Polyphenols Suppress and Modulate Inflammation

C H A P T E R

29 Polyphenols Suppress and Modulate Inflammation: Possible Roles in Health and Disease Jiyoung Kim*,†, Ki Won Lee* and Hyong Joo Lee* *Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea †Advanced Institutes of Convergence Technology, Seoul National University, Seoul, Republic of Korea

1. INTRODUCTION

2. POLYPHENOL EFFECTS ON INFLAMMATION-MEDIATED DISEASES

Residents of Okinawa, the southernmost prefecture of Japan, are known for their long average life expectancy, high number of centenarians, and accompanying low risk of age-associated diseases.1 Much of the longevity advantage in Okinawa is thought to be related to a healthy lifestyle, particularly the traditional diet, which is low in calories yet nutritionally dense, especially with regard to phytonutrients in the form of polyphenolic flavonoids.1 The Mediterranean diet, which is also characterized by high intake of vegetables, fruits, nuts and unrefined cereals, also appears to influence longevity.2 Overall, this epidemiological evidence supports the claim that diets rich in polyphenols lead to a relative improvement in aging. Inflammatory responses comprise one of the main causes of senescence for cells and organisms3 and are implicated in numerous chronic diseases, such as cardiovascular diseases, metabolic diseases, cancer, and neurodegenerative disorders.4 In fact, it has been reported that healthy centenarians show low levels of inflammatory biomarkers.5 Considering the inverse association of dietary pattern characterized by a higher proportion of vegetables and fruits with blood inflammation markers,6 dietary polyphenols, which are thought to be safe for human use, have emerged as modulators of a number of diseases, due to their anti-inflammatory properties.7
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Polyphenols in Human Health and Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-398456-2.00029-3

2.1 Allergy Different researchers have analyzed the potential benefits of polyphenols as anti-allergic substances. Subjects with persistent allergic rhinitis to house dust mite showed that a high dose consumption of apple polyphenols could help alleviate symptoms such as sneezing and runny nose in a placebo-controlled trial.10,11 Nasal examination in the apple polyphenol-treated group of subjects showed decreased swelling of the nasal turbinates.10,11 A study conducted in Japan on subjects sensitized to cedar pollen showed that the administration of apple polyphenols to the subjects 2 weeks before the start of the pollen season, and continued throughout the season, helped to significantly reduce the reported incidence of sneezing in allergic subjects when compared with the placebo group.11,12 Oral administration of the polyphenol-rich tomato extract for 8 weeks to the subjects relieved sneezing and improved the quality of life of the subjects with perennial allergic rhinitis.11,13 In children, daily consumption of bananas and apple juice from concentrate were independently associated with a reduced likelihood of wheezing symptoms.14,15 A high intake of so-called fruity vegetables, citrus fruit, kiwifruit and a Mediterranean style diet has been reported to be associated with a reduced likelihood of wheezing outcomes in children as well.15
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Indirect epidemiological studies have reported negative associations of apple intake with prevalence and incidence of asthma.20,21 In a cohort of 10,054 male and female participants, a significant inverse association between the intake of polyphenols such as quercetin, naringenin, and hesperetin, and the incidence of asthma was reported.21 Patients with asthma have been studied in a 4-week randomized, placebo-controlled, double-blind trial with oral administration of purple passion fruit peel extract, a novel mixture of polyphenolic bioflavonoids, or placebo pills, and it was concluded that the prevalence of wheeze, cough, and shortness of breath were reduced significantly in the group treated with purple passion fruit peel extract.22 These findings are in keeping with other observations that hard fruit consumption was negatively associated with incidence of asthma.23 In addition to human studies, experimental data based on animals and cells have proved that dietary polyphenols have effects against major allergic diseases, atopic eczema, food allergy and asthma. Singh et al.11 and Magrone and Jirillo24 have reviewed the anti-allergic impact of polyphenols in detail.

2.2 Cardiovascular Diseases In terms of cardiovascular disease, analysis has revealed that chronic inflammation is a crucial factor in its etiology.25 Based on current studies, a general consensus has been achieved to sustain the hypothesis that the specific intake of foods and beverages containing relatively high concentrations of polyphenols may play a meaningful role in reducing cardiovascular disease risk through an improvement in vascular function and a modulation from inflammation.26 To date, on the basis of clinical studies, the demonstration is particularly convincing for polyphenols from cocoa-derived products and to a lesser extent for those from tea.26 For polyphenols from fruits such as berries, pomegranate, grapes or citrus fruits and those from beverages such as red wine or coffee, the evidence is so far inconclusive, primarily due to the limited number and the weakness of experimental designs of the studies performed with these dietary sources.26 The beneficial effects of polyphenols on inflammation-mediated cardiovascular diseases has been reviewed in detail by Zern and Fernandez,27 Johnston28 and Curin and Andriantsitohaina.29

2.3 Metabolic Diseases Obesity, metabolic syndrome and diabetes represent multifactorial conditions, which have a strong inflammatory component that can potentially be impacted by the diet.30 Working knowledge of the impact of nutrients,

especially dietary polyphenols, makes it possible to develop a general outline of an anti-inflammatory diet that offers a unique, non-pharmacological approach for treating obesity, metabolic syndrome and diabetes.30 One of the most frequently studied compounds is epigallocatechin-3-gallate (EGCG) and/or its source green tea extract.31 EGCG treatment has been shown to increase insulin levels in type-2 diabetic patients;31,32 however, no improvement of insulin resistance was observed.31,33 Promising results have been obtained for dark chocolate, the consumption of which (100 g dark chocolate bar containing approximately 500 mg of polyphenols for 15 days) improved insulin sensitivity along with reducing blood pressure in healthy31,34 and hypertensive subjects.31,35 Grape seed extract (600 mg per day for 4 weeks), given to type-2 diabetic patients, had a positive effect on several inflammatory markers and glycemia, but did not result in statistically significant changes in the homeostasis model assessment index of insulin resistance.31,36 Other promising plant food candidates with diabetes-preventive potential include cinnamon, bitter melon and fenugreek.31,37 On the other hand, a randomized double-blind crossover study in healthy obese men showed that resveratrol (150 mg per day for 30 days) exerts caloric-restriction-like effects, improves lipid profiles and decreases inflammatory markers.38,39

2.4 Cancer Chronic inflammation is linked to the development of 30% of all cancers.38,40 Chronic use of antiinflammatory agents prevents a wide range of human tumors.38,41
43 Polyphenols have the capacity to modulate the associated biological states of chronic inflammation that are found to contribute to the etiology of some cancers.44,45 There is evidence that polyphenolic flavonoids, when consumed at high levels, may be beneficial in preventing lung cancer,21,46 esophageal cancer,47 prostate cancer,21 renal cell carcinoma,48 and colorectal cancer.49 Preventive effects of green tea on colon, prostate, lung, oesophageal, and other cancers have been documented.38,50
52 A cohort study conducted among 384 Japanese cancer patients showed that consumption of green tea over 10 cups per day delayed the cancer onset by 8.7 and 3.0 years in women and men, respectively.53 Another Japanese study in patients following removal of colon polyps demonstrated that consumption of polyphenols equivalent to 12 cups of tea per day reduced the risk of adenoma recurrence by 50%.38,54 On the other hand, consistent data suggest curcumin is a promising candidate for colorectal cancer prevention.38 Curcumin in combination with quercetin decreased aberrant crypt foci by 40% in a phase IIa trial,38,55 and decreased the

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4. EFFECTS ON CELLULAR REDOX SYSTEM

incidence of colon adenomas in patients with familial adenomatous polyposis.38,56

2.5 Neurodegenerative Disorders Although neuroinflammation plays a critical role in brain host defence, it also contributes to the underlying neuronal loss in neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease57
60 and to damage associated with cerebral ischemia.60,61 Since long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to lower the risk of Alzheimer’s disease in later life,60,62 there has been much interest in the development of new drugs capable of preventing neuroinflammatory-mediated brain injury.60 Emerging evidence suggests that dietary polyphenols may exert neuroprotective effects by suppressing the activation of microglia, which mediates inflammatory processes in the central nervous system (CNS).60 It was observed that the people drinking three to four glasses of wine per day had 80% decreased incidence of dementia and Alzheimer’s disease compared to those who drank less or did not drink at all.63,64 It was found that the consumption of fruit and vegetable juices containing high concentrations of polyphenols, at least three times per week, may delay the onset of Alzheimer’s disease.63,65 An inverse association between the intake of flavonols and flavones and the risk of dementia has been observed in a French cohort.66,67 Recently, it was reported that administration of polyphenols provide protective effects against Parkinson’s disease, as well.63,68 On the other hand, polyphenolic compounds such as catechins from green tea, curcumin from turmeric (Curcuma longa), and resveratrol in red grape skin have been observed to have antidepressant-like effects.69
71 This suggests that polyphenols could improve psychiatric disorders like depression or anxiety.69

3. ANTI-INFLAMMATORY EFFECTS OF POLYPHENOLS: EVIDENCE FROM HUMAN STUDIES Selected studies have suggested that a higher consumption of vegetables, fruits and legumes in healthy volunteers was inversely correlated to blood inflammation markers, such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF)-α.72
76 A recent clinical trial study has demonstrated that a fermented food concentrate rich in polyphenols has promising immunoregulatory and anti-inflammatory potential, with significant reductions in intercellular adhesion molecule (ICAM)-1 and

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vascular cell adhesion molecule (VCAM)-1 and changes in natural killer cell cytotoxicity in response to IL-2 stimulation.77 It has been demonstrated that red wine consumption (30 g per day for 4 weeks) decreased the expression of several adhesion molecules on monocytes and T-lymphocytes.72,78 It was also shown that supplementation with a grape polyphenol extract containing anthocyanins, quercetin, myricetin, kaempferol and resveratrol (36 g per day for 4 weeks) led to a significant decrease in plasma TNF-α and IL-6 levels.72,79 Results of a survey performed on 120 men and women suggested that an intake of anthocyanin extract from blueberries (300 mg per day for 3 weeks) significantly decreased nuclear factor-κB (NF-κB)related pro-inflammatory cytokines and chemokines (IL-4, IL-13, IL-8 and interferon-γ [IFN-γ]) plasma levels.72,74 Results of a study with 18 healthy men and women, which supplemented their diets with cherries (280 g per day for 28 days), suggest a selective modulatory effect on CRP and nitric oxide (NO).80,81 In an epidemiological study conducted with 1031 healthy Belgian men, serum CRP concentrations were inversely associated with tea consumption.80,82 In another double blind placebo-controlled trial, regular tea consumption reduced platelet activation and plasma CRP concentrations.80,83 These polyphenols exert anti-inflammatory effects by several mechanisms including antioxidant activities, reduction of the activities of arachidonic acid metabolism enzymes (phospholipase A2 [PLA2], cyclooxygenase [COX], lipoxygenase [LOX]), and nitric oxide synthase (NOS), and modulation of the production of other proinflammatory molecules and proinflammatory gene expression (Figure 29.1).72,84 The cellular molecules which polyphenolic compounds exerted on to suppress inflammation is listed in Table 29.1.

4. EFFECTS ON CELLULAR REDOX SYSTEM Most studies conducted to date have suggested that the anti-inflammatory effects of polyphenols are attributable to their antioxidant properties.85,86 Polyphenols have often been generically referred to as “antioxidants.” Some phenolic phytochemicals, including gallic acid and quercetin, exhibit stronger antioxidant activity than vitamin C.87 In general, polyphenols have the capacity to chelate metal ions and directly quench free radical species including superoxide and peroxynitrite anions that contribute to oxidative damage.88
91 On the other hand, recent studies suggest that the antioxidative effects of polyphenols are derived not only from direct scavenging of various radicals, but also from direct regulation of oxidative stress-mediated enzyme activity. Some

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29. POLYPHENOLS SUPPRESS AND MODULATE INFLAMMATION: POSSIBLE ROLES IN HEALTH AND DISEASE

FIGURE 29.1 Mechanisms involved in the anti-inflammatory effects of polyphenols. Inflammatory stimuli induce inflammation by different pathways. Arachidonic acid is released by PLA2 and further metabolized by COX and LOX pathways which are responsible for inflammatory responses. On the other hand, protein kinases and nuclear molecules (PPAR, PARP, CBP, p300 (HAT) and HDACs) regulate transcription factors NF-κB, AP-1, STAT-1, and C/EBP that modulate the expression of proinflammatory molecules and enzymes such as IL-6, TNF-α, ICAM-1, VCAM-1, CRP, COX-2, LOX, and iNOS. Polyphenols exhibit antioxidative activities derived not only from direct scavenging of various ROS, but also regulation of antioxidant enzyme expression through Nrf2. Θ is where polyphenols inhibit and * is where they promote.

polyphenols can decrease the activities of pro-oxidant enzymes to exert antioxidative effects.92
94 Some polyphenols can increase the activities and expression of antioxidant enzymes.95
100 Emerging evidence suggests that activation of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway may better account for the antioxidative benefits of polyphenols.7 Many polyphenolic phytochemicals have been shown to activate adaptive cellular stress response pathways that induce the expression of networks of genes encoding antioxidant enzymes.96 In contrast to direct antioxidants such as vitamin C that have short half-lives, activators of the Keap1-Nrf2-ARE pathway have long-lasting effects because their action is based on the induction of transcription-mediated

signaling.101,102 Recent studies have demonstrated that Nrf2 signaling is involved in attenuating inflammation-associated pathogenesis, such as neuroinflammation, autoimmune diseases, rheumatoid arthritis, asthma, emphysema, gastritis, colitis, and atherosclerosis.103
105 Therefore, efficient polyphenolic inducers of Nrf2 activation could be considered effective modulators of prevention or treatment of inflammation-mediated diseases.

5. EFFECTS ON ARACHIDONIC ACID METABOLISM Prostanoids and leukotrienes synthesized from arachidonic acid are involved in inflammation.106 It has been reported that polyphenolic flavonoids are able to

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5. EFFECTS ON ARACHIDONIC ACID METABOLISM

TABLE 29.1

Molecular Targets of Polyphenols to Suppress and Modulate Inflammation

PLA2

Bilobetin,109 curcumin,110 ginkgetin,109 ochnaflavone,183 quercetin.108

COX-2

Apigenin,123,155,184
188 curcumin,110,189 galangin,114 genistein,112,123 green tea polyphenols,124 isoliquiritigenin,190,191 kaempferol,123,192 luteolin,154,186,193 mallotophilipens,194, morin,195 nobiletin, 113oroxylin A,126 prodelphinidin B-4-30 -O-gallate,124 quercetin,114,127,184,192 rutin,127 theaflavin,154 wogonin,127,196 vexibinol.194

5-LOX or 12-LOX

Apigenin,186,187 curcumin,110 kaempferol, 197 kazinol B,117 kuwanon C,117 luteolin,186 morin,198,199 morusin,117 prenylated flavonoids,117 quercetin.87,197,199

iNOS

Apigenin,114,123,155 daidzein,153 genistein,153 EGCG,128,200
202 isoliquiritigenin,190,191 kaempferol,123,192 luteolin,155,193 mallotophilipen,194 oroxylin A,126 procyanidins,203 prodelphinidin B-4-30 -O-gallate,124 quercetin,114,125,127,192,204 quercetin gallate,156 rutin,127 theaflavin,154 wogonin.127

Pro-inflammatory cytokines (e.g., TNF-α, IFN-γ, IL-1β, IL-2, IL-6)

Apigenin,155,205 kaempferol,130 luteolin,151 quercetin.130,206,207

Th2-type cytokines (e.g., IL-4, IL-5, IL-13)

Apigenin,131 fisetin,131 genistein,208 luteolin,131 quercetin.206

Chemokines (e.g., MCP-1, IP-10, MIP-2, IL-8)

Apigenin,132 butein,209 quercetin,171 EGCG,133 green tea polyphenols.134

Adhesion molecules (e.g., ICAM-1, VCAM-1, E-selectin)

Apigenin139,155, chrysin,210 galangin,139 glabridin,139 hesperidin,211 kaempferol,138,210,212 luteolin,155 phellopterin,211 proanthocyanidins,165 quercetin,212,213 theaflavin.154

C-Reactive protein

Kaempferol,192 quercetin.192

NF-κB

Amentoflavones,164 apigenin,123,185,205 catechins,214 EGCG,134,215,216 genistein,123,153,160 genistin,160 kaempferol,192,212 liquiritigenin,217 morin,195 oroxylin A,126 poncirin,218 procyanidins,203 prodelphinidin B-4-30 -O-gallate,125 quercetin.192,212,219
222

AP-1

Chrysin,210 kaempferol,210 luteolin,149,150 8-prenylkaempferol,151 quercetin.223

STAT-1

Apigenin, 155 daidzein, 153 genistein, 153 kaempferol, 153 luteolin, 155 quercetin, 153 theaflavin. 154

C/EBP

Baicalein, 161 baicalin, 161 genistein, 160 genistin. 160

PPAR

Amentoflavone,

PARP-1

Delphinidin, 167 fisetin, 167,168gossypetin, 167 myricetin, 167 quercetin, 167 tricetin. 167,168

CBP, p300(HAT), or HDACs

EGCG, 172 nobiletin, 170 quercetin.171

PI3K or Akt

Cryptotanshinone, 174 glabridin,140 hesperidin,211 myricetin, 225 phellopterin,

MAPKs (e.g., JNK, ERK, p38)

Apigenin, 226 butein, 135 chrysin,210 EGCG, 227,228 glabridin, 140 hesperetin, 228 hesperidin, 228 kaempferol,210 luteolin, 178,210 quercetin, 176,213 wogonin. 226

Protein kinase C

Fisetin, 179 luteolin, 179 quercetin. 179

134

EGCG, 224 proanthocyanidins. 165

modulate arachidonic acid metabolism by inhibiting PLA2 activity and by inhibiting the enzymatic activity or protein expression of COX and LOX.72 Inhibition of PLA2, COXs and LOXs, thereby reducing the concentrations of prostanoids and leukotrienes, might be the mechanism for the anti-inflammatory activity of polyphenols.107

5.1 Phospholipase A2 PLA2 is essential to inflammation and the immune response.107 Arachidonic acid is released from phospholipids by PLA2 and is further oxidized to prostaglandins or thromboxanes by the actions of COX or

211

quercetin.225

5-LOX, respectively.107 The inhibition of PLA2 by polyphenolic flavonoids has been reported in a number of in vitro and in vivo studies. Quercetin was found to be an effective inhibitor of PLA2 in human leukocytes.9,108 Bioflavonoids such as amentoflavone, bilobetin, morelloflavone and ginkgetin derived from certain medicinal plants have been shown to inhibit PLA2 as well.107,109 Curcumin affects arachidonic acid metabolism by blocking the phosphorylation of cytosolic PLA2, resulting in decreased COX-2 expression.9,110 Since PLA2 is coupled with COXs and LOXs depending on the cells, PLA2 becomes the molecular target of polyphenols to cause the inhibition of COX or LOX activity and inflammation.

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5.2 Cyclooxygenase-2 Prostanoids including various types of prostaglandins and thromboxanes are arachidonate metabolites produced and released in response to a variety of physiological and pathological stimuli and function to maintain the body homeostasis.111 COX-2 is known as an inducible enzyme that produces, in most cases, large amounts of prostaglandins and is highly expressed in the inflammation-related cell types including macrophages and mast cells after pro-inflammatory stimulations.111 There are an increasing number of studies reporting downregulation of COX-2 expression or activity by naturally occurring polyphenols.8,112
114 The polyphenolic compounds, which have been shown to inhibit COX-2 expression or activity in the literature are listed in Table 29.1.

5.3 Lipoxygenase LOXs are responsible for the production of hydroxyl acids and leukotrienes from arachidonic acid and are related to the onset and the development of different human diseases.72 In particular, 5-LOX and 12-LOX are associated with allergic and inflammatory disorders such as asthma and psoriasis.72,115,116 It has been reported that polyphenols have inhibitory effects on 5-LOX and 12LOX.72,117
119 In asthma patients, dietary soy isoflavone supplementation (100 mg per day for 4 weeks) decreases the activation of 5-LOX and reduces eosinophil leukotriene 4 synthesis and eosinophilic airway inflammation suggesting that isoflavones may represent good candidates for the treatment of asthma.72,120 Flavonols such as kaempferol, quercetin, morin and myricetin were found to be especially effective lipoxygenase inhibitors.121

6. EFFECTS ON NITRIC OXIDE SYNTHASE Nitric oxide influences many aspects of the inflammatory cascade, ranging from its own production by immune-competent cells to the recruitment of leukocytes.122 Because iNOS is induced by bacterial products and inflammatory cytokines, experimental data support the idea that compounds inhibiting expression or activity of iNOS are potential anti-inflammatory agents.106 The effect of polyphenols on iNOS and NO has been extensively studied in order to elucidate the antiinflammatory properties. Polyphenols such as apigenin, kaempferol, oroxylin A, prodelphinidin B-4-30 -O-gallate, quercetin, and wogonin inhibit iNOS expression and NO production in the mouse macrophage-like cell line RAW264.7.114,123
127 EGCG has been demonstrated to possess anti-metastatic effects against cancer cells: it

decreases NO production in, and thus migration potential of, 4T1 murine mammary cancer cells.128

7. EFFECTS ON PROINFLAMMATORY MOLECULES 7.1 Cytokines and Chemokines Cytokines are the major mediators of local, intercellular communications required for an integrated response to a variety of stimuli in immune and inflammatory processes.106 Different cytokines are associated with inflammatory diseases, with the clinical outcome partly determined by the balance between proinflammatory (e.g., IL-1β, IL-2, IL-6, IFN-γ, and TNF-α) and anti-inflammatory (e.g., IL-10 and tumor growth factor [TGF]-β) molecules.8 A large number of polyphenolic flavonoids have been reported to inhibit the expression of pro-inflammatory cytokines (Table 29.1). For example, baicalin inhibits the induction of IL-1β, IL-6, TNF-α and IFN-γ in human blood monocytes treated with enterotoxin.129 Quercetin and kaempferol have shown the gene expression and secretion of TNFα, IL-1β, and IL-6 in RBL-2H3 cells.130 Luteolin, fisetin, and apigenin inhibit Th2-type cytokine production, including IL-4, IL-5, and IL-13, by activated human basophils.131 The inhibitory action exerted by polyphenolic flavonoids is coupled in some cases to the enhancement of anti-inflammatory cytokines.106 Chemokines are a family of small chemotactic cytokines that have diverse roles in controlling leukocyte migration.106 In the last few years, a growing body of evidence has suggested that flavonoids inhibit chemokines.106 For example, apigenin and EGCG inhibit the production of monocyte chemoattractant protein-1 (MCP-1),132,133 a chemokine secreted by activated macrophages and endothelial cells.132,133 Green tea polyphenols inhibit the production of IL-8, a chemoattractant for neutrophils, in human nasal fibroblasts and A549 epithelial cells.134 Butein significantly inhibits IL-8 secretion, as well.135 Quercetin inhibits the gene expression of TNF-induced IFN-γ-inducible protein 10 (IP-10) and macrophage inflammatory protein 2 (MIP-2) in the murine small intestinal epithelial cell line Mode-K.136 Castilla and co-workers137 described that after 3 weeks of supplementation of concentrated red grape juice, which contains a couple of polyphenols, the concentration of MCP-1 decreased progressively in both hemodialysis patients and healthy controls.

7.2 Adhesion Molecules Polyphenolic flavonoids also exert their beneficial action in cardiovascular diseases by modulating

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8. EFFECTS ON INFLAMMATORY GENE EXPRESSION

monocyte adhesion during the inflammatory process.106 Different dietary flavonoids have been shown to decrease the expression of cell adhesion molecules on endothelial cells.80,106,121 Gerritsen and colleagues demonstrated that hydroxyl flavones and flavonols are effective in inhibiting cytokine-induced expression of intercellular adhesion molecules (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and endothelial cell selectin (E-selectin) in human umbilical vein endothelial cells (HUVECs).138 Hydroxyl flavones such as apigenin and chrysin; flavonols such as galangin, kaempferol, and quercetin; isoflavanes such as glabridin; and 20 - and 40 -hydroxychalcones such as isoliquiritigenin or butein are able to inhibit endothelial adhesion molecule expression.139
141 A recent clinical trial study in 48 healthy men aged 20
48 years has demonstrated that a fermented food concentrate consisting of fruits, nuts and vegetables rich in polyphenols has promising immunoregulatory and antiinflammatory potential, with significant reductions in ICAM-1 and VCAM-1 in response to IL-2 stimulation.77,80 Estruch et al.78 and others found that 4 weeks of red wine consumption reduced plasma levels of VCAM-1 and ICAM-1 and increased the plasma levels of epigallocatechin.121 Long-term intervention studies conducted using soya as a source of bioactive molecules showed a reduction in levels of VCAM-1, as well.121,142

7.3 C-Reactive Protein CRP is an acute phase reactant, elevated serum levels of which are considered an indicator of chronic inflammation.106 In addition to the expression of adhesion molecules, activated endothelial cells release IL-6 that stimulates hepatocyte fibrinogen and CRP production, which contributes to the exacerbation of endothelial dysfunction.143 The interaction of CRP with endothelial cells may be the mechanistic link to atherosclerosis.144 It has been found that the dietary pattern characterized by a higher portion of vegetables, fruits and legumes is inversely associated with the level of blood CRP.73,75,80,106,121 In a study of 285 adolescent boys aged 13
17 years, a diet rich in fruits and vegetables and, therefore, rich in antioxidants, folate and flavonoids, was associated with lower levels of CRP.80,145 Results of a study with 18 healthy men and women, which supplemented their diets with cherries (280 g per day for 28 days), suggested a selective modulatory effect on CRP.80,81 In an epidemiological study conducted with 1031 healthy Belgian men, serum CRP concentrations were inversely associated with tea consumption.80,82 In another double-blind, placebocontrolled trial with 37 healthy men, regular tea

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consumption reduced platelet activation and plasma CRP concentrations.80,83

8. EFFECTS ON INFLAMMATORY GENE EXPRESSION There are several critical steps at which flavonoids can modulate the cascade of molecular events leading to the overexpression of inflammatory mediators.106 These include inhibition of transcription factors (NFκB, activator protein 1 (AP-1), signal transducers and activators of transcription-1 (STAT-1), and CCAAT/ enhancer binding protein (C/EBP)), nuclear molecules (peroxisome proliferator-activated receptor (PPAR), poly(ADP-ribose) polymerase (PARP), and CREB binding protein (CBP)), protein kinases (phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinases (MAPKs)).72,106,107,146

8.1 Transcription Factors 8.1.1 NF-κB The most widely studied as a target of polyphenols to regulate the inflammatory gene expression is NF-κB, an oxidative stress-sensitive transcription factor that plays a critical role in the regulation of a variety of genes important in inflammation and innate immunity.106 Different studies have shown that polyphenolic flavonoids can modulate the NF-κB signaling pathway during inflammation and that this modulation can occur at early (regulation of I-κB kinase activation) as well as late (binding of NF-κB to DNA) stages.106,147 There is a report that intervention with an anthocyanin extract from blueberries (300 mg per day for 3 weeks) significantly reduced the plasma concentration of NFκB-related pro-inflammatory cytokines and chemokines in a group of 120 men and women aged 40
74 years.74,80 The list of polyphenols which have been shown to inhibit NF-κB is shown in Table 29.1. 8.1.2 AP-1 The transcription factor AP-1 regulates the inflammatory gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections.106,148 Several in vitro and in vivo studies have demonstrated that polyphenolic compounds can inhibit the AP-1 signaling pathways.106,146 For example, in lipopolysaccharide (LPS)-activated mouse alveolar macrophages, luteolin significantly inhibits the LPSinduced DNA binding activity of AP-1.149 The prenylflavonoid 8-prenylkaempferol, isolated from the roots of Sophora flavescens, blocks AP-1 activation by interfering with c-Jun N-terminal kinase (JNK)-mediated c-Jun

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phosphorylation.150 It has been similarly reported that luteolin inhibits AP-1 activation through the loss of JNK phosphorylation and reduces the amount of IL-6 in primary murine microglia and BV-2 microglial cells.151 8.1.3 STAT-1 The STAT proteins take part in the regulation of cellular responses to cytokines and growth factors.106 STAT-1 is involved in the signaling events mediated by toll like receptor 4 (TLR4), leading to increased expression of several pro-inflammatory and proatherogenic mediators.152 Genistein, kaempferol, quercetin, and daidzein inhibit the activation of STAT1 and the mRNA and the protein expression of iNOS in activated macrophages.106,153 Theaflavin, a major constituent of black tea, significantly protected neurons from cerebral ischemia-reperfusion injury by limiting expression of ICAM-1 and suppressing upregulation of iNOS and COX-2 at least in part via reducing the phosphorylation of STAT-1.154 In cultured microglia, both N9 and primary cells, apigenin and luteolin markedly inhibited IFN-γ-induced phosphorylation of STAT-1 and suppressed CD40 expression and TNF-α and IL-6 production in a dose-dependent manner.155 An interesting finding is the fact that most potent inhibitors of iNOS expression and NO production (e.g., quercetin, genistein, and kaempferol) inhibit the activation of both NF-κB and STAT-1.106,156 Because NF-κB and STAT-1 are involved in the activation of several inflammatory genes, flavonoids that inhibit activation of both transcription factors are likely to downregulate the production of an array of proinflammatory mediators.106 8.1.4 C/EBP C/EBP transcription factors are known to be involved in regulating various aspects of inflammation and immunity in liver, lung and in cells of the myelomonocytic lineage.106,157
159 The isoflavones genistein and genistin have been reported to suppress iNOS expression and NO production in LPS-activated RAW264.7 macrophage-like monocytes through the inhibition of NF-κB and C/EBPβ.106,160 Baicalein and baicalin, two flavonoids present in the root of Scutellaria baicalensis, have also been examined for their anti-inflammatory effects in RAW264.7 cells, and found to mediate the effects through the inhibition of C/EBPβ DNA binding activity.106,161

8.2 Nuclear Molecules 8.2.1 PPAR PPARs are nuclear hormone receptors that are activated by specific endogenous and exogenous

ligands.146 Some NSAIDs are able to activate PPARγ isoforms, and PPARγ ligands have been shown to hinder the production of pro-inflammatory cytokines and to inhibit iNOS expression partially by antagonizing the activities of transcription factors such as AP-1 and NF-κB.146,162,163 Thus, PPAR activation by certain polyphenols is one possible mechanism for achieving their anti-inflammatory effects.9,146 The biflavonoid amentoflavone was shown to upregulate PPARγ expression in TNF-α-activated A549 human lung epithelial cells, which might be the reason for the observed inhibition of the NF-κB pathway, resulting in reduced COX-2 expression.146,164 It has been demonstrated that grape seed proanthocyanidin extracts induce an activation of PPARγ, and contribute to protecting the function of endothelial cells through the inhibition of VCAM1.80,165 8.2.2 PARP PARP-1 participates in the regulation of NF-κBmediated production of pro-inflammatory cytokines, and inhibition of PARP-1 has been reported to reduce the DNA-binding activity of NF-κB and the transcription of NF-κB target genes.106,166 The polyphenolic flavonoids myricetin, tricetin, gossypetin, delphinidin, quercetin, and fisetin have been identified as significant inhibitors of purified PARP-1.106,167 Quercetin, fisetin, and tricetin reduced the formation of the PARpolymers in N-methyl-N0 -nitro-N-nitrosoguanidine (MNNG)-treated human pulmonary epithelial cells.106,167 The PARP-1-inhibiting flavonoids fisetin and tricetin were able to attenuate LPS-induced cytokine release from leukocytes of patients with chronic systemic inflammation, indicating a potential application as nutraceutical agents for these patient groups.168 8.2.3 CBP, p300 (HAT) and HDACs CBP and its homolog p300 are large nuclear molecules that coordinate a variety of transcriptional pathways through chromatin remodeling.7,106 Pro-inflammatory cytokines activate transcription factors, such as NF-κB, recruiting CBP/p300 containing intrinsic histone acetyltransferase (HAT), resulting in histone acetylation and DNA unwinding, allowing DNA polymerases access to the DNA and proinflammatory gene expression.7 Dietary polyphenols have been reported to inhibit epigenetic modifications, such as DNA methylation and histone modification through regulation of DNA methyltransferase, CBP/ HAT activity, and histone deacetylases (HDACs), leading to resolution of inflammation.169 Nobiletin was thought to disrupt the binding of CBP and p300 and to suppress NF-κB, AP-1, and cAMP response elementbinding protein (CREB) activation.146,170 Quercetin has been reported to inhibit TNF-α-induced expression of

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IP-10 and MIP-2 by inhibiting the recruitment of CBP/ p300 to the IP-10 and MIP-2 gene promoters in primary murine small intestinal epithelial cells.8,171 EGCG decreased NF-κB activity through hypoacetylation of RelA/p65 by directly inhibiting the activity of HAT.169,172 Resveratrol, curcumin and catechins are shown to modulate NF-κB activation and chromatin remodeling through the modulation of SIRT1 and HDAC2 activity attenuating inflammatory gene expression in lung epithelium and macrophages.169 These observations suggest that polyphenols may specifically affect chromatin remodeling at proinflammatory gene promoters.

part to competitive binding of polyphenols at nucleotide binding sites.107 In some studies, it was observed that the isoflavone, orobol, and flavonols, such as quercetin and fisetin, inhibited the phosphoinositol kinase from Streptomyces and that orobol competed with ATP at the active site.107,180 Similarly, fisetin and luteolin competitively inhibited ATP binding to protein kinase C.107,179 Apigenin has also been observed to competitively inhibit ATP binding to protein kinase C and to reduce the level of ATP stimulated phosphorylation of cellular proteins.107,181,182

9. CONCLUSION 8.3 Protein Kinases Cell activation during inflammation involves a variety of protein kinases (e.g., PI3K, Akt kinase, MAPKs, and protein kinase C) responsible for signal transduction.80,106,107,119,146 Effects of polyphenols on transcription factors, such as NF-κB, AP-1, STAT-1, and C/EBP, which modulate the expression of pro-inflammatory markers such as COX-2, iNOS, TNF-α, IL-1β, and IL-6, have been reported to be regulated through the inhibition of protein kinases.80,106,119 PI3K is an upstream regulator of Akt/mTOR signaling that also interacts with several polyphenols.45 Cryptotanshinone, isolated from Salvia miltiorrhiza, inhibits complement 5a (C5a)-evoked migration in RAW264.7 cells in a concentration-dependent manner through an effect that involves inhibition of PI3K activation with consequent reduction of phosphorylation of Akt.106,173 Acacetin was able to inhibit LPSstimulated expression of COX-2 and iNOS in RAW264.7 cells by interfering in the activation of PI3K/Akt, ERK and NF-κB.146,174 Numerous studies have shown that polyphenols modulate MAPKs (e.g., JNK, ERK, and p38 MAPK) by acting at several steps of the activation cascade.45 It has been reported that quercetin inhibits iNOS expression through inhibition of p38 MAPK175 and that it blocks AP-1 binding in LPS-induced RAW264.7 cells by inhibiting JNK.176 Data from LPS-activated macrophages show that quercetin is able to suppress proinflammatory cytokines and NF-κB activation through ERK and p38 MAPK.177 In RAW264.7 cells, luteolin also inhibits LPS-stimulated pathways through inhibition of ERK and p38 MAPK.178 On the other hand, the roles of polyphenol inhibition of protein kinase C in modulating lymphocyte function and antigen-induced basophil histamine release has been extensively reviewed.107,179 In the last few years, studies have shown that polyphenol inhibition of protein kinases may be due in

The amount of evidence gathered in the field of inflammatory/immunological modulation by polyphenols over the last few years is impressive. The main conclusion of the studies is that polyphenols are almost without exception anti-inflammatory on the different cell types studied, lowering the expression and/ or function of a variety of inflammatory mediators, including NO, prostanoids, leukotrienes, cytokines, chemokines, adhesion molecules, and CRP. The impact of polyphenols is generally reported as broad rather than specific, and this is in keeping with the fact that NF-κB, AP-1, STATs, and C/EBP, a master regulator of these mediators, are common targets of polyphenols, although the specific details are more variable. This also applies to other signaling pathways, such as those of nuclear factors and protein kinases, which to a great extent converge on the activation of proinflammatory transcription factors. There are other emerging signaling targets of flavonoids, such as Nrf2, that deserve further exploration. In general, synthetic drugs target one protein because they have high specificity. However, there are many situations in which synthetic drugs have high toxicity or cause severe side effects in clinical trials. Conversely, a single polyphenol can bind multiple protein targets and inhibit many signaling molecules. Since numerous signaling proteins are correlated with each other in the development of inflammatory chronic diseases, polyphenols act as inhibitors of multiple pathways in disease prevention and treatment. In addition, polyphenols have relatively low toxicity when compared to synthetic drugs because they are commonly consumed over long periods as food components. Along with the effort to elucidate molecular targets of polyphenols, polyphenol bioavailability and metabolism should be considered if they are to be used effectively. Because people mostly eat polyphenols in food matrices, the effects of food matrices on polyphenol

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bioavailability and the differences in age-related absorptive capacity need to be considered. Observational studies are limited in their conclusions because the protection afforded by the consumption of a particular food may be multifactorial, with different components exerting potentially beneficial effects. In many studies, the daily intake of polyphenols has been estimated by questionnaires, and a more precise analysis of quantity and quality is required. The disappointing outcome of various trials on the preventive effects of flavonoid supplementation in healthy subjects reinforces the necessity for more prospective randomized trials with larger sample sizes, longer follow-up, and extended durations of treatment.80 Understanding the mechanisms and modes of action of polyphenols in various disease processes has proven to be a challenging but achievable goal. As the field produces evidence in favor of the preventive and therapeutic benefits of polyphenols, public interest also expands. The available data demonstrate the potential utility of dietary polyphenols for the possible treatment of inflammatory diseases.

Acknowledgments This work was supported by the World Class University Program (R31-2008-00-10056-0), and the Basic Science Research Program (2012R1A1A3011954), National Research Foundation, Ministry of Education, Science and Technology, Republic of Korea. This chapter was also funded by the National Platform Technology Project (10033818), Ministry of Knowledge Economy, Republic of Korea.

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5. INFLAMMATION AND POLYPHENOLS