Abstract
Many studies have been performed to assess the potential utility of natural products as immunomodulatory agents to enhance host responses against infection or to ameliorate immune-based pathologies. To determine whether eriodictyol has immunomodulatory effects and clarify which types of immune effector cells are stimulated in vitro, we investigated the stimulatory effect of eriodictyol on spleen cells isolated from BALB/c mice. Eriodictyol significantly stimulated splenocyte proliferation. However, only B lymphocytes (not T lymphocytes) could be stimulated by eriodictyol in a dose-related manner. Studies assessing potential effect of eriodictyol on innate immunity reported that eriodictyol enhanced significantly the killing activity of natural killer (NK) cells, T lymphocytes, and macrophages. We also demonstrated that eriodictyol inhibited nitric oxide (NO) production and lysosomal enzyme activity in murine peritoneal macrophages cultured ex-vivo, suggesting a potential anti-inflammatory effect in situ. Eriodictyol revealed also a cellular anti-oxidant activity in splenocytes and macrophages. Furthermore, eriodictyol increased catalase activity in spleen cells. From this data, it can be concluded that eriodictyol exhibited an immunomodulatory effect that could be ascribed in part to a cytoprotective effect related to its anti-oxidant activity.
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References
Areias FM, Rego AC, Oliveira CR, Seabra RM (2001) Anti-oxidant effect of flavonoids after ascorbate/Fe2+-induced oxidative stress in cultured retinal cells. Biochem Pharmacol 62:111–118
Caligiuri MA (2008) Human natural killer cells. Blood 112:461–469
Chayen J, Bitensky L, Butcher RG, Poulter LW, Ubhi GS (1970) Methods for direct measurement of anti-inflammatory action on human tissue maintained in vitro. Br J Dermatol 82:62–66
Cherng JM, Chiang W, Chiang LC (2007) Immunomodulatory activities of common vegetables and spices of Umbelliferae and related coumarins and flavonoids. Food Chem 106:944–950
Clavin M, Gorzalczany S, Macho A, Muñoz E, Ferraro G, Acevedo C, Martino V (2007) Anti-inflammatory activity of flavonoids from Eupatorium arnottianum. J Ethnopharmacol 112:585–589
Comalada M, Ballester I, Bailón E et al (2006) Inhibition of pro-inflammatory markers in primary bone marrow derived marrow derived mouse macrophages by naturally-occurring flavonoids: analysis of the structure-activity relationship. Biochem Pharmacol 72:1010–1021
Delaporte RH, Sánchez GM, Cuellar AC, Giuliani A, Palazzo de Mello JC (2002) Anti-inflammatory activity and lipid peroxidation inhibition of iridoid lamiide isolated from Bouchea fluminensis (Vell.) Mold (Verbenaceae). J Ethnopharmacol 82:127–130
Dumont S, Hartmann D, Poindron P, Oberling F, Faradji A, Bartholeyns J (1985) Control of antitumoral activity of human macrophages produced in large amounts in view of adoptive transfer. Eur J Cancer Clin On 24:1691
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem 126:131–138
Guo TL, Mccay JA, Zhang LX, Brown RD, You L, Karrow NA, Germolec DR, White KLJR (2001) Genistein modulates immune responses and increases host resistance to B16-F10 tumor in adult female B6C3F1 mice. J Nutr 131:3251–3258
Harizi H, Chaabane F, Ghedira K, Chekir-Ghedira L (2011) Inhibition of proinflammatory macrophage responses and lymphocyte proliferation in vitro by ethyl acetate leaf extract from Daphne gnidium. Cell Immunol 267:94–101
Hodek P, Trefil P, Stiborova M (2002) Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450. Chem Biol Interact 139:1–21
Huang DW, Chung CP, Kuo YH, Lin YL, Chiang W (2009) Identification of compounds in adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) seed hull extracts that inhibit lipopolysaccharide-induced inflammation in Raw 264.7 macrophages. J Agr Food Chem 57:10651–10657
Ismail N, Abdullah H, Seidel V, Rotondo D (2012) Human natural killer (NK) cell activation by luteolin from Brucea javanica leaves. J. Cancer Res. Exp. Oncol. ISSN: 2141–2243
Johnson J, Maher P, Hanneken A (2009) The flavonoid, eriodictyol, induces long term protection in ARPE-19 cells through its effects on Nrf2 activation and phase 2 gene expression. Invest Ophthalmol Vis Sci 50:2398–2406
Kang KA, Lee KH, Chae S, Zhang R, Jung MS, Ham YM, Baik JS, Lee NH, Hyun JW (2006) Cytoprotective effect of phloroglucinol on oxidative stress induced cell damage via catalase activation. J Cell Biochem 97:609–20
Keller R, Kelst R, Wechsler A, Leist TP, Van Der Meide PH (1990) Mechanisms of macrophage-mediated tumor-cell killing: a comparative analysis of the roles of reactive nitrogen intermediates and tumor necrosis factor. Int J Cancer 46:682–686
Kovacs EJ, Palmer JL, Fortin CF, Fülöp T Jr, Goldstein DR, Linton PJ (2009) Aging and innate immunity in the mouse: impact of intrinsic and extrinsic factors. Trends Immunol 30:319–324
Lee JK (2011) Anti-inflammatory Effects of Eriodictyol in Lipopolysaccharide stimulated raw 264.7 murine macrophages. Arch Pharm Res 34:671–679
Lee SE, Yang H, Son GW, Park HR, Park CS, Jin YH, Park YS (2015) Eriodictyol Protects endothelial cells against oxidative stress-induced cell death through modulating ERK/Nrf2/ARE-dependent heme oxygenase-1 expression. Int J Mol Sci 16:14526–14539
Li CZ, Jin HH, Sun HX, Zhang ZZ, Zheng JX, Li SH, Han SH (2016) Eriodictyol attenuates cisplatin-induced kidney injury by inhibiting oxidative stress and inflammation. Eur J Pharmacol 772:124–30
Lindqvist C, Bobrowska-Hägerstrand M, Mrówczyńska L, Engblom C, Hägerstrand H (2014) Potentiation of natural killer cell activity with myricetin. Anticancer Res 34:3975–9
Ljunggren HG, Karre K (1990) In search of the “missing self”: MHC molecules and NK cell recognition. Immunol Today 11:237–244
Lu CC, Chen JK (2010) Resveratrol enhances perforin expression and NK cell cytotoxicity through NKG2D-dependent pathways. J Cell Physiol 223:343–51
MacMicking J, Xie QW, Nathan C (1997) Nitric oxide and macrophage function. Annu Rev Immunol 15:323–350
Manosroi A, Saraphanchotiwitthaya A, Manosroi J (2005) In vitro immunomodulatory effect of Pouteria cambodiana (Pierre ex Dubard) Baehni extract. J Ethnopharmacol 101:90–94
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63
Nworu CS, Temchura V, Okoye FB, Akah PA, Esimone CO, Uberla K (2010) Activation of murine lymphocytes and modulation of macrophage functions by fractions of Alchornea cordifolia (Euphorbiaceae) leaf extract. Immunopharmacol Immunotoxicol 32:28–36
Orsolić N, Basić I (2005) Water-soluble derivative of propolis and its polyphenolic compounds enhance tumoricidal activity of macrophages. J Ethnopharmacol 102:37–35
Rada B, Leto TL (2008) Oxidative innate immune defenses by Nox/Duox family NADPH oxidases. Contrib Microbiol 15:164–187
Rossato MF, Trevisan G, Walker CI, Klafke JZ, de Oliveira AP, Villarinho JG, Zanon RB, Royes LF, Athayde ML, Gomez MV, Ferreira J (2011) Eriodictyol: a flavonoid antagonist of the TRPV1 receptor with antioxidant activity. Biochem Pharmacol 81:544–551
Russell SW, Doe WF, McIntosh AT (1977) Functional characterization of a stable nonlytic stage of macrophage activation in tumors. J Exp Med 146:1511
Sarangi I, Ghosh D, Bhutia SK, Mallick SK, Maiti TK (2006) Anti-tumor and immunomodulating effects of Pleurotus ostreatus mycelia-derived proteoglycans. Int Immunopharmacol 6:1287–1297
Sharififar F, Pournourmohammadi SH, Arabnezhad M, Rastegarianzadeh R, Ranjbaran O, Pourhemati A (2009) Immunomodulatory activity of aqueous extract of Heracleum persicum Desf. Mice Iran J Pharm Res 8:287–292
Whiteside TL, Herberman RB (1995) The role of natural killer cells in immune surveillance of cancer. Curr Opin Immunol 7:704–710
Wolfe KL, Liu RH (2007) Cellular antioxidant activity (CAA) assay for assessing antioxidants, foods, and dietary supplements. J Agric Food Chem 55:8896–8907
Zhang X, Hung TM, Phuong PT, Ngoc TM, Min BS, Song KS, Seong YH, Bae K (2006) Anti-inflammatory activity of flavonoids from Populus davidiana. Arch Pharm Res 29:1102–8
Zhu GF, Guo HJ, Huang Y, Wu CT, Zhang XF (2015) Eriodictyol, a plant flavonoid, attenuates LPS-induced acute lung injury through its antioxidative and anti-inflammatory activity. Exp Ther Med 10:2259–2266
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The authors acknowledge the “Ministère Tunisien de l’enseignement supérieur et de la recherché scientifique” for financial support of this study.
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Mokdad-Bzeouich, I., Mustapha, N., Sassi, A. et al. Investigation of immunomodulatory and anti-inflammatory effects of eriodictyol through its cellular anti-oxidant activity. Cell Stress and Chaperones 21, 773–781 (2016). https://doi.org/10.1007/s12192-016-0702-8
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DOI: https://doi.org/10.1007/s12192-016-0702-8