Immunomodulating Effects of Flavonoids on Acute and Chronic Inflammatory Responses Caused by Tumor Necrosis Factor α

Abstract

Flavonoids have beneficial activities which modulate oxidative stress, allergy, tumor growth and viral infection, and which stimulate apoptosis of tumor cells. In addition to these activities, dietary flavonoids are able to regulate acute and chronic inflammatory responses. Here we describe new aspects of regulatory mechanisms by which flavonoids suppress production of tumor necrosis factor-alpha (TNF-alpha) by macrophages, microglial cells and mast cells stimulated with lipopolysaccharide (LPS) and others via toll-like receptors (TLRs), and TNF-alpha-mediated acute and chronic inflammatory responses. Treatment with flavonoids such as luteolin, apigenin, quercetin, genistein, (-)-epigallocatechin gallate, and anthocyanidin resulted in significant downregulation of LPS-elicited TNF-alpha and nitric oxide (NO) production and diminished lethal shock. In chronic diseases, pathogenesis of collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis which is triggered by TNF-alpha, was improved by the oral administration of flavonoids after the onset of CIA. Here, we discuss that inhibitory effects of flavonoids on acute and chronic inflammation are due to regulation of signaling pathways, including the nuclear factor kappaB (NF-kappaB) activation and mitogen-activated protein (MAP) kinase family phosphorylation. FcetaRI expression by NF-kappaB activation was also reduced by flavonoids; while accumulation of lipid rafts, which is the critical step for signaling, was blocked by flavonoids. The intake of dietary flavonoids reduces acute and chronic inflammation due to blocking receptor accumulation and signaling cascades, and would assist individuals at high-risk from life-style related diseases.

Photoprotection of natural flavonoids

“…Apigenin (5,7,4'-trihydroxyflavone) is a widely distributed plant flavone occurring in cereal grains and aromatic herbs (parsley, rosemary, thyme), fruit (apples, cherries, grapes), vegetables (beans, broccoli, celery, leeks, onions, barley, tomatoes) and beverages (tea, wine) (Peterson and Dwyer, 1998). Apigenin possesses anti-inflammatory (Patel et al, 2007;Nicholas et al, 2007;Smolinski et al, 2003;Crespo et al, 2008;Kumazawa et al, 2006) and free radical scavenging properties (Kim et al, 1999;Raso et al, 2001). The protective effects of apigenin in the prevention of UVA and UVB-induced skin carcinogenesis in SKH-1 mice have been demonstrated.…”

“…This natural ingredient shows preventative and therapeutic effects for breast and prostate cancers (Hwang et al, 2009;Severson et al, 1989;Shimizu et al, 1991;Lee et al, 1991;Wu et al, 1996), postmenopausal syndrome (Evans et al, 2011), osteoporosis (Pavese et al, 2010, and cardiovascular diseases in animals and humans (Altavilla et al, 2004). Genistein modulates photocarcinogenesis through enhancement of antioxidant enzyme activities and scavenging of oxygen free radicals (Wei et al, 1993;Giles et al, 1997), inhibition of UVR-induced oxidative DNA damage in purified DNA and culture cells (Wei et al, 1993;Wei et al, 1996;, suppression of UVR-induced protooncogene (c-fos and c-jun) expression in mouse epidermis and downregulation of UVR-activated phosphorylation of epidermal growth factorreceptor and tyrosine kinase activities .…”

“…These catechins are present in higher quantities in green tea than in black or oolong tea. These polyphenolic compounds are capable of scarvenging the free radicals such as lipid free radicals (Vinson et al, 1995;Cholbi et al, 1991), superoxide radicals (Harada et al, 1999), hydroxyl radicals (Nanjo et al, 1999), hydrogen peroxide (Weisburg et al, 2004;Lambert et al, 2007), and singlet oxygen (Higdon and Frei, 2003;Khan and Mukhtar, 2007).…”

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“…iNOS Suppresses iNOS expression [33], [35], [34], [43], [81], [82], [84] NO Supresses NO production [33], [35], [48], [34], [43], [56], [81] PGD-2 Inhibits PGD-2 release from human mast cells [51], [52] Leukotrienes Inhibits leukotriene release from human mast cells [51], [52] Leukotriene B4 inhibits LT B4 synthesis [87] Leukotriene C4 No effect [37] Thromboxane B2 Inhibits TX B2 synthesis [87] Histamine Inhibits histamine release from human mast cells [51], [52] GM-CSF Inhibits GM-CSF release from human mast cells [51], [52] TNF-α Suppresses TNF-α expression [48], [34], [36], [42], [53], [55], [56], [81], [93] COX-2 Suppresses COX-2 expression [28], [57], [81], [84] NFκB Inhibits DNA binding and transcription [32], [35], [36], [81], [82] NFκB Does not inhibit NFκB nuclear translocation, DNA binding or phosphorylation but inhibits transcription [85] AP-1 Induces AP-1 DNA binding <...>…”

Oral Quercetin Supplementation Lowers Plasma sICAM-1 Concentrations in Female db/db Mice

“…Data suggests that the flavonol quercetin (Figure 1) inhibits intestinal glucose transporter 2 (GLUT 2) [18], improves glucose uptake in adipocytes [19], inhibits adipocyte differentiation [19] and possesses anti-inflammatory and anti-oxidant properties [20,21]. In rats fed a high-fat diet, quercetin stimulated adiponectin secretion [21] and increased adiponectin mRNA concentration in adipose tissue via a PPAR-γ-independent mechanism [21].…”