Introduction

The prevalence of allergic diseases has increased all over the world during the last two decades. Dietary change is considered to be one of the environmental factors that cause this increase and worsen allergic symptoms [11. Kawai M, Hirano T, Higa S, Arimitsu J, Maruta M, et al. (2007) Flavonoids and related compounds as anti-allergic substances. Allergol Int 56: 113-23. ]. One of the major questions in food allergy research is therefore which impact nutrition and food processing may have on allergenicity of food and perhaps on sensitization [22. Lepski S, Brockmeyer J (2013) Impact of dietary factors and food processing on food allergy. Mol Nutr Food Res 57: 145-152. ].

The anti-inflammatory activities of some triterpenenic acids, sesquiterpene lactones, and polysaccharides may be due to their immunomodulating activities on the complement and/or T-lymphocyte populations, respectively. As the antiallergic and antiasthmatic compounds are effective also thiosulfates [33. Wagner H (1998) Search for new plant constituents with potential antiphlogistic and antiallergic activity, Planta Medica 55: 235-241.]. Nowadays, the preventive effects of polyphenols, carotenoids, polysaccharides, and non-digestible oligosaccharides and amines on allergic diseases are discussed [44. Venkatesh P, Mukherjee PK, Kumar NS, Bandyopadhyay A, Fukui H, et al. (2010) Anti-allergic activity of standardized extract of Albizia lebbeck with reference to catechin as a phytomarker Immunopharmacol Immunotoxicol 32: 272-276. ,55. Akiyama H, Katayama S, Kanda T, Maeda-Yamamoto M, Totsuka M, et al. (2014) Prevention of allergic disease development and symptoms by food factors. Curr Pharm Des 20: 892-905.].

Polyphenolic compounds have and continue to attract the interest of numerous scientists due to possible relations between their content in diet and lower incidence of cancer or cardiovascular diseases [66. La Vecchia C, Altieri A, Tavani A (2001) Vegetables, fruit, antioxidants and cancer: A review of Italian studies. Eur J Nutr 40: 261-267.,77. Long H, Zhu YX, Cregor M, Tian FF, Coury L, et al. (2001) Liquid chromatography with multi-channel electrochemical detection for the determination of epigallocatechin gallate in rat plasma utilizing an automated blood sampling device. J.Chromatogr B 763: 47-51.]. Their antimutagenic, anticarcinogenic and anti-inflammatory effects have been confirmed as well [88. Hodek P, Hanustiak P, Krízková J, Mikelova R, Krízková S, et al. (2006) Toxicological aspects of flavonoid interaction with biomacromolecules. Neuroendocrinol Lett 27: 14-17.-1111. Jurikova T, Sochor J, Rop O, Mlček J, Balla S, et al. (2012) Evaluation of Polyphenolic Profile and Nutritional Value of Non-Traditional Fruit Species in the Czech Republic — A Comparative Study. Molecules 17: 8968-8981.].

Recent evidence has brought to the spotlight plant-derived polyphenols as a promising tool to prevent allergy. Phenolic acids and flavonoids, are the best studied natural substances known to possess an anti-inflammatory and anti-allergic potential [1212. Chirumbolo S (2014) Dietary assumption of plant polyphenols and prevention of allergy. Curr Pharm Des 20: 811-839.]. Polyphenols represent such class of compounds that are found plant sources and have been investigated for their anti-allergic effect in different disease models and in human clinical trials [1313. Singh A, Holvoet S, Mercenier A (2011) Dietary polyphenols in the prevention and treatment of allergic diseases. Clin Exp Allergy 41:1346-59. ].

1. They are capable of influencing multiple biological pathways and immune cell functions in the allergic immune response.

2. The interaction of polyphenols with proteins can modulate the process of allergic sensitization and their direct effect on allergic effector cells, such as mast cells, inhibits mediator release, resulting in the alleviation of symptoms

3. Endogenous anti-oxidant ability can limit the extent of cellular injury from free radicals during any reaction [1212. Chirumbolo S (2014) Dietary assumption of plant polyphenols and prevention of allergy. Curr Pharm Des 20: 811-839.].

Mechanism of selected polyphenols action in allergic immune response

We distinguish at least 4 types of allergic immune responses induced by drugs and allergens but the most studied is type is type by T- helper cells. Type-1 allergic diseases consist of two phases. An inductive phase comprises IgE formation to allergens based on the immune system being based to predominant T-helper type 2 responses. In a triggering phase allergic symptoms are triggered due to a robust secretion of mediators from mast cells and other cells after re-exposure to the same allergen [1414. Kumazawa Y, Takimoto H, Matsumoto T, Kawaguchi K (2014) Potential use of dietary natural products, especially polyphenols, for improving type-1 allergic symptoms. Curr Pharm Des 20: 857-863.]. Interference of polyphenols with T-helper 2 activation seems to be the main mechanism of their inhibitory effects on allergy development. Moreover, deficits of T-regulatory cells seem to play a pathogenic role in allergic disease and, therefore, these cells may represent a major target of polyphenol activity [1515. Magrone T, Jirillo E (2012) Influence of polyphenols on allergic immune reactions: mechanisms of action. Proc Nutr Soc 71: 316-321.].

The most studied group of polyphenols are flavonoids. A variety of in vitro and in vivo experiments have shown that selected flavonoids possess anti-allergic, anti-inflammatory, antiviral and antioxidant activities. They possess potent inhibitory activity against a wide array of enzymes, but of particular note is their inhibitory effects on several enzyme systems intimately connected to cell activation processes such as protein kinase C, protein tyrosine kinases, phospholipase A (2), and other. The stimulated activities of numerous cell types, including mast cells, basophils, neutrophils, eosinophil's, T & B lymphocytes, macrophages, platelets, smooth muscle, hepatocytes, and others, can be influenced by particular flavonoids [1616. Middleton E (1988) Effect of plant flavonoids on immune and inflammatory cell function. Flavonoids in the living system. Advances in experimental medicine and biology 439: 175-182.].

Intake of representative polyphenols - flavonoids (flavones, flavone-3-ols, catechins, anthocyanidins, flavanones, procyanidins) can improve a skewed Th1/Th2 (T – helper type 1/ T – helper type 2) balance and suppress antigen-specific IgE antibody formation [1717. Kumazawa Y, Takimoto H, Matsumoto T, Kawaguchi K (2014) Potential use of dietary natural products, especially polyphenols, for improving type-1 allergic symptoms, Curr Pharm Des 20: 857-863.].

Flavonoids inhibit the activation of mast cells and basophils and therefore suppress the release of chemical mediators, synthesis of Th2 type cytokines such as interleukin (IL)-4 and IL-13, and CD 40 ligand expression. They also reportedly inhibit IL-4-induced signal transduction and affect the differentiation process of naïve CD4+ T cells into effector T cell subsets [1818. Tanaka T (2014) Flavonoids for allergic diseases: present evidence and future perspective. Curr Pharm Des. 20: 879-885.]. Except for inhibition of (IL)-4 and IL-13 synthesis, flavonoids inhibit histamine release and CD40 ligand expression by basophils. The inhibitory activity of flavonoids on IL-4 and CD40 ligand expression was possibly mediated through their inhibitory action on activation of nuclear factors of activated T cells and AP-1 [11. Kawai M, Hirano T, Higa S, Arimitsu J, Maruta M, et al. (2007) Flavonoids and related compounds as anti-allergic substances. Allergol Int 56: 113-23. ].

Among all studied polyphenols luteolin, fisetin and apigenin were found to be the strongest inhibitors of both IL-4 [11. Kawai M, Hirano T, Higa S, Arimitsu J, Maruta M, et al. (2007) Flavonoids and related compounds as anti-allergic substances. Allergol Int 56: 113-23. ,1919. Hirano T, Higa S, Arimitsu J, Naka T, Shima Y, et al. (2004) Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interleukin-13 production by activated human basophils. Int Arch Allergy Immunol 134: 135-140. ] and IL-13 production by basophils but did not affect leukotriene C4 synthesis [2020. Hirano T, Higa S, Arimitsu J, Naka T, Ogata A, et al. (2006) Luteolin, a flavonoid, inhibits AP-1 activation by basophils. Biochem Biophys Res Commun 340: 1-7. ].

The luteolin is able to inhibit CD40 ligand expression in human basophils.

Luteolin did not suppress Syk or Lyn phosphorylation in basophils, nor did suppress p54/46 SAPK/JNK, p38 MAPK, and p44/42 MAPK activation by a basophilic cell line, KU812 cells, stimulated with A23187 and PMA. However, luteolin did inhibit phosphorylation of c-Jun and DNA binding activity of AP-1 in nuclear lysates from stimulated KU812 cells [1919. Hirano T, Higa S, Arimitsu J, Naka T, Shima Y, et al. (2004) Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interleukin-13 production by activated human basophils. Int Arch Allergy Immunol 134: 135-140. ]. The flavone luteolin is also a strong inhibitor of human autoimmune T cells [2121. Chirumbolo S (2012) Flavonoids in propolis acting on mast cell-mediated wound healing. Inflammopharmacology 20: 99-101.].

Fisetin suppressed the induction of IL-4, IL-13, and IL-5 mRNA expression by A23187-stimulated KU812 cells and basophils in response to cross-linkage of the IgE receptor. Fisetin reduced IL-4, IL-13, and IL-5 synthesis (inhibitory concentration of 50% [IC(50)] = 19.4, 17.7, and 17.4 micromol/L, respectively) but not IL-6 and IL-8 production by KU812 cells. In addition, fisetin inhibited IL-4 and IL-13 synthesis by anti-IgE antibody-stimulated human basophils (IC(50) = 5.1 and 6.2 micromol/L, respectively) and IL-4 synthesis by allergen-stimulated basophils from allergic patients (IC(50) = 4.8 micromol/L) [2222. Higa S, Hirano T, Kotani M, Matsumoto M, Fujita A, et al. (2003) Fisetin, a flavonol, inhibits TH2-type cytokine production by activated human basophils. J Allergy Clin Immunol 111: 1299-1306.].

Apigenin is promising flavone for atopic and chronic allergy [1212. Chirumbolo S (2014) Dietary assumption of plant polyphenols and prevention of allergy. Curr Pharm Des 20: 811-839.]. Apigenin exhibited an anti-inflammatory activity, switching the immune response to allergens toward the Th1 profile in a murine asthma model [2323. Li RR, Pang LL, Du Q, Shi Y, Dai WJ, et al. (2010) Apigenin inhibits allergen-induced airway inflammation and switches immune responsein a murine model of asthma. Immunopharmacol Immunotoxicol 32: 364-370.]. Apigenin contained in the diet of NC/NGa mice reduced atopic dermatitis. The flavone alleviated the development of skin lesions, accompanied by lower serum immunoglobulin IgG1 and IgE levels and reduction of IFN-γ mRNA expression level in spleen cells [2424. Yano S, Umeda D, Yamashita S, Yamada K, Tachibana H (2009) Dietary apigenin attenuates the development of atopic dermatitis-like skin lesions in NC/Nga mice. J Nutr Biochem 20: 876-881.].

Among another flavonoids, kaempferol and quercetin showed substantial inhibitory activities in cytokine expression but less so than those of fisetin [2222. Higa S, Hirano T, Kotani M, Matsumoto M, Fujita A, et al. (2003) Fisetin, a flavonol, inhibits TH2-type cytokine production by activated human basophils. J Allergy Clin Immunol 111: 1299-1306.].

Park et al. [2525. Park HH, Lee S, Son HY, Park SB, Kim MS, et al. (2008) Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res 10: 1303-1311. ], compared the effect of six flavonoids (astragalin, fisetin, kaempferol, myricetin, quercetin, and rutin) on the mast cell-mediated allergic inflammation. Fisetin, kaempferol, myricetin, quercetin, and rutin inhibited IgE or phorbol-12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-mediated histamine release in RBL-2H3 cells. These five flavonoids also inhibited elevation of intracellular calcium. Gene expressions and secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-8 were assessed in PMACI-stimulated human mast cells (HMC-1). Fisetin, quercetin, and rutin decreased gene expression and production of all the pro-inflammatory cytokines after PMACI stimulation. Fisetin inhibited PMACI-induced phosphorylation of p38 mitogen-activated protein kinase, extracellular-regulated kinase, and c-Jun N-terminal kinase [2626. Park HH, Lee S, Oh JM, Lee MS, Yoon KH, et al. (2007) Anti-inflammatory activity of fisetin in human mast cells (HMC-1). Pharmacol Res 55: 31-37. ]. Myricetin attenuated TNF-alpha and IL-6 but not IL-1beta and IL-8. Fisetin, myricetin, and rutin suppressed activation of NF-kappaB indicated by inhibition of nuclear translocation of NF-kappaB, NF-kappaB/DNA binding, and NF-kappaB-dependent gene reporter assay.

Chrysin has recently attracted the attention for its protective effects on allergic inflammation. This compound possesses in vivo anti-inflammatory and anti-nociceptive potential, which are supported in silico by an interaction with COX-2 binding site [2727. Rauf A, Khan R, Raza M, Khan H, Pervez S, et al. (2015) Suppression of inflammatory response by chrysin, a flavone isolated from Potentilla evestita Th. Wolf. In silico predictive study on its mechanistic effect. Fitoterapia 103: 129-135. ].

Helioscopinin-A extracted from Euphorbia helioscopia showed a certain inhibitory activity on capillary permeability in passive cutaneous anaphylaxis responses of rats and also on antigen-induced bronchial constriction in an experimental asthma model of guinea pigs. The compound at a high concentration weakly inhibited histamine release from isolated mast cells [2828. Park KH, Koh D, Lee S, Jung I, Kim KH, et al. (2001) Anti-allergic and anti-asthmatic activity of Helioscopinin-A, a polyphenol compound, isolated from Euphorbia helioscopia. Journal of microbiology and biotechnology 11: 138-142.].

The objective of the work of Aswar et al. [2929. Aswar UM, Kandhare AD, Mohan V, Thakurdesai PA (2015) Anti-allergic effect of intranasal administration of type-A procyanidin polyphenols based standardized extract of cinnamon bark in ovalbumin sensitized BALB/c mice. Phytother Res 29: 423-433. ], was to evaluate anti-allergic effects of intranasal administration of type-A procynidines polyphenols (TAPP) based standardized hydro alcoholic extract of Cinnamomum zeylanicum bark (TAPP-CZ) in ovalbumin (OVA)-induced experimental allergic rhinitis (AR) in BALB/c mice. Treatment with TAPP-CZ (10 and 30µg/kg in nostril) showed significant attenuation in OVA-induced alterations of the nasal (number of nasal rubbing and sneezing), biochemical markers (serum IgE and histamine), haematological, morphological (relative organ weight of spleen and lung) and histopathological (nasal mucosa and spleen) parameters.

Compound 2((-)-epigallocatechin-7-gallate), 3(-)-5,7, 3',4',5'-pentahydroxyflavan), and 5((-)-tetra hydroxyflavan-7-gallate) isolated from Pithecellobium clypearia showed significant inhibition effect on histamine release [3030. Bao L, Yao X, Xu J, Guo X, Liu H, et al. (2009) Effects of Pithecellobium clypearia Benth extract and its main components on inflammation and allergy. Fitoterapia 80: 349-353. ]. In experiment Lee et al. [3131. Lee SH, Park HH, Kim JE, Kim JA, Kim YH, et al. (2007) Allose gallates suppress expression of pro-inflammatory cytokines through attenuation of NF-kappaB in human mast cells. Planta Med 73: 769-773. ] three gallotannins from Euphorbia such as 1,2,3,4,6-penta- O-galloyl-beta-D-glucose, 1,2,6-tri-O-galloyl-beta-D-allopyanose, and 1,2,3,6-tetra-O-galloyl-beta-D-allopyranose suppressed the gene expression and secretion of pro-inflammatory cytokines in a dose-dependent manner. In addition, these three gallotannins blocked the activation of NF-kappaB as indicated by an NF-kappaB-dependent gene reporter assay.

Recent advances in allergology have reported that quercetin is more effective than chromolyn in blocking mast cell cytokine release [3232. Weng Z, Zhang B, Asadi S, Sismanopoulos N, Butcher A, et al. (2012) Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PLoS One 7: 33805.]. In food allergies i tis very important inhibition of dendric cells function. Quecretin together eith kaempferol, isoflavones are able to regulate mucosal immunity during hypersensitivity reaction [3333. Wei J, Bhatt S, Chang LM, Sampson HA, Masilamani M (2012) Isoflavones, genistein and daidzein, regulate mucosal immune response by suppressing dendritic cell function. PLoS One 7: e47979.].

Among other types of allergic reactions induced by flavonoids we can mention the inhibition of mast cell degradation by hesperetin as a main naturally component of citrus fruits. Another flavanone, naringenin suppressed contact hypersensitivity (CHS), a T cell-mediated immune reaction, by inhibiting activation and migration of macrophages. Naringenin potently suppressed picryl chloride-induced contact hypersensitivity by inhibiting the proliferation and activation of T lymphocytes. Both of the activated hapten-specific Th2 cells and the Th2 cells stimulated with anti- CD3/anti-CD28 showed growth arrest in vitro after naringenin treatment [1212. Chirumbolo S (2014) Dietary assumption of plant polyphenols and prevention of allergy. Curr Pharm Des 20: 811-839.].

Conclusion

Flavonoids play an important role in allergic imunne response. Interference of polyphenols with T-helper 2 activation seems to be the main mechanism of their inhibitory effects on allergy development. Nowadays the mostly studied flavonoids are quercetin, luteolin, fisetin and apigenin.