxygenase-2 expression and other inflammatory mediators in UVB-exposed skin and skin tumors of SKH-1 hairless mice. Pharm Res 27:1092–1102

    Article  PubMed  CAS  Google Scholar 

  • Sorescu D, Weiss D, Lassegue B, Clempus RE, Szocs K et al (2002) Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 105:1429–1435

    Article  PubMed  CAS  Google Scholar 

  • Stankiewicz W, Dabrowski MP, Chcialowski A, Plusa T (2002) Cellular and cytokine immunoregulation in patients with chronic obstructive pulmonary disease and bronchial asthma. Mediat Inflamm 11:307–312

    Article  Google Scholar 

  • Starnes T, Robertson MJ, Sledge G, Kelich S, Nakshatri H, Broxmeyer HE et al (2001) Cutting edge: IL-17F, a novel cytokine selectively expressed in activated T cells and monocytes, regulates angiogenesis and endothelial cell cytokine production. J Immunol 167:4137–4140

    PubMed  CAS  Google Scholar 

  • Terra X, Montagut G, Bustos M, Llopiz N, Ardevol A, Blade C et al (2009) Grape-seed procyanidins prevent low-grade inflammation by modulating cytokine expression in rats fed a high-fat diet. J Nutr Biochem 20:210–218

    Article  PubMed  CAS  Google Scholar 

  • Tillie-Leblond I, Pugin J, Marquette CH, Lamblin C, Saulnier F, Brichet A et al (1999) Balance between proinflammatory cytokines and their inhibitors in bronchial lavage from patients with status asthmaticus. Am J Respir Crit Care Med 159:487–494

    PubMed  CAS  Google Scholar 

  • Vanaudenaerde BM, Wuyts WA, Dupont LJ, Van Raemdonck DE, Demedts MM, Verleden GM (2003) Interleukin-17 stimulates release of interleukin-8 by human airway smooth muscle cells in vitro: a potential role for interleukin-17 and airway smooth muscle cells in bronchiolitis obliterans syndrome. J Heart Lung Transplant 22:1280–1283

    Article  PubMed  Google Scholar 

  • Wong CK, Ho CY, Li EK, Lam CW (2000) Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 9:589–593

    Article  PubMed  CAS  Google Scholar 

  • Wong CK, Wang CB, Ip WK, Tian YP, Lam CW (2005) Role of p38 MAPK and NF-kB for chemokine release in coculture of human eosinophils and bronchial epithelial cells. Clin Exp Immunol 139:90–100

    Article  PubMed  CAS  Google Scholar 

  • Wuyts WA, Vanaudenaerde BM, Dupont LJ, Van Raemdonck DE, Demedts MG, Verleden GM (2005) Interleukin-17—induced interleukin-8 release in human airway smooth muscle cells: role for mitogen-activated kinases and nuclear factor-kappaB. J Heart Lung Transplant 24:875–881

    Article  PubMed  Google Scholar 

  • Yagi Y, Andoh A, Inatomi O, Tsujikawa T, Fujiyama Y (2007) Inflammatory responses induced by interleukin-17 family members in human colonic subepithelial myofibroblasts. J Gastroenterol 42:746–753

    Article  PubMed  CAS  Google Scholar 

  • Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J, Shellito JE, Bagby GJ, Nelson S, Charrier K, Peschon JJ, Kolls JK (2001) Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 194:519–527

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The present research has been conducted by attached research institute research grant of Keimyung University in 2007.

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Correspondence to Eunyoung Ha.

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Hyeongseok Kim and Jin Young Kim contributed equally to this work.

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Kim, H., Kim, J.Y., Song, H.S. et al. Grape seed proanthocyanidin extract inhibits interleukin-17-induced interleukin-6 production via MAPK pathway in human pulmonary epithelial cells. Naunyn-Schmiedeberg's Arch Pharmacol 383, 555–562 (2011). https://doi.org/10.1007/s00210-011-0633-y

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