Dietary Polyphenols in Modulation of the Immune System

In: Polyphenols and Health: New and Recent Advances ISBN 978-1-60456-349-8 Editor: Neville Vassallo, pp. © 2008 Nova Science Publishers, Inc.

Chapter 10

Dietary Polyphenols in Modulation of the Immune System

Manzoor A. Mir and Javed N. Agrewala∗

Institute of Microbial Technology, Chandigarh-160036, India

Abstract

Polyphenols are a diverse group of naturally occurring compounds with multiple biological functions. Polyphenols like curcumin, resveratrol, quercetin, catechin, chlorogenic acid, myricetin and apigenin can modulate the immune response through their potent antioxidant and anti-inflammatory mechanisms. In addition, many polyphenols can regulate immunological reactions by modulating pro-inflammatory cytokines, chemokines, adhesion molecules, NF-κB, inducible enzymes, etc, or by influencing the activity of cells of the immune system. For instance, it has been shown that resveratrol and curcumin suppress the immune system by mainly modulating the expression of CD28/CTLA-4 and CD80 costimulatory molecules. Curcumin also blocks the cyclosporin A-resistant CD28 pathway of T-cell activation and induces apoptosis. It inhibits allergic encephalomyelitis by blocking IL-12 signaling and exerts inhibitory effects on the production of IL-8, IL-1β, and TNF-α. Tea polyphenols have been shown to scavenge reactive oxygen and nitrogen species and reduce their damage to lipid membranes, proteins and nucleic acids in cell-free systems. Green tea polyphenols also prevent ultraviolet-B induced cyclobutane pyrimidine dimers, which are considered to be mediators of ultraviolet-B induced immune suppression. In conclusion, although the exact manner through which polyphenols produce their effects is not fully understood, they have potential for use as drugs to correct immune system disorders like allergies, autoimmune diseases, inflammation and hypersensitivity.

∗ Address correspondence: Dr. Javed N Agrewala, Institute of Microbial Technology, Sector 39A, Chandigarh

160036, INDIA. Email: [email protected], Tel: +++91-172-2636680, Fax: ++91-172-2690585, 2690632.

Dietary Polyphenols in Modulation of the Immune System 2

Abbreviations IL-2 interleukin-2 IL-4 interleukin-4 IFN-γ interferon-gamma TNF-α: tumor necrosis factor-alpha SOD superoxide dismutase NF-kB nuclear factor-kappa B ROS reactive oxygen species RNS reactive nitrogen species NO nitric oxide iNOS inducible nitric oxide synthase COX-2 cyclohexogenase-2 AP-1 activating protein–1 EGCG Epigallocatechin gallate MAPK mitogen-activated protein kinase PMA phorbol-12-myristate-13-acetate ConA concanavalin A PHA phytohemagglutinin LPS lipopolysaccharide LDL low density lipoproteins PGE2 prostaglandin E2 PKC protein kinase C PLC-γ1 phospholipase C-γ1 Keywords: Polyphenols, T cells, B cells, macrophages, neutrophils, antigen presenting

cells, NF-κB, free radicals.

Introduction Polyphenols, with more than 8000 structural variants, are the secondary metabolites of

plants. In plants, they are generally involved in the defense mechanism against ultraviolet radiations and insects. They have aromatic rings bearing one or more hydroxyl moieties and can be broadly divided into four different groups: flavonoids, stilbenes, lignas and phenolic acids. These compounds have received considerable attention from the public because of their anti-oxidant, anti-inflammatory and health promoting effects. Intake of these compounds in food in small amounts has a potent effect in reducing chronic inflammatory diseases like bronchiectasis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, cardiovascular diseases etc. Epidemiological studies have indicated that populations who consume foods rich in specific polyphenols have a lower incidence of chronic inflammatory diseases. Polyphenols modulate important cellular signaling processes such as cellular growth, differentiation and host of other cellular features. In addition, they modulate nuclear factor kappa of B cells (NF-κB) activation, glutathione biosynthesis, nuclear redox factor


(Nrf2) activation, chromatin structure, scavenge effect of reactive oxygen species (ROS) directly or via glutathione peroxidase activity. As a consequence they regulate inflammatory genes in macrophages and other immune cells [1]. Polyphenols like resveratrol and curcumin suppress the activity of T cells, B cells and macrophages, as evident by significant inhibition in proliferation, antibody production and lymphokine secretion. Curcumin exerts its immunosuppressive activity mainly by down-regulating the expression of cluster of differentiation (CD)-28 and CD80 molecules and up-regulating cytotoxic T cell associated antigen (CTLA-4) costimulatory molecule. Resveratrol too exerts its activity by decreasing the expression of CD28 and CD80 molecules, as well as by enhancing the production of interleukin (IL)-10. Both of these polyphenols also inhibit the production of pro-inflammatory cytokines like IL-1, IL-6 and tumor necrosis factor-alpha (TNF-α) [2].

Polyphenols modulate the immune system in a diverse manner but mainly through the inhibition of enzymes related to inflammation such as cyclooxygenase and lipooxygenase and the key regulatory transcription factors like peroxisome proliferator activated receptors (PPAR), nitric oxide synthase (NOS), NF-κB and NSAID activated gene-1 (NAG-1); hence modulating many pathways. Besides endogenous defenses, the consumption of dietary antioxidants play an important role in protecting against pathological events of oxidative diseases, such as cardiovascular diseases, cancer, inflammation, and brain dysfunction. The ability of the polyphenolic compounds to act as antioxidants depends on the redox properties of their phenolic hydroxyl groups and the potential for electron delocalization across the chemical structure [3]. Polyphenols modulate the activity of almost all cells of the immune system.

Modulation of T-Cell Function by Polyphenols T cells constitute an important class of lymphocytes that play a cardinal role in mediating

protective immunity for the host. They control both cell-mediated and humoral immunity. Further, they also regulate inflammation and oxidative stress and other disorders of the immune system. T cells are divided into T-helper (Th) and cytotoxic T cells (CTL). In response to many stimulants, granulocytes and lymphocytes produce small diffusible ROS molecules. ROS are highly unstable and extremely reactive molecules, which act as defense mechanism against pathogens but also damage the cells of our body and hence need to be neutralized. They are generated during electron transfer reactions in aerobic cells, especially by mitochondrial electron transport chain [4]. They include hydroxyl radical (-OH), superoxide anion (O2

-), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), and singlet oxygen (1O2). Furthermore, they are involved as secondary messengers in physiological responses as well as in pathological conditions and activate key transcription factors like NF-κB and activating protein–1 (AP-1) [5, 6]. The production of ROS is well controlled under physiological conditions and exerts microbicidal activities without accompanying toxic side-effects. Most of the ROS are scavenged by antioxidant defense systems of the body like catalase, peroxidase, superoxide dismutase (SOD) and glutathione peroxidase/glutathione system [7]. However, ROS that are produced excessively or ROS that have escaped from antioxidant defense systems easily react with DNA, proteins, and lipids; leading to the development of many diseases, including cancer, arteriosclerosis, and gastric mucosal injury


as well as the aging process [8]. Because antioxidant defense systems in humans are not completely efficient, it is desirable to take exogenous antioxidants to scavenge excess ROS. It has been reported that dietary antioxidants such as vitamin C, vitamin E, and carotenoids reduce the risk for development of certain diseases, because they scavenge excess ROS. It is now well established that polyphenols have potent antioxidant capacity to neutralize or inactivate these free radicals. Cocoa liquor polyphenol (CLP), which is a major component of chocolate, has antioxidant activity and modulates immune functions in human T cells. This liquor polyphenol has been shown to neutralize H2O2 and scavenge O2

- production from activated T cells. Moreover, CLP inhibits O2

- and H2O2 from normal human T cells. Cocoa liquor polyphenol has been shown to inhibit the proliferation of T cells as a result of its inhibitory effect on IL-2 production [9]. Therefore, the additive polyphenol intake such as CLP in chocolate may avert oxidative damage caused by various oxidative stresses. Prickly pear polyphenols have been shown to exert an immunosuppressive effect on T cells by curtailing the IL-2 mRNA expression and blastogenesis. They also increase the intracellular Ca2+ concentrations [10]. Furthermore, dietary intake of polyphenols may contribute to the prevention of excessive consumption of glutathione and to enrich the intracellular glutathione redox system. Black tea extract which contains theaflavins and tearubigins formed by enzymatic oxidation of catechins has been shown to decrease the Fe2+ induced oxidative damage to DNA by inducing the anti-oxidant enzyme glutathione peroxidase activity in T cells [11]. Theaflavin-3,-3’-digallate blocks the nitric oxide synthase by downregulating the activation of NF-κB in macrophages and inhibits tumor proliferation, epidermal growth factor or platelet-derived growth factor receptor kinase activities [12, 13].

Curcumin, a yellow coloured polyphenol from turmeric (C. longa), has been shown to scavenge ROS, such as O2-, H2O2 and nitric oxide (NO), both in vitro and in vivo [14]. Moreover, it has been shown to be highly protective against H2O2-induced damage in human T cells, keratinocytes, fibroblasts and in a mouse neuroblastoma-rat glioma hybrid cell line (NG 108-15) [15]. Further, curcumin works much faster in terms of quenching ROS than other polyphenols like resveratrol and quercetin. The antioxidant properties of curcumin are based on its lipid peroxidation lowering effects through its ability to maintain the cellular status of antioxidant enzymes like SOD, catalase and glutathione peroxidase [16]. Indeed curcumin has also been shown to increase reduced glutathione levels, which leads to lowered ROS production [17]. Moreover, pharmacologically, curcumin has been found to be safe and human clinical trials indicated no dose-limiting toxicity and have low oral toxicity in humans as well [18]. Curcumin also inhibits NF-κB activation, with concomitant suppression of IL-8 release, cyclo-oxygenase (COX)-2 expression and neutrophil recruitment in the lungs [19]. It has also been demonstrated to downregulate other NF-κB-regulated genes involved in inflammation and cellular proliferation such as leukotriens, lipooxygenase (LOXs), phospholipase A2 (PLA2), COX-2 and cyclin D1 and c-myc, anti-apoptotic factors, e.g. IAP1, IAP2, XIAP, Bcl2, Bcl-xL, Bf1-1/A1, TRAF1, cFLIP and metastatic factors such as vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP-9) and intra-cellular adhesion molecule 1 (ICAM-1) on T cells. Curcumin-mediated suppression of NF-κB transactivation has been shown to inhibit nuclear translocation of p65, which is further associated with the sequential suppression of IκB kinase activity and phosphorylation, IκBa degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acetylation [20]. Curcumin also abolishes the cigarette smoke-mediated induction of NF-κB binding to DNA, blocks I kappa kinase (Iκk) activation, IκBa phosphorylation and degradation as well as NF-


κB p65 translocation [21]. Inhibition of NF-κB by curcumin is certainly an interesting strategy in chronic inflammatory diseases where NF-κB is activated [22]. Curcumin has been reported to downregulate expression of inducible nitric oxide synthase (iNOS), MMP-9, TNF-α, chemokines, cell surface adhesion molecules and growth factor receptors (EGFR and HER2) [23]. Curcumin also modulates a number of other kinase signaling pathways such as Jun kinase (JNK), p38 mitogen-activated protein kinase (MAPK), AKT, JAK, ERK and PKC in a variety of cell types [24]. Interestingly, curcumin and TNF-α related apoptosis-inducing ligand (TRAIL) has been reported to promote cell death in a cooperative manner [25]. As the inhibition of TNF-α, COX, PLA2, H2O2, iNOS and NF-κB are directly associated with anti-inflammatory activities, the ability of curcumin to prevent the cross-talk between the myriad of signaling pathways is a pre-requisite for its anti-inflammatory properties. Since the upregulation of these factors have been implicated in the pathogenesis of various chronic and inflammatory conditions, curcumin therefore has the potential to control these diseases through its potent antioxidant and anti-inflammatory activity.

Peripheral lymphocyte homeostasis (self-tolerance) and normal physiology of the immune system is maintained by the peripheral deletion of autoreactive T cells by a process known as activation-induced cell death in which there is repeated stimulation of TCR which causes increase in intracellular ROS and Ca2+ leading to CD95L (Fas) expression and consequently apoptosis [26]. Nevertheless, this process is also involved in terminating the immune response through elimination of activated lymphocytes. The imbalance in this apoptotic process is dangerous and leads to severe diseases associated with autoimmunity and immunodeficiency [27]. Polyphenols mangiferin, catechin and epicatechin from mango (Mangifera indica) diminishes the increase of intracellular ROS and free Ca2+ induced by T lymphocyte triggering thereby protecting from activation-induced cell death. Mangiferin also shows many pharmacological properties like immunomodulatory, analgesic, anti-oxidant, anti-diabetic, anti-inflammatory, anti-tumor, and anti-HIV effects [28, 29]. Green tea polyphenols ameliorate the immune dysfunction of mice bearing Lewis lung carcinoma. The pathology of these mice shows decrease in the weight of thymus and therefore affecting proportion of CD4+ T cells and the ratio of CD4+ to CD8+ T cells. Further, there is also decrease in B lymphocytes population. When these mice are fed with green tea containing polyphenols as drinking water, all these immune dysfunctions are ameliorated [30]. Epigallocatechin gallate (EGCG) and curcumin have also been reported in neuroprotection in Alzheimer’s disease [31].

Polyphenols influence the production of cytokines by Th1 and Th2 lymphocytes. Th1 lymphocytes mainly produce cytokines such as IL-2 and IFN-γ which activate monocytes/macrophages, natural killer cells and cytotoxic T cells and are associated with host defense against bacteria, viruses and fungi [32]. In contrast, Th2 lymphocytes chiefly secrete IL-4, IL-5 and IL-13 and are associated with allergic responses. The balance between the productions of Th1- and Th2-type cytokines is believed to be important in regulating cell-mediated immune versus allergic reactions [33]. Polyphenolic compounds have been shown to decrease the IL-1β and enhance IL-10 production by human lymphocytes in cultures [34]. Polyphenol kaempferol decreases the production of IFN-γ significantly in cultures of human whole blood stimulated with the T lymphocyte mitogen Con A. The decrease in IFN-γ in the presence of kaempferol suggests an effect on Th1 lymphocyte cytokine production which has been further supported by the non-significant trend for a reduced IL-2 concentration [35]. Similar results have been observed on murine spleen cells and T cell lines which showed the


dose-dependent inhibition of IFN-γ production by kaempferol [36]. However, the Th2 cytokine IL-4 is not affected by the addition of kaempferol to these cultures. It is known that Th1-type cytokines can drive the inflammatory response in atherosclerotic lesions [37]. Thus the inhibition of IFN-γ production by polyphenol kaempferol could confer protection against the development of coronary heart disease. CD8+ T cells play an important role in immune response especially against intracellular pathogens. CD8+ T cells bind to ICAM-1 and migrate in response to chemokines to the site of infection, but excessive migration of these cells has been shown to be involved in inflammatory disorders. Green tea polyphenol EGCG has been shown to attenuate the adhesion and migration of peripheral blood CD8+ T cells by downregulating the CD11b expression on their surface and in consequence inhibiting the infiltration into the sites of inflammation. Hence, EGCG serves as a potent anti-inflammatory agent [38]. Quercetin and rutin (quercetin-3-rutinoside) are known to increase intracellular glutathione in lymphocytes by multiple mechanisms via direct ROS scavenging, chelation of transitional metal, and upregulation of antioxidant genes. Intracellular redox of antigen-activated mast cells is downregulated by tobacco polyphenols, concomitantly with inhibition of histamine release.

Many polyphenols have been shown to have protective effects against HIV infection, part of which is mediated by inhibiting binding of virions to the target cells. CD4+ T cells are the host cells to HIV, and gp120 an envelope protein of HIV-1 plays an important role in the entry of virus into the CD4+ T cells. The EGCG molecule has been shown to bind to CD4+ T cells and interfere (block) with gp120 binding [39]. Fruit juice polyphenols have been shown to restore disturbances in T cell homeostasis by increasing the phytohemagglutinin-induced lymphocyte proliferation in HIV (+) patients [40].

Modulation of B-Cells by Polyphenols B cell is an important class of lymphocytes involved in the production of antibodies and

plays a central role in the immune system. Polyphenols have been shown to modulate the function of B cells and thereby modulating the immune response. Cocoa liquor polyphenol is shown to inhibit the polyclonal IgG production by human B cells [9]. Resveratrol, a grape phytoalexin polyphenol, induced apoptosis in B-cell lines and fresh chronic lymphocytic leukemia (CLL) cells, by inhibiting NOS, an enzyme producing NO which is a well recognized inhibitor of caspases [41]. Similarly, polyphenols like flavones, luteolin, apigenin, genistein, quercetin and fistein can induce apoptosis in B cell lymphoma cell lines by disruption of mitochondrial membranes and activation of caspase-3 [42]. Quercetin induces the cleavage of caspase-3, caspase-7 and poly ADP-ribose polymerase, but could also modulate oncogene Akt-1 and the extracellular signal-regulated kinase (ERK) [43]. EGCG has been shown to have clinical effects in patients with low-grade B cell malignancies [44]. Further, it also induces apoptotic cell death in CLL. Bioflavonoid polyphenols have been used for anti-inflammatory and anti-spasmodic remedies since decades. These polyphenols possess: anti-oxidant activity; induction of detoxification enzymes; inhibition of ATP-binding, especially by tyrosine kinases in the TGF-β pathway; estrogenic/anti-estrogenic activity by binding to estrogen-receptors; inhibition of telomerases and proteasomes (e.g. by EGCG); induction of DNA damage and inhibition of the catalytic activity of DNA


topoisomerase II resulting in DNA breakage, like the podophyllotoxin derivatives VP16 and VM26 used in cancer therapy; and anti-tumorigenic activity by induction of cell cycle arrest and apoptosis [45-48]. Catechin, has been shown to induce apoptosis of human malignant B cells by the production of reactive oxygen species [49]. Quercitin and resveratrol have been shown to induce apoptosis in malignant human Namalwa B-cell lymphoma by elevating the levels of mobile lipid domains and caspase-3 activation [50]. Resveratrol and a synthetic flavone diaminomethoxy-flavone have been shown to induce the apoptosis of leukemic B-cells and simultaneously inhibit the production of endogenous NO through iNOS down-regulation in both leukemia B-cell lines and B-cell chronic lymphocytic leukemia patients' cells [51]. This inhibition of the NO pathway could be one of the mechanisms involved in the proapoptotic properties of these phytoalexins in leukemia B-cells. Polyphenols such as gossypol from cotton seed extracts and purpurogallin extracted from quercus and their derivatives bind and antagonize the antiapoptotic effects of B-cell lymphocyte/leukemia-2 (Bcl-2) family proteins such as Bcl-x(L). This indicates that there exists possibility of utilizing polyphenols for the development of novel cancer treatments [52].

Polyphenols Suppress the Inflammatory Response of Macrophages

Macrophage represents an important cell type of the immune system and plays a critical

role in inflammation and other immune responses by producing key inflammatory mediators, cytokines and NO. Inflammation, on the one hand, is the immunological defense mechanism by which the body fights against infection or injury from bacteria, viruses, fungi, etc, but on the other hand excessive activation of the system can have detrimental effects and is the basic underlying factor in many diseases. Inflammation depends upon the production of many inflammatory proteins, the main source of which are activated macrophages which secrete inflammatory mediators in considerable amounts. Cytokines serve as intercellular signals that recruit cells and modulate cell function. Cytokines produced predominantly by activated macrophages and lymphocytes mediate many inflammatory processes. Activated macrophages are known to secrete large amounts of pro-inflammatory cytokines, e.g. IL-1β and TNF-α, and these regulatory proteins contribute to the development of bacterial sepsis, hypercholesterolemia, hypertension, and multiple sclerosis [53-55]. Polyphenols like kaempferol and apigenin, significantly suppress TNF-α and IL-1β gene expression in macrophages. Chrysin polyphenol suppresses IκB degradation and decreases the NF-κB level in nuclei of LPS/IFN-γ stimulated macrophages. Chrysin, galangin, quercetin, kaempferol and myrecitin polyphenols have been shown not only to decrease the mRNA expression of IL-1β but also its concentration in cell culture supernatants and lysates [56, 57]. Pretreatment of macrophages with polyphenols like luteolin, quercetin and genistein inhibited LPS induced TNF-α and IL-6 secretion which is due to the inhibition of IκB degradation [58]. Resveratrol inhibits the production of IFN-γ and IL-2 by splenic lymphocytes and the production of TNF-α and IL-12 by peritoneal macrophages. It also inhibits the mitogen, IL-2, or alloantigen-induced proliferation of splenic lymphocytes and cell-mediated cytotoxicity at least in part through the inhibition of NF-κB activation [59]. Th1-type cytokine IFN-γ has a prominent role in atherogenesis and inflammation, as it triggers the production of ROS by macrophages


[60]. The IFN-γ also activates the enzyme GTP-cyclohydrolase I (EC 3.5.4.16), the first and rate-limiting enzyme in the biosynthesis of neopterin and indoleamine 2, 3-dioxygenase (IDO) which degrades the essential amino acid tryptophan. The production of neopterin in humans is specific for activated monocyte-derived macrophages and dendritic cells, but tryptophan degradation is inducible in several cells of various species. Resveratrol suppresses these IFN-γ mediated biochemical pathways of neopterin production and tryptophan degradation. Mitogens ConA or PHA significantly increases tryptophan degradation and neopterin production in human PBMC, and upon co-incubation of these cells with resveratrol this activity is suppressed. This shows that addition of resveratrol modifies tryptophan degradation and neopterin formation in unstimulated PBMC. Hence the effect of resveratrol to suppress IFN-γ mediated pathways could be of great relevance to interrupt development and progression of atherosclerosis. [61].

Resveratrol has been shown to modulate the MAP kinase signaling by inhibiting the phosphorylation of MAPK, depressing MAPK activity and reducing phosphorylation at the active sites of ERK1/2, JNK1 and p38MAP kinase [62]. Resveratrol has also been shown to increase the tyrosine phosphorylation of IκB, p50-NF-κB, and p65-NF-κB hence suggesting the involvement of such alterations in the modulation of NF-κB transcriptional activity in human endothelial cells and subsequently the inflammatory processes [63]. Cis-isoform of resveratrol has been shown to attenuate the expression of NF-κB family of genes, adhesion molecules and acute phase proteins from macrophages activated with LPS and IFN-γ. It also inhibits the transcription of Scya2 (chemokine monocytechemotactic peptide-1 (MCP-1)), the chemokine RANTES (expressed and secreted by activated T cells), proinflammatory cytokines that attract monocyte–granulocyte cells such as colony-stimulating factor 1 (M-CSF), colony stimulating factor 2 (GM-CSF) and colony-stimulating factor 3 (G-CSF), the transforming growth factor beta (TGF-β) and the extracellular ligand IL-1α [64]. Resveratrol is found to be an inhibitor of vascular cell adhesion molecule-1 (VCAM-1) gene expression by TNF-α-induced human endothelial cells [65]. Quercetin suppressed TNF-α induced increase in the IL-8 and MCP-1 mRNA levels in human synovial cells [66]. IL-8 cytokine is mainly produced by monocytes and macrophages but may also be generated by tissue cells like fibroblasts and bronchial epithelial cells. Recruitment of neutrophils in airway inflammation may account for IL-8 generation and its generation is associated with many diseases like rhinitis, bronchitis, pulmonary fibrosis, inflammatory bowel disease, psoriasis and other disorders [67-69]. Green tea polyphenols like EGCG, ECG and EGC and EC inhibit IL-8 production in both nasal fibroblasts and in bronchial epithelial cells when pretreated with these polyphenols [70]. So these green tea polyphenols may help to suppress airway inflammation by inhibiting IL-8 production in airway tissue fibroblasts and epithelial cells. Bioflavonoids extracted from the bark of Pinus maritime significantly inhibit the IL-1β gene expression in macrophages [71]. Oral administration of luteolin and apigenin has been shown to suppress serum TNF-α production in mice. Kaempferol and apigenin exhibit the inhibitory effects on TNF-α-induced E-selectin expression in human endothelial cells [72]. Apigenin inhibits the cytokine-induced ICAM-1, VCAM-1 and E-selectin expression in human endothelial cells [73]. It may therefore be inferred that the anti-inflammatory action of these polyphenolic compounds may be partly mediated by transcriptional inhibition of IL-1β and TNF-α gene expression in macrophages by inhibiting NF-κB activation.

In addition to the oxidation of cellular biomolecules, nitration of protein tyrosine residues is of significant interest in human pathology of inflammation. Nitration of tyrosine may be


due to the formation of peroxynitrite and myeloperoxidase formation because of macrophage activation. Activated neutrophils also secrete myeloperoxidase and are present in these cells up to 5% of their dry weight [74]. Nitration of the protein tyrosine forms 3-nitrotyrosine which has been found to be associated with numerous infectious and inflammatory diseases. In some diseases, 3-nitrotyrosine formation has been linked to pathogenesis through the modulation of signaling cascades, structural protein assembly and interference with enzyme function [75, 76]. Epicatechin, a cell-permeable dietary polyphenol from tea, certain chocolates and red wine, has been found to inhibit peroxynitrite and myeloperoxidase formation in macrophages. Nitration of protein tyrosine has been found to be involved in the pathology of many inflammatory diseases. Epicatechin also inhibits the NO-related oxidation of cellular biomolecules [77].

Interleukin-12 (IL-12) is an inducible heterodimeric cytokine comprising p40 and p35 subunits but the bioactive IL-12 cytokine is a heterodimeric p70 molecule and both subunits are co-expressed in the same cell to generate the bioactive form. It is mainly produced by monocytes, macrophages and dendritic cells and plays an essential role in the regulation of Th1 differentiation. IL-12 is critical for host defense against a variety of pathogens and is also involved in the pathogenesis of Th1-mediated chronic inflammatory disorders, such as diabetes mellitus, multiple sclerosis, arthritis, and inflammatory bowel disease [78-80]. Several gallate-containing catechin polyphenols found in green tea have been shown to suppress the production of IL-12p40 by macrophages. Decrease in protein production is primarily due to down-regulation of the transcription of IL-12p40 mRNA by inhibiting p38 MAPK while enhancing p44/p42 ERK, leading to the inhibition of IkBα degradation and NF-κB activation [81].

Procyanindin extract (PE), consisting of a mixture of polyphenols obtained from grape seeds, has been shown to modulate inflammatory responses in activated macrophages by the inhibition of NO and prostaglandin E2 (PGE2) production, suppression of iNOS expression, and NF-κB translocation to the nucleus in LPS/IFN-γ activated macrophages. So this polyphenol mixture has potential health-benefits in inflammatory conditions as it controls macrophage overproduction of inflammatory mediators such as PGE2 and NO [82]. Polyphenols like rutin, quercetin, and quercetin pentaacetate inhibit LPS-induced NO production. This decrease of NO production is consistent with the inhibition on LPS-induced iNOS gene expression. Quercetin pentaacetate shows the strong inhibitory activity on PGE2

production and COX-2 protein expression in N-nitro-L-arginine (NLA)/LPS or N-nitro-L-arginine methyl ester (L-NAME)/LPS co-treated macrophages. The NLA and L-NAME are NOS inhibitors. Thus a combinatorial treatment of L-arginine analogs and polyphenol derivatives, such as quercetin pentaacetate, effectively inhibits LPS-induced NO and PGE2 productions, at the same time, inhibited enhanced expressions of iNOS and COX-2 genes. This indicates that polyphenols can be used as a complement agent with NOS inhibitors in treatment of LPS-mediated inflammatory responses [83]. Both green tea and black tea contain polyphenols that are able to protect against NO toxicity in several ways; like scavenging NO and peroxynitrite, inhibit the excessive production of NO by the iNOS, and suppress the LPS mediated induction of iNOS. In etiology of cardiovascular heart diseases, massive production of superoxide anion and NO by inflammatory cells results in peroxynitrite toxicity. The ability of tea to protect against this toxicity is of great interest [84].

The overproduction of ROS and RNS by macrophages causes oxidative damage to membrane lipids, DNA, proteins and lipoproteins. Macrophages generate large quantities of


ROS in response to a variety of membrane stimulants, by a coordinated sequence of biochemical reactions known as the oxidative burst. These reactions have functional consequences, which may be deleterious to cells and tissues. Thus, the inhibition of ROS and RNS production is a popular target for the attenuation of many inflammatory, cardiovascular and neurodegenerative diseases [85, 86]. In addition to their microbicidal activity, macrophages have been implicated in a number of pathological processes like atherogenesis, etc. Epicatechin found in green tea, certain chocolates, and red wine has been shown to be a potent scavenger of peroxynitrite and preferentially inhibits NO-related nitration and oxidation reactions without affecting nitric oxide synthesis and cyclic-GMP signaling [77]. The major tea polyphenol EGCG is capable of modulating ROS production by macrophages by acting as a superoxide anion scavenger. EGCG also has been found to inhibit iNOS protein transcription in activated macrophages [87]. Further, it has also been shown to block LPS induction of iNOS in macrophages, by down-regulating the LPS-induced activity of the transcription factor NF-κB [12]. EGCG may therefore be useful in the prevention and treatment of immune disorders involving ROS production by macrophages, and it may also be able to protect cells from ROS-mediated oxidative modification [88]. Studies have also shown that EGCG treatment of mouse skin inhibits UVB-induced infiltration of CD11b+ leukocytes. CD11b is a cell surface marker for activated macrophages and neutrophils, which are associated with induction of UVB-induced suppression of contact hypersensitivity responses. The EGCG treatment also results in reduction of the UVB-induced immunoregulatory cytokine IL-10 and elevates IL-12 production. These above observations suggest that green tea polyphenols are photoprotective, and can be used as pharmacological agents for the prevention of solar UVB light-induced skin disorders associated with immune suppression and DNA damage. Green tea polyphenols prevent UV-induced oxidative damage and expression of matrix metalloproteinase in mouse skin [89].

Catechins have been shown to inhibit Cu2+ catalyzed oxidation of lipoprotein in macrophages and to prevent DNA oxidative damage [90]. Peroxynitrite is a powerful oxidant produced by macrophages, neutrophils and lymphocytes as a signaling and cytotoxic molecule from their primary production of NO and superoxide anion. Peroxynitrite in the vascular space will likely oxidize lipoproteins and promote atherogenesis. Pure wine flavonoids (catechin, epicatechin, myricetin), hydroxycinnamates (caffeic acid, ferulic acid, chlorogenic acid), and plain argentine red wines are effective inhibitors of the peroxynitrite driven oxidation reactions. The amphipatic nature of wine polyphenols will lead to their accumulation at the lipoprotein surface, according to the Gibbs adsorption equation, where they are likely to prevent peroxynitrite induced tyrosine nitration and low density lipoproteins (LDL) modification [91]. Polyphenols found in red wine like catechin, epicatechin, quercetin and trans-resveratrol have antioxidant and anti-inflammatory effects. Hence they play an important role not only in the prevention of oxidative stress but also in inflammatory diseases [92, 93]. It has been postulated that the antioxidant and free radical scavenging properties of phenolic compounds, present in red wine, may partly explain why French and Mediterranean populations have a lower incidence of coronary heart disease, despite having a fat rich diet [94].

Polyphenols found in pomegranate juice have anti-atherogenic and anti-oxidative properties. They also reduce oxidative stress in serum and in macrophages in atherosclerotic mice, as well as in diabetic patients and reduce cellular cholesterol accumulation [95-97]. Pomegranate juice has been found to decrease the macrophage oxidative state and reduce the


activation of redox-sensitive genes (ELK-1) while increasing eNOS expression in cultured endothelial cells and in atherosclerosis-prone areas of hypercholesterolemic mice [98]. Resveratrol too can potently protect against copper catalyzed oxidation and have anti-lipogenic and anti-atherogenic properties since it inhibits the oxidation of polyunsaturated fatty acids (PUFA) that play a major role in atherosclerosis [99]. Paraoxonase 2 (PON2) is a member of the multigene family of paraoxonases, which is expressed in various tissues and cells, including macrophages, and possesses anti-oxidative properties [100]. The PON2 expression increases in monocytes during their differentiation into macrophages, and this effect has been shown to be mediated via the transcription factor AP-1 [101]. Pomegranate juice polyphenols upregulate the macrophage PON2 expression, both at the mRNA and protein levels through the activation of AP-1 and PPARγ transcription factors. The upregulation of macrophage PON2 protects macrophages against oxidative stress and acts as a potent cellular anti-oxidant. Further, it has been shown that PON2 protein is present abundantly in the macrophage cytoplasm. Incubation of macrophages with pomegranate juice polyphenols induces the translocation of PON2 to the cell nucleus. This effect may represent a regulatory function of PON2 in the nucleus [102].

The azuki beans (Vigna angularis) contain polyphenols like proanthocyanidins which have been shown to have remarkable anti-oxidant activities and beneficial effects on inflammation, and can modulate the immune response in diabetes and cancer. Recently, it has been shown that azuki bean seed coat polyphenols suppress the increase of infiltrating macrophages in the damaged kidney and may lead to amelioration of interstitial fibrosis [103]. Diabetic nephropathy is known to be the leading cause of end-stage renal disease and the most frequent cause of mortality in patients with diabetes. Oxidative stress has been thought to be a potential factor in the progression of diabetic complications [104]. The treatment with azuki bean seed coat polyphenols has been demonstrated to suppress the increased number of infiltrating macrophages and MCP-1 mRNA expression, and attenuate glomerular expansion (which is a characteristic of experimental diabetic animals and humans with diabetes mellitus) in streptozotocin-induced rat diabetic nephropathy. Thus in the future azuki bean seed polyphenols may represent a potential strategy for the preventive care of diabetic nephropathy [105].

Polyphenolic compounds found in propolis (bee glue: used by bees to maintain their hives) have been shown to possess immuno-modulatory and anti-tumor activity. Propolis has pro-apoptotic effects on T cell acute lymphoblastic leukemia cell line by inhibiting the expression of telomerase [106]. Treatment of mice with these components from propolis increased the number of polymorphonuclear (PMN) cells and decreased the number of macrophages in the peritoneal cavity. Immunostimulant activity of propolis may be associated with macrophage activation and enhancement of macrophage phagocytic capacity. The macrophage spreading activity revealed that these compounds affected the functional state of macrophages and also increased their tumoricidal activity [107].

Effects of Polyphenols on Other Antigen-Presenting Cells


Antigen presenting cells (APCs) such as dendritic cells, macrophages and B cells are very important since they are responsible for the processing and presentation of antigens for activation of T cells. Besides antigen presentation, they are also responsible for variety of functions like secretion of cytokines, inflammatory mediators, etc. It has been proposed that appropriate redox homeostasis of APCs is crucial in maintaining competence for antigen presentation. Many polyphenols can influence the function of APCs. The polyphenols quercetin and rutin (quercetin-3-rutinoside) are known to increase intracellular glutathione by multiple mechanisms via direct ROS scavenging, chelation of transitional metals, and upregulation of antioxidant genes. These are capable of directly inhibiting antigen-presenting function of APCs. It has been shown that not only B cell and B cell lines but also normal bone marrow-derived mast cells (BMMC) and splenocytes, antigen presentation capacity can be inhibited by rutin. Polyphenols quercetin and rutin have been shown to abrogate APCs function and the effect of rutin to downregulate antigen presentation in B cells is concordant with its capacity to downregulate basal and PMA-stimulated levels of ROS [108].

Polyphenols are known to exert three major antioxidant activities: scavenging ROS, chelation of transitional metal and induction of phase II detoxifying enzymes [109]. Antioxidant polyphenols not only modulate mast cell activation but also affect the vital functioning of antigen presenting cells. It has been shown that competent antigen presentation by APCs to T cells is redox-dependent, besides providing adequate levels of antigenic peptides and costimulation. EGCG shows immunosuppressive effects by blocking specific cell surface molecules of the donor tissues. In mixed-lymphocyte cultures the anergic state of alloreactive T cells may be induced by either weakening of antigen signaling or by blockage of co-stimulatory signals like CD80 and CD86 by EGCG [110]. It is possible that daily intakes of antioxidants present in food and beverage may be important in influencing the function of APCs. By fine-tuning levels of intracellular ROS, natural occurring polyphenols thus modulate APCs activation or deactivation, and play a key role in immune defense as well as chemo-protection against overt immune-mediated inflammation under chronic antigenic stimulations [108].

Effects of Polyphenols on Mast Cells and Neutrophils

Mast cells play a central role in inflammatory and immediate allergic reactions. Mast

cells play an important protective role as well, being intimately involved in wound healing and defense against pathogens. They are able to release potent inflammatory mediators, such as histamine, proteases, chemotactic factors, cytokines and metabolites of arachidonic acid that act on the vasculature, smooth muscle, connective tissue, mucous glands and inflammatory cells. Mast cells express a high-affinity receptor (FcεRI) for the Fc region of IgE antibodies. In allergic reactions, mast cells remain inactive until an allergen binds to IgE. Th2 cells produce IL-4, which helps in the production of IgE [111-113]. Tobacco polyphenols, chlorogenic acid and rutin potentiate in vivo IgE production. Polyphenolic antioxidants also augment IgG1 but not IgG2a and IgG2b levels indicating a Th2 response development. Hence it can be said that IgE production and T cell dichotomy may be critically influenced by the redox microenvironment. Enhanced Th2 development and IgE production


henceforth may counteract more severe Th1-mediated tissue damage triggered by environmental oxidative stress [111]. However, quillaja saponin, which contains polyphenols, can suppress allergen-specific IgE-mediated reactivity in food allergy, which results by shifting from a Th2 to a Th1-dominated immune response. Quillaja saponin can modulate ovalbumin-induced IgE allergic responses through regulation of Th1/Th2 balance [112]. Rutin and chlorogenic acid effectively scavenge ROS and inhibit histamine release, but upregulating multiple cytokines, including IL-10, IL-13, IFN-γ, IL-6 and TNF-α in antigen-IgE activated mast cells. This indicates that polyphenolic antioxidants differentially modulate two important effector functions, histamine release and cytokine expression of antigen-IgE activated mast cells. The release of pre-stored mediator and de novo cytokine gene expression are mediated by PKC and MAPK pathways, respectively. These two pathways are differentially influenced by polyphenol treatments. The PKC activation plays an important role in mast cell degranulation and polyphenols inhibit PKC activation, henceforth histamine release. The MAPK pathway and its downstream AP-1 transcription factor are considered important for cytokine gene expression in mast cells. Polyphenol treatment of antigen-IgE activated mast cells lead to enhanced MAPK and AP-1 activation. The consequence of cytokine production by a polyphenol-modulated mast cell in the inflammatory lesion depends in turn on its interactions with other cell types, and the outcome is likely complex. Thus, IFN-γ and IL-13 produced by mast cells can positively or negatively influence mast cell functions via other cell types. The NO produced by IFN-γ-activated macrophages in turn can inhibit IgE-mediated mast cell degranulation. The IFN-γ indirectly inhibits mast cell activation by downregulating IgE production. In contrast, IL-13 can enhance IgE production and IgE-mediated mast cell activation [113]. Polyphenol-enriched apple extracts have been shown to be useful for preventing and treating allergic diseases because they inhibit the binding between the IgE antibody and FcεR1, which is the first key step in the allergic reaction mediated by mast cells. The inhibition of binding between IgE antibody and FcεR1 leads to the blockage of phosphorylation of several downstream protein tyrosine kinases, and this is the target of polyphenol-enriched apple extracts for their anti-allergic activity. These polyphenol enriched apple extracts also reduce the degranulation of mast cells caused by cross-linking of the high-affinity FcεR1 with IgE and the antigen [114]. Furthermore, EGCG has been shown to inhibit superoxide-induced histamine release from mast cells, suggesting that they act as cell membrane stabilizers as well as radical scavengers [115]. Triphenol structure of tea polyphenols plays an important role in the inhibitory activity of histamine release by mast cells. Among tea polyphenols, EGCG most strongly and dose-dependently inhibits histamine release from cells stimulated with a calcium ionophore. Their activity seemed to be exerted through the metabolic events occurring after the elevation of intracellular Ca2+ concentration [116].

Resveratrol inhibits mast cell degranulation and reduces the FcεR1-mediated tyrosine phosphorylation of ERK and PLC-γ1, suggesting that FcεR1-mediated tyrosine phosphorylation of PLCγ1 and ERK could be potential cellular targets of resveratrol for the inhibition of mast cell degranulation [117]. Resveratrol has also been shown to act as anti-ageing agent in treating age-related human diseases and can be used in the prevention of age related oxidative stress-based pathologies [118, 119]. Resveratrol significantly inhibits the release of histamine, TNF-α and IgE-mediated release of leukotriens and PGE2. It also reduces the ionophore-mediated release of histamine and leukotriens. Resveratrol exhibits its behavior without a significant cytotoxic activity against mast cells. Hence, resveratrol is a


potent non-selective inhibitor of mediators released from mast cells which cause inflammation and inflammatory diseases [120].

Neutrophils are the most abundant type of white blood cells and form an integral part of the immune system. The neutrophil's main role is in inflammation. They are the first cells to arrive at the site of inflammation by leaving the blood, through the endothelium into the tissue. In chronic experimentally-induced colitis, resveratrol ameliorates the degree of neutrophil infiltration and the levels of TNF-α, reduces COX-2 and NF-κB p65 protein expression, prevents up-regulation of IL-1β and increases mucus production in colon mucosa. These anti-inflammatory and powerful antioxidant properties of resveratrol suggest that the polyphenolic compound may have a chemopreventive role in ulcerative colitis, which is a chronic inflammatory disorder primarily involving the mucosa and sub-mucosa of the colon [121]. Resveratrol exert its anti-inflammatory effects because of the ability to disrupt arachidonic acid metabolism by inhibiting COX-1 and its hydroxyperoxidase [122]. This compound has also been able to reduce COX-2 levels induced by LPS and phorbol-12-myristate (PMA) and impaired the over expression of COX-2. Besides inhibiting COX-2, resveratrol has been shown to suppress iNOS expression and subsequent NO production in culture cells [123, 124]. The anti-inflammatory effects seem to be related to impairment of neutrophil function, absence of up-regulation of IL-1β and increase of mucus production in colon mucosa. Resveratrol also reduced PGE2 and caused a significant increase of TNBS-induced apoptosis. A resveratrol tetramer known as Vaticanol B has been shown to protect the neutrophils against endoplasmic reticulum (ER) stress induced cell death [125]. Resveratrol and curcumin in combination with insulin has been shown to attenuate the diabetic neuropathic pain hence showing anti-nociceptive activity possibly through the inhibition of NO and TNF-α release which cause nitrosative stress in diabetes and promote pain and inflammatory signals respectively [126].

Modulation of NF-κB by Polyphenols NF-κB (nuclear factor-kappa B) is a protein complex which functions as a transcription

factor. NF-κB is found in all cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, UV, bacterial and viral infections. NF-κB plays a key role in regulating the immune response to infection. Consistent with this role, incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development. NF-κB activation is modulated by MAPK/ERK kinase kinase-1, a kinase upstream of JNKs which induces site-specific phosphorylation of an inhibitory protein called IκB [127]. Polyphenols have been shown to modulate NF-κB activity in several cancer cell lines, rendering them susceptible to apoptosis. Green tea polyphenols inhibit the endotoxin-mediated TNF-α production by blocking NF-κB activation [128]. They also inhibit the phosphorylation of IκBα resulting in a reduction in NF-κB activation. The activation of NF-κB may play a critical role in the development and perpetuation of many inflammatory disorders such as inflammatory bowel disease and rheumatoid arthritis [129, 130]. Several groups have reported increased intestinal NF-κB activation in patients with inflammatory bowel disease and in animal models of inflammatory bowel disease. NF-κB, therefore, is a potential target for anti-inflammatory therapies. Many of the currently accepted


medical therapies for these diseases inhibit NF-κB (e.g., glucocorticoids, sulfasalazine). Gallotannins, the water soluble plant-derived polyphenols suppress expression of pro-inflammatory cytokines through attenuation of NF-κB in human mast cells [131]. EGCG is an effective inhibitor of IκB activity. The identification of new, more selective, inhibitors of NF-κB may lead to more effective treatment of inflammatory disorders. The IκB represents a key control point for NF-κB activation and may be a suitable target for modulating NF-κB mediated cellular responses. The identification of EGCG as an inhibitor of IκB may potentially lead to the development of new IκB inhibitors that are more potent and hopefully more selective [132]. EGCG mediates activation of caspases which are critical for inhibition of NF-κB and subsequent apoptosis of human epidermoid carcinoma [133]. EGCG has a concurrent effect on the two important transcription factors p53 and NF-κB, causing a change in the ratio of Bax/Bcl-2 in a manner that favors apoptosis. This altered expression of Bcl-2 family members triggers the activation of initiator capsases-9 and 8 followed by activation of effector caspase-3 to induce apoptosis.

Polyphenols in the Prevention of Immunological Diseases

Green tea polyphenols have been shown to ameliorate the dysfunction in many diseases

which affects the immune system. In case of Lewis lung carcinoma, which includes decrease in the weight of thymus and therefore frequency of T cell population, the immune dysfunctions are improved, when the animals are fed with green tea polyphenols [30]. Influenza infection is a common respiratory disease, causing high morbidity in the general population, as well as considerable costs of hospitalization and treatment and losses in productivity. Polyphenols have been shown to have inhibitory effects on the influenza virus [134, 135]. Polyphenolic complex, obtained from the medicinal plant Geranium sanguineum has been shown to inhibit the reproduction of influenza viruses type A and B in vitro and in vivo and protected mice from mortality [136]. The plant extract significantly reduced the level of H2O2 and NO secreted by macrophages as a response to influenza virus infection. The favorable immuno-potentiating capacity of the plant extract in viral infection is in concert with the reduction in mortality, virus load in the lungs and the severity of the macroscopic lung lesions. Polyphenol-rich extract from G. sanguineum is a promising candidate immune modifier, useful for the treatment of influenza virus infection [137].

In recent years, polyphenols have received considerable attention because of their health promoting and disease preventing properties. They also possess potent anti-inflammatory and antioxidant properties. It is now well established that regular intake of small amounts of polyphenols in food has a potent cumulative effect in attenuating autoimmune and chronic inflammatory diseases like rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, skin diseases, etc. Hence dietary flavonoids and other polyphenols have the potential to develop as effective food-supplemented drugs. However, their poor oral bioavailability, mainly due to extensive conjugation by glucuronidation and sulfation, may be a severe limiting factor. The permethylation of polyphenols effectively blocks the metabolic conjugation reactions, thereby dramatically increasing both metabolic stability and intestinal


absorption, while maintaining or even increasing the biological activities. Thus, permethylated polyphenols may have a future as chemoprotective agents [138].

Tea polyphenols have antibacterial, antiviral and antifungal activities in addition to their inhibitory effects on exotoxins. Many other polyphenols including catechins and their oxidation products, proanthocyanidins, and hydrolysable tannins, also show antibacterial activities. [139-143]. The sensitivity of bacteria to polyphenols depends on bacterial species and polyphenol structure; 3,4,5-trihydroxyphenyl groups are important in antibacterial activity of polyphenols [144]. Infection by Mycobacterium tuberculosis is efficiently controlled by the immune system, as the vast majority of the 2 billion infected humans contain infection unless their immune system is compromised [145]. Macrophages are the niche of Mycobacterium tuberculosis and the lack of phagosome maturation has been considered as a critical factor for the persistence of this pathogen. An important host molecule, tryptophan-aspartate containing coat protein (TACO), plays a crucial role in the arrest of phagosome maturation. Upon infection TACO is expressed and causes phagosome maturation arrest. Green tea polyphenol EGCG has been shown to downregulate TACO gene transcription in human macrophages through its ability to inhibit Sp1 transcription factor. This downregulation of TACO gene expression by EGCG causes the inhibition of mycobacterium survival within macrophages [146].

The beneficial anti-inflammatory effect of polyphenols has been demonstrated in a Finnish study involving over 10,000 participants, wherein they observed a significant inverse correlation between polyphenol intake and the incidence of asthma [153]. In chronic obstructive pulmonary disease (COPD), in which oxidative stress plays a key role in pathogenesis, similar beneficial associations have been observed in a study encompassing over 13,000 adults. In this study, it has been shown that increased polyphenol intake correlated with improved symptoms, as assessed by cough, phlegm production and breathlessness, and improved lung function [154]. Another study has shown beneficial protective effect against COPD symptoms for increased fruit intake, high in polyphenol and vitamin E content. It has been further shown that oral administration of these polyphenols is effective in reducing oxidant stress and increasing partial pressure of oxygen in arterial blood, as well as improving forced expiratory volume (FEV1) [155]. More importantly, while single component intake, such as catechin, is independently associated with FEV1 and all three COPD symptoms, flavonol and flavones intake has been independently associated with chronic cough only. Further, there is also a report on the protective effect of fruit polyphenols and vitamin E intake against COPD symptoms in a 20-year COPD mortality study from three European countries consisting of the Finnish, Italian and Dutch cohorts [156]. These important studies certainly encourage for carrying out further multinational clinical studies to explore the beneficial effects of high intake of polyphenols/bioflavanoids not only against COPD but other diseases as well.

Conclusions Understanding the complex interactions between diet and the optimal functioning of the

immune system may be of paramount significance for the welfare of the human being. Immune system related diseases like autoimmunity, allergies, chronic inflammatory


responses, cancer, ageing, etc., can be prevented, to some extent, by a diet rich in polyphenols. The polyphenols have antioxidant properties and play a potentially important role in modulating our immune system and therefore can influence the activity of all the key players in cellular immunity, including T cells, B cells, macrophages, mast cells, and neutrophils. Polyphenols not only helps in boosting immunity but also in skewing the immune response in favor of the host to alleviate disease.

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Dietary Polyphenols in Modulation of the Immune System

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