Influence of Hesperidin on the Systemic and Intestinal Rat Immune Response

Mariona Camps-Bossacoma, Àngels Franch, Francisco J Pérez-Cano, Margarida Castell, Mariona Camps-Bossacoma, Àngels Franch, Francisco J Pérez-Cano, Margarida Castell

Abstract

Polyphenols, widely found in edible plants, influence the immune system. Nevertheless, the immunomodulatory properties of hesperidin, the predominant flavanone in oranges, have not been deeply studied. To establish the effect of hesperidin on in vivo immune response, two different conditions of immune system stimulations in Lewis rats were applied. In the first experimental design, rats were intraperitoneally immunized with ovalbumin (OVA) plus Bordetella pertussis toxin and alum as the adjuvants, and orally given 100 or 200 mg/kg hesperidin. In the second experimental design, rats were orally sensitized with OVA together with cholera toxin and fed a diet containing 0.5% hesperidin. In the first approach, hesperidin administration changed mesenteric lymph node lymphocyte (MLNL) composition, increasing the TCRαβ+ cell percentage and decreasing that of B lymphocytes. Furthermore, hesperidin enhanced the interferon (IFN)-γ production in stimulated MLNL. In the second approach, hesperidin intake modified the lymphocyte composition in the intestinal epithelium (TCRγδ+ cells) and the lamina propria (TCRγδ+, CD45RA+, natural killer, natural killer T, TCRαβ+CD4+, and TCRαβ+CD8+ cells). Nevertheless, hesperidin did not modify the level of serum anti-OVA antibodies in either study. In conclusion, hesperidin does possess immunoregulatory properties in the intestinal immune response, but this effect is not able to influence the synthesis of specific antibodies.

Keywords: antibody; flavanone; flavonoids; hesperidin; immune system; immunoregulatory; polyphenol.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Experimental designs. (a) First experimental design: rats were immunized by intraperitoneal (i.p.) route the first day of the study (day 0), and hesperidin was given by oral gavage three times per week (indicated by arrows) for 4 weeks; (b) Second experimental design: rats were sensitized by oral route (per os, p.o.) three times per week (indicated by arrows), and hesperidin was included in the rat food throughout the 4 weeks. BW, body weight; OVA, ovalbumin; CT, cholera toxin.
Figure 2
Figure 2
Proportion of mesenteric lymph node lymphocytes (MLNL) according to their phenotype in the first experimental design. (a) TCRαβ+ and CD45RA+ lymphocytes; (b) TCRαβ+/CD45RA+ ratio; (c) Th (TCRαβ+CD4+) and Tc (TCRαβ+CD8+) lymphocytes; (d) Th/Tc ratio; (e) CD25+ cells in CD4+, CD8+, and CD45RA+ lymphocytes. Data are expressed as mean ± standard error (n = 6). Statistical difference: * p < 0.05 (by Mann-Whitney U).
Figure 3
Figure 3
Cytokine concentrations in the second experimental design. Cytokines from stimulated MLNL (a–e) and gut lavage (f–j). Data are expressed as mean ± standard error (n = 6). Statistical difference: * p < 0.05 (by Mann-Whitney U).
Figure 4
Figure 4
Anti-OVA antibodies (Ab) and total immunoglobulin (Ig)A levels from the first experimental design. (a) Serum anti-OVA Ab at the last day of the study; Total IgA from (b) gut lavage and (c) faecal homogenates from the last day of the study. Data are expressed as mean ± standard error (n = 6).

References

    1. Garg A., Garg S., Zaneveld L.J.D., Singla A.K. Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phyther. Res. 2001;15:655–669. doi: 10.1002/ptr.1074.
    1. Cuevas A., Saavedra N., Salazar L.A., Abdalla D.S.P. Modulation of immune function by polyphenols: possible contribution of epigenetic factors. Nutrients. 2013;5:2314–2332. doi: 10.3390/nu5072314.
    1. Tsao R. Chemistry and biochemistry of dietary polyphenols. Nutrients. 2010;2:1231–1246. doi: 10.3390/nu2121231.
    1. Gabriele M., Frassinetti S., Caltavuturo L., Montero L., Dinelli G., Longo V., Di Gioia D., Pucci L. Citrus bergamia powder: Antioxidant, antimicrobial and anti-inflammatory properties. J. Funct. Foods. 2017;31:255–265. doi: 10.1016/j.jff.2017.02.007.
    1. Scalbert A., Manach C., Morand C., Rémésy C. Dietary polyphenols and the prevention of diseases. Crit. Rev. Food Sci. Nutr. 2005;45:287–306. doi: 10.1080/1040869059096.
    1. Scalbert A., Johnson I.T., Saltmarsh M. Polyphenols: Antioxidants and beyond. Am. J. Clin. Nutr. 2005;81:215S–217S.
    1. Pérez-Cano F.J., Franch À., Pérez-Berezo T., Ramos-Romero S., Castellote C., Castell M. The effects of flavonoids on the immune system. Bioact. Food Diet. Interv. Arthr. Relat. Inflamm. Dis. 2014;12:205–210.
    1. Castell M., Perez-Cano F., Abril-Gil M., Franch À. Flavonoids on allergy. Curr. Pharm. Des. 2014;20:973–987. doi: 10.2174/13816128113199990041.
    1. Kim S.-H., Kim B.-K., Lee Y.-C. Antiasthmatic effects of hesperidin, a potential Th2 cytokine antagonist, in a mouse model of allergic asthma. Med. Inflamm. 2011;2011:485402. doi: 10.1155/2011/485402.
    1. Parhiz H., Roohbakhsh A., Soltani F., Rezaee R., Iranshahi M. Antioxidant and Anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models. Phyther. Res. 2015;29:323–331. doi: 10.1002/ptr.5256.
    1. Kawaguchi K., Mizuno T., Aida K., Uchino K. Hesperidin as an inhibitor of lipases from porcine pancreas and Pseudomonas. Biosci. Biotechnol. Biochem. 1997;61:102–104. doi: 10.1271/bbb.61.102.
    1. Kobayashi S., Tanabe S., Sugiyama M., Konishi Y. Transepithelial transport of hesperetin and hesperidin in intestinal Caco-2 cell monolayers. Biochim. Biophys. Acta Biomembr. 2008;1778:33–41. doi: 10.1016/j.bbamem.2007.08.020.
    1. Hemanth Kumar B., Dinesh Kumar B., Diwan P.V. Hesperidin, a citrus flavonoid, protects against l-methionine-induced hyperhomocysteinemia by abrogation of oxidative stress, endothelial dysfunction and neurotoxicity in Wistar rats. Pharm. Biol. 2017;55:146–155. doi: 10.1080/13880209.2016.1231695.
    1. Qian W., Hasegawa J., Cai X., Yang J., Ishihara Y., Ping B., Tsuno S., Endo Y., Matsuda A., Miura N. Effects of hesperidin on the progression of hypercholesterolemia and fatty liver induced by high-cholesterol diet in rats. Yonago Acta Med. 2016;59:67–80.
    1. Chiba H., Kim H., Matsumoto A., Akiyama S., Ishimi Y., Suzuki K., Uehara M. Hesperidin prevents androgen deficiency-induced bone loss in male mice. Phyther. Res. 2014;28:289–295. doi: 10.1002/ptr.5001.
    1. Ikemura M., Sasaki Y., Giddings J.C., Yamamoto J. Preventive effects of hesperidin, glucosyl hesperidin and naringin on hypertension and cerebral thrombosis in stroke-prone spontaneously hypertensive Rats. Phyther. Res. 2012;26:1272–1277. doi: 10.1002/ptr.3724.
    1. Wei D., Ci X., Chu X., Wei M., Hua S., Deng X. Hesperidin suppresses ovalbumin-induced airway inflammation in a mouse allergic asthma model. Inflammation. 2012;35:114–121. doi: 10.1007/s10753-011-9295-7.
    1. Dourado G.K.Z.S., Ribeiro L.C.D.A., Carlos I.Z., César T.B. Orange juice and hesperidin promote differential innate immune response in macrophages ex vivo. Int. J. Vitam. Nutr. Res. 2014;83:162–167. doi: 10.1024/0300-9831/a000157.
    1. Abril-Gil M., Massot-Cladera M., Pérez-Cano F.J., Castellote C., Franch A., Castell M. A diet enriched with cocoa prevents IgE synthesis in a rat allergy model. Pharmacol. Res. 2012;65:603–608. doi: 10.1016/j.phrs.2012.02.001.
    1. Camps-Bossacoma M., Abril-Gil M., Franch À., Pérez-Cano F.J., Castell M. Induction of an oral sensitization model in rats. Clin. Immunol. Endocr. Metab. Drugs. 2014;1:1–10. doi: 10.2174/2212707002666150402225609.
    1. Camps-Bossacoma M., Pérez-Cano F.J., Franch À., Untermayr E., Castell M. Effect of a cocoa diet on the small intestine and gut-associated lymphoid tissue composition in a rat oral sensitization model. J. Nutr. Biochem. 2017;42:182–193. doi: 10.1016/j.jnutbio.2017.01.005.
    1. Camps-Bossacoma M., Abril-Gil M., Saldaña-Ruiz S., Franch À., Pérez-Cano F.J., Castell M. Cocoa diet prevents antibody synthesis and modifies lymph node composition and functionality in a rat oral sensitization model. Nutrients. 2016;8:242. doi: 10.3390/nu8040242.
    1. Jain D., Somani R. Antioxidant potential of hesperidin protects gentamicin induced nephrotoxicity in experimental rats. Austin J. Pharmacol. Ther. 2015;3:1071.
    1. Eisenbarth S.C. Use and limitations of alum-based models of allergy. Clin. Exp. Allergy. 2008;38:1572–1575. doi: 10.1111/j.1365-2222.2008.03069.x.
    1. Dong W., Selgrade M.J.K., Gilmour M.I. Systemic administration of Bordetella pertussis enhances pulmonary sensitization to house dust mite in juvenile rats. Toxicol. Sci. 2003;72:113–121. doi: 10.1093/toxsci/kfg015.
    1. Pilegaard K., Madsen C. An oral Brown Norway rat model for food allergy: Comparison of age, sex, dosing volume, and allergen preparation. Toxicology. 2004;196:247–257. doi: 10.1016/j.tox.2003.11.010.
    1. Hassanain E., Silverberg J.I., Norowitz K.B., Chice S., Bluth M.H., Brody N., Joks R., Durkin H.G., Smith-Norowitz T.A. Green tea (Camelia sinensis) suppresses B cell production of IgE without inducing apoptosis. Ann. Clin. Lab. Sci. 2010;40:135–143. doi: 10.1016/j.jaci.2009.12.079.
    1. Nakazato T., Ito K., Ikeda Y., Kizaki M. Green tea component, catechin, induces apoptosis of human malignant B cells via production of reactive oxygen species. Clin. Cancer Res. 2005;11:6040–6049. doi: 10.1158/1078-0432.CCR-04-2273.
    1. Domínguez Ortega J., León F., Martínez Alonso J.C., Alonso Llamazares A., Roldán E., Robledo T., Mesa M., Bootello A., Martínez-Cócera C. Fluorocytometric analysis of induced sputum cells in an asthmatic population. J. Investig. Allergol. Clin. Immunol. 2004;14:108–113.
    1. Chung F. Anti-inflammatory cytokines in asthma and allergy: Interleukin-10, interleukin-12, interferon-γ. Med. Inflamm. 2001;10:51–59. doi: 10.1080/09629350120054518.
    1. Teixeira L.K., Fonseca B.P., Barboza B.A., Viola J.P. The role of interferon-gamma on immune and allergic responses. Mem. Inst. Oswaldo Cruz. 2005;100:137–144. doi: 10.1590/S0074-02762005000900024.
    1. Horcajada M.N., Habauzit V., Trzeciakiewicz A., Morand C., Gil-Izquierdo A., Mardon J., Lebecque P., Davicco M.J., Chee W.S.S., Coxam V., et al. Hesperidin inhibits ovariectomized-induced osteopenia and shows differential effects on bone mass and strength in young and adult intact rats. J. Appl. Physiol. 2008;104:648–654. doi: 10.1152/japplphysiol.00441.2007.
    1. Habauzit V., Sacco S.M., Gil-Izquierdo A., Trzeciakiewicz A., Morand C., Barron D., Pinaud S., Offord E., Horcajada M.N. Differential effects of two citrus flavanones on bone quality in senescent male rats in relation to their bioavailability and metabolism. Bone. 2011;49:1108–1116. doi: 10.1016/j.bone.2011.07.030.
    1. Akiyama H., Sato Y., Watanabe T., Nagaoka M.H., Yoshioka Y., Shoji T., Kanda T., Yamada K., Totsuka M., Teshima R., et al. Dietary unripe apple polyphenol inhibits the development of food allergies in murine models. FEBS Lett. 2005;579:4485–4491. doi: 10.1016/j.febslet.2005.07.019.
    1. Hänninen A., Harrison L.C. Gamma delta T cells as mediators of mucosal tolerance: The autoimmune diabetes model. Immunol. Rev. 2000;173:109–119. doi: 10.1034/j.1600-065X.2000.917303.x.
    1. Paul S., Singh A.K., Shilpi Lal G. Phenotypic and functional plasticity of gamma-delta (γδ) T cells in inflammation and tolerance. Int. Rev. Immunol. 2014;33:537–558. doi: 10.3109/08830185.2013.863306.
    1. Bol-Schoenmakers M., Marcondes Rezende M., Bleumink R., Boon L., Man S., Hassing I., Fiechter D., Pieters R.H.H., Smit J.J. Regulation by intestinal γδ T cells during establishment of food allergic sensitization in mice. Allergy Eur. J. Allergy Clin. Immunol. 2011;66:331–340. doi: 10.1111/j.1398-9995.2010.02479.x.
    1. Frossard C.P., Asigbetse K.E., Burger D., Eigenmann P.A. Gut T cell receptor-γδ+ intraepithelial lymphocytes are activated selectively by cholera toxin to break oral tolerance in mice. Clin. Exp. Immunol. 2015;180:118–130. doi: 10.1111/cei.12561.
    1. Agace W.W., Higgins J.M., Sadasivan B., Brenner M.B., Parker C.M. T-lymphocyte-epithelial-cell interactions: Integrin αE(CD103)β7, LEEP-CAM and chemokines. Curr. Opin. Cell Biol. 2000;12:563–568. doi: 10.1016/S0955-0674(00)00132-0.
    1. Annacker O., Coombes J.L., Malmstrom V., Uhlig H.H., Bourne T., Johansson-Lindbom B., Agace W.W., Parker C.M., Powrie F. Essential role for CD103 in the T cell-mediated regulation of experimental colitis. J. Exp. Med. 2005;202:1051–1061. doi: 10.1084/jem.20040662.
    1. Okazaki Y., Han Y., Kayahara M., Watanabe T., Arishige H., Kato N. Consumption of curcumin elevates fecal immunoglobulin A, an index of intestinal immune function, in rats fed a high-fat diet. J. Nutr. Sci. Vitaminol. 2010;56:68–71. doi: 10.3177/jnsv.56.68.
    1. Taira T., Yamaguchi S., Takahashi A., Okazaki Y., Yamaguchi A., Sakaguchi H., Chiji H. Dietary polyphenols increase fecal mucin and immunoglobulin A and ameliorate the disturbance in gut microbiota caused by a high fat diet. J. Clin. Biochem. Nutr. 2015;57:212–216. doi: 10.3164/jcbn.15-15.
    1. Chang J.H. Anti-inflammatory effects and its mechanisms of hesperidin in an asthmatic mouse model induced by ovalbumin. J. Exp. Biomed. Sci. 2010;16:83–90.

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