Quercetin and Its Anti-Allergic Immune Response

Abstract

Quercetin is the great representative of polyphenols, flavonoids subgroup, flavonols. Its main natural sources in foods are vegetables such as onions, the most studied quercetin containing foods, and broccoli; fruits (apples, berry crops, and grapes); some herbs; tea; and wine. Quercetin is known for its antioxidant activity in radical scavenging and anti-allergic properties characterized by stimulation of immune system, antiviral activity, inhibition of histamine release, decrease in pro-inflammatory cytokines, leukotrienes creation, and suppresses interleukin IL-4 production. It can improve the Th1/Th2 balance, and restrain antigen-specific IgE antibody formation. It is also effective in the inhibition of enzymes such as lipoxygenase, eosinophil and peroxidase and the suppression of inflammatory mediators. All mentioned mechanisms of action contribute to the anti-inflammatory and immunomodulating properties of quercetin that can be effectively utilized in treatment of late-phase, and late-late-phase bronchial asthma responses, allergic rhinitis and restricted peanut-induced anaphylactic reactions. Plant extract of quercetin is the main ingredient of many potential anti-allergic drugs, supplements and enriched products, which is more competent in inhibiting of IL-8 than cromolyn (anti-allergic drug disodium cromoglycate) and suppresses IL-6 and cytosolic calcium level increase.

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Review
Quercetin and Its Anti-Allergic Immune Response
Jiri Mlcek 1, *, Tunde Jurikova 2, Sona Skrovankova 1and Jiri Sochor 3
1Department of Food Analysis and Chemistry, Faculty of Technology, Tomas Bata University in Zlín,
Vavreckova 275, CZ-760 01 Zlín, Czech Republic; skrovankova@ft.utb.cz
2Institute for Teacher Training, Faculty of Central European Studies,
Constantine the Philosopher University in Nitra, Drazovska 4, SK-949 74 Nitra, Slovakia; tjurikova@ukf.sk
3Department of Viticulture and Enology, Faculty of Horticulture, Mendel University in Brno, Valticka 337,
CZ-691 44 Lednice, Czech Republic; sochor.jirik@seznam.cz
*Correspondence: mlcek@ft.utb.cz; Tel.: +420-57-603-3030
Academic Editor: Norbert Latruffe
Received: 22 February 2016; Accepted: 3 May 2016; Published: 12 May 2016
Abstract:
Quercetin is the great representative of polyphenols, flavonoids subgroup, flavonols.
Its main natural sources in foods are vegetables such as onions, the most studied quercetin containing
foods, and broccoli; fruits (apples, berry crops, and grapes); some herbs; tea; and wine. Quercetin is
known for its antioxidant activity in radical scavenging and anti-allergic properties characterized
by stimulation of immune system, antiviral activity, inhibition of histamine release, decrease in
pro-inflammatory cytokines, leukotrienes creation, and suppresses interleukin IL-4 production.
It can improve the Th1/Th2 balance, and restrain antigen-specific IgE antibody formation. It is
also effective in the inhibition of enzymes such as lipoxygenase, eosinophil and peroxidase and
the suppression of inflammatory mediators. All mentioned mechanisms of action contribute to the
anti-inflammatory and immunomodulating properties of quercetin that can be effectively utilized
in treatment of late-phase, and late-late-phase bronchial asthma responses, allergic rhinitis and
restricted peanut-induced anaphylactic reactions. Plant extract of quercetin is the main ingredient of
many potential anti-allergic drugs, supplements and enriched products, which is more competent in
inhibiting of IL-8 than cromolyn (anti-allergic drug disodium cromoglycate) and suppresses IL-6 and
cytosolic calcium level increase.
Keywords:
quercetin; flavonoids; immune response; anti-allergic effect; anti-inflammatory properties
1. Introduction
The expansion of allergic diseases has been extended during last three decades all over the world.
Different changes in environmental factors (sensitizers such as indoor and outdoor allergens, air
pollution, and various infections) may contribute to this problem [
1
]. Dietary alterations relating to
nutritional changes of foods and their amount could be one of the factors that cause increase and
worsening of allergic symptoms too. The interaction of environmental and genetic factors with the
immune system can thus lead to the development of allergic diseases [
2
]. Mainly respiratory, skin,
and food allergies are included in the inherent allergic problems. The immune system reacts quite
sensitively to familiar substances that are, after re-exposure, sensed as allergens. This leads to a massive
secretion of allergy-related mediators that could generate allergic symptoms [3].
Therapy with different synthetic agents or drugs could cause certain patients various adverse
side effects. Phytochemicals, such as flavonoids, polysaccharides, lactones, alkaloids, diterpenoids
and glucosides, are naturally present in many plant foods. These compounds have been reported to
be responsible for immunomodulating and anti-inflammatory properties [
4
]. Dietary polyphenols as
natural therapies have been more frequently studied with regard to major allergic diseases such as
atopic eczema, food allergy and asthma [
5
–
7
]. Therefore, the attention concerning the compounds
Molecules 2016,21, 623; doi:10.3390/molecules21050623 www.mdpi.com/journal/molecules

Molecules 2016,21, 623 2 of 15
with anti-allergic effect and anti-inflammatory properties has been presently focused on flavonoids,
especially quercetin. Its anti-inflammatory and anti-allergic properties have been proven in the
treatment of respiratory and food allergies [8–10].
Quercetin belongs to the most frequently studied flavonoids that is, together with kaempferol, the
most ubiquitous in plant foods although they are generally presented at relatively low concentrations
of 15–30 mg/kg FW (fresh weight) [
11
] except several vegetable varieties with extensive content,
such as onions and shallots. Quercetin and its glycosylated forms represent 60%–75% of flavonoid
intake [
12
]. Generally, quercetin occurs in natural plant sources such as various types of vegetable
(onions, broccoli, and peppers) [
13
–
15
], caper fruits [
16
], different kinds of fruits (apples, various
berries, and grapes) [17–19], herbs (dill) [20], and some types of tea [21] and wine [22,23].
Besides other natural forms of quercetin, its plant extract is the main ingredient of many potential
anti-allergic drugs, supplements and enriched products with quercetin, such as functionally enhanced
white and red wines [
24
]. Quercetin is also a promising component that can prevent lifestyle related
diseases [
25
]. Quercetin extracts are now largely used as a nutritional supplements and curative
ingredients for many illnesses such as diabetes related with obesity and circulatory dysfunction,
including inflammation, as well as moods troubles [
26
]. Quercetin exhibits similar anti-allergic
potential as a Chinese herbal formula (Food Allergy Herbal Formula) that has been related with
blocking of anaphylaxis to peanuts in mouse models [27].
2. Quercetin, Its Structure and Main Sources
Quercetin (3,3
1
,4
1
,5,7-pentahydroxyflavone) (Figure 1) is one of the most abundant dietary
flavonoids and belongs to the flavonols subgroup. Flavonols (C6-C3-C6 polyphenols) have two
hydroxylated benzene rings, A and B. Flavonols differ in the number and type of substitution in the B
ring, where quercetin is dihydroxylated in positions 31and 41.
Molecules 2016, 21, 623 2 of 15
with anti-allergic effect and anti-inflammatory properties has been presently focused on flavonoids,
especially quercetin. Its anti-inflammatory and anti-allergic properties have been proven in the
treatment of respiratory and food allergies [8–10].
Quercetin belongs to the most frequently studied flavonoids that is, together with kaempferol, the
most ubiquitous in plant foods although they are generally presented at relatively low concentrations
of 15–30 mg/kg FW (fresh weight) [11] except several vegetable varieties with extensive content, such
as onions and shallots. Quercetin and its glycosylated forms represent 60%–75% of flavonoid intake
[12]. Generally, quercetin occurs in natural plant sources such as various types of vegetable (onions,
broccoli, and peppers) [13–15], caper fruits [16], different kinds of fruits (apples, various berries, and
grapes) [17–19], herbs (dill) [20], and some types of tea [21] and wine [22,23].
Besides other natural forms of quercetin, its plant extract is the main ingredient of many
potential anti-allergic drugs, supplements and enriched products with quercetin, such as functionally
enhanced white and red wines [24]. Quercetin is also a promising component that can prevent lifestyle
related diseases [25]. Quercetin extracts are now largely used as a nutritional supplements and curative
ingredients for many illnesses such as diabetes related with obesity and circulatory dysfunction,
including inflammation, as well as moods troubles [26]. Quercetin exhibits similar anti-allergic
potential as a Chinese herbal formula (Food Allergy Herbal Formula) that has been related with
blocking of anaphylaxis to peanuts in mouse models [27].
2. Quercetin, Its Structure and Main Sources
Quercetin (3,3′,4′,5,7-pentahydroxyflavone) (Figure 1) is one of the most abundant dietary
flavonoids and belongs to the flavonols subgroup. Flavonols (C6-C3-C6 polyphenols) have two
hydroxylated benzene rings, A and B. Flavonols differ in the number and type of substitution in the
B ring, where quercetin is dihydroxylated in positions 3′ and 4′.
Figure 1. Chemical structure of quercetin.
Quercetin is present in plants in many different glycosidic forms. It is usually found in conjugated
forms with sugars such as glucose, galactose and rhamnose [28]. The prevalent forms are quercetin
conjugated with one or two glucose molecules, such as isoquercetin; and quercetin conjugated with
rutinose such as quercetin rutinoside—rutin. However, the aglycone form of quercetin occurs in
much lower levels in foods. Different quercetin forms represent 60%–75% of flavonoid intake [12].
The quercetin content of plant foods differs depending on the cultivars or cultivation conditions
[25,29,30]. Its content has been shown to also be dependent on light exposure [31].
Quercetin is a flavonol that is found in a considerable quantity in various vegetables such as onions
and shallots that are affordable throughout the year. In many countries, onions are the main sources of
dietary quercetin [32–34]. Onions are thus qualitatively and quantitatively the most important source
of quercetin. Other vegetables, including broccoli, asparagus, green peppers, tomatoes and red leaf
lettuce, could be great sources of ubiquitous quercetin, especially in the summer [25,33,35]. Fruits
(apples as well as berry crops, such as strawberry, red raspberry, blueberry, cranberry and black
currants), green tea and wine could also be considered abundant dietary sources [22,25,33–37].
Figure 1. Chemical structure of quercetin.
Quercetin is present in plants in many different glycosidic forms. It is usually found in conjugated
forms with sugars such as glucose, galactose and rhamnose [
28
]. The prevalent forms are quercetin
conjugated with one or two glucose molecules, such as isoquercetin; and quercetin conjugated with
rutinose such as quercetin rutinoside—rutin. However, the aglycone form of quercetin occurs in much
lower levels in foods. Different quercetin forms represent 60%–75% of flavonoid intake [12].
The quercetin content of plant foods differs depending on the cultivars or cultivation
conditions [25,29,30]. Its content has been shown to also be dependent on light exposure [31].
Quercetin is a flavonol that is found in a considerable quantity in various vegetables such as onions
and shallots that are affordable throughout the year. In many countries, onions are the main sources
of dietary quercetin [
32
–
34
]. Onions are thus qualitatively and quantitatively the most important
source of quercetin. Other vegetables, including broccoli, asparagus, green peppers, tomatoes and
red leaf lettuce, could be great sources of ubiquitous quercetin, especially in the summer [
25
,
33
,
35
].
Fruits (apples as well as berry crops, such as strawberry, red raspberry, blueberry, cranberry and
black currants), green tea and wine could also be considered abundant dietary sources [
22
,
25
,
33
–
37
].

Molecules 2016,21, 623 3 of 15
In Finland, onions and apples are the best sources of this dietary flavonoid, while in the Netherlands
apples rank third behind tea and onions as top sources of flavonoids [33,38].
Onions (Allium cepa) are one of the richest sources of flavonoids in the human diet. The main
flavonoids of onions are represented by quercetin and its conjugates [
39
,
40
]. The principal forms
are quercetin 4
1
-glucoside, quercetin dimers, 3,4
1
-diglucoside, and quercetin 3-glucoside, with the
content in the range of 284–486 mg/kg [
33
,
41
]. The amount of quercetin in onions varies with bulb
color and type [
42
,
43
], being distributed mostly in the outer skins and rings [
44
,
45
], as flavonols are
mainly located in the outer epidermis of the skin, because they have a UV-protecting function [
46
].
Thus, the highest loss of quercetin happens when onions are peeled [
40
,
47
]. According to the part
of onions and shallots that is consumed, quite various amounts and forms of quercetin are ingested.
The quercetin forms of onion flesh include especially glucosides, with only minimal amounts of
quercetin aglycone. The skin and outermost layers of onions, similar to shallots, encompass much
more quercetin aglycone [
32
,
48
–
50
]. The forms of quercetin in shallot flesh are composed of about
99.2% quercetin glucosides and 0.8% quercetin aglycone. In dry shallot skin, the form distribution is
nearly reversed—83.3% quercetin aglycone and 16.7% quercetin glucosides [51].
In apples, another great quercetin source, there are well studied antioxidant compounds such as
quercetin-3-galactoside, quercetin-3-glucoside, and quercetin-3-arabinoside [
33
,
41
] in the content range
of 21–72 mg/kg; quercetin-3-rhamnoside [
52
]; and quercetin-3-rutinoside [
28
]. Quercetin conjugates
are present entirely in the apple peels [
28
,
53
]. Due to the presence of more antioxidants such as
quercetin in the apple peel than in the flesh, the apple peels may be considered to have higher
antioxidant capacity and also bioactivity [
54
]. In apples, other dietary quercetin glycosides such as
quercetin galactosides are also found [34].
Berry crops are great representatives of quercetin glycosides, especially quercetin-3-glucoside
(strawberry and red raspberry), quercetin-3-glucuronide (strawberry, red raspberry and blueberry),
quercetin-3-rutinoside (strawberry, red raspberry and blueberry), qurecetin-3-rhamnoside (red
raspberry, black currants, blueberry, and cranberry), quercetin-3-galactoside (blueberry, cranberry, and
black currants), and quercetin-3-arabinose (cranberry) [33,34,41,55].
Also lesser known fruit species could be considered as notable sources of quercetin. Saskatoon
berries (Amelanchier alnifolia) can be characterized by exceptionally high value of quercetin, as
determined by Jurikova et al. [
56
]. The quercetin content in some cultivars was quantified from 236 to
307 mg/kg FW. Saskatoon berry fruits contain quercetin-3-galactoside as the main abundant flavonol
(169.5 mg/kg FW) [
57
]. In six cultivars of edible honeysuckle (Lonicera sp.), quercetin-3-rutinoside and
quercetin-3-glucoside are identified as dominated flavonols. The quercetin level is high especially in
Lonicera caerulea var. edulis Turcz. (‘Altaj’) (294.1 mg/kg) [
58
]. Quercetin was the main flavonol
detected in chokeberry (Aronia sp.) with the content 89 mg/kg FW [
36
]. In black chokeberry
(Aronia melanocarpa) Määttä-Riihinen et al. [
59
] detected the overall amount of 348 mg/kg, which
was the fourth highest quercetin value of 18 berries they studied from six families (Grossulariaceae,
Ericaceae,Rosaceae,Empetraceae,Elaeagnaceae,Caprifoliaceae), after the amounts of three bog whortleberry
(Vaccinium uliginosum) genotypes. Quercetin is the third most representative flavonoid in cornelian
cherry (Cornus mas) in the amount from 120 up to 360 mg/kg [
60
]. Quercetin rhamnosyl hexoside and
dirhamnosyl hexoside, and isoquercetin are the main flavonols, which follow after kaempferol, in the
fruits of Chinese hawthorn (Crateagus pinnatifida) [56].
Flavonol glycosides are one of the most important groups of polyphenols besides catechins
in tea. The composition of tea varies with type, variety, season, age of leaves, climate, and
horticultural practices [
61
]. Black tea and oolong tea, both fermented tea types, have the highest
content of quercetin types of flavonol glycosides (50%–52% in oolong tea and 54%–71% in black tea,
respectively); green tea manufactured without the process of fermentation has a higher content of
kaempferol glycosides, while quercetin represents about 18%–38% of all flavonol glycosides [
62
].
The predominant quercetin glycosides in black tea are quercetin glucoside, rutinoside (rutin), and
galactoside; minor representatives are quercetin dirhamnoglucoside and rhamnogalactoside; and

Molecules 2016,21, 623 4 of 15
quercetin rhamnodiglucoside is present in the lowest levels. Oolong tea contains mainly quercetin
glucorhamnoglucoside, rutinoside, rhamnogalactoside and quercetin dirhamnoglucoside. Quercetin
rhamnogalactoside, rhamnodiglucoside and quercetin glucorhamnoglucoside are principal glycosides
presented in green tea [
62
]. The main quercetin forms of green pu-erh tea comprise two constituents,
quercetin 3-rhamnosylgalactoside and 3-glucoside. White tea has as predominant flavonol quercetin
3-glucosylrutinoside [63]. There is about 15–35-times higher content of rutin than quercetin [21].
Quercetin is synthesized in white and light red grape varieties together with other mono- and
di-substituted B-ring derivatives, kaempferol and isorhamnetin [
64
], which is the methylated form
of quercetin. Quercetin is therefore the main flavonol of white wine varieties (Chardonnay, Riesling,
and Sauvignon Blanc), representing over 70% of the total flavonol content [
65
]; and also of some light
red/rosé wine varieties (Pinot Noir, Sangiovese, and Gewürztraminer). Glucose or glucuronic acid
and galactose are the main sugars in conjugated forms of quercetin in wines [19].
3. Antioxidant Activity of Quercetin
Quercetin is a frequently studied phenolic compound due to its known great antioxidant
properties. Its flavonoid structure, 2,3 double bound in conjunction with 4-oxo bond in the C ring of
quercetin, allows electron delocalization from the B ring and shows extensive resonance. This results
in the significant efficiency for radical scavenging [
66
]. Therefore, quercetin has a structure that is
responsible for higher antioxidant activity effectiveness than the structure of anthocyanins.
Quercetin seems to be one of the most powerful flavonoids for protecting the body against reactive
oxygen species [
4
,
67
]. Quercetin, similar to fisetin, catechin, and myricetin, are flavonoid aglycones
that have 3-OH groups and are potent inhibitors of lipid oxidation [
68
]. Quercetin inhibits the initiation
step in chain oxidation and prevents chain propagation. This may also include the termination of a
chain by the reaction of two radicals [3,8].
Endogenous antioxidant ability of quercetin modifies the range of cellular injury during the
allergic damage that is caused by free radicals. Enzymes, such as repair and de novo ones (lipases, DNA
repair enzymes, proteases and transferases), act as the third line of defense by repairing damage and
reconstituting membranes [4,69].
4. Polyphenols and Quercetin as Effective Anti-Allergic Secondary Metabolites
Polyphenols are considered effective anti-allergy agents capable of influencing multiple
biological pathways and immune cell functions in the allergic immune response. Among the most
investigated plant-derived polyphenolic compounds (flavonoids), quercetin, together with resveratrol,
epigallocatechol-3-gallate, and genistein, have exhibited potent effects on cellular and humoral immune
functions in pre-clinical investigations [
70
]. The interaction of polyphenols with proteins can modulate
the process of allergic sensitization and their direct effect on allergic effector cells such as mast cells
inhibit mediator release, resulting in the alleviation of symptoms [
3
]. Polyphenols inhibit histamine
release from human basophils and murine mast cells [71,72].
Intake of polyphenols such as flavones, flavone-3-ols, catechins, anthocyanidins, flavanones,
procyanidins, and resveratrol can improve a skewed balance of T-helper (Th) type 1 and 2 cells
(Th1/Th2) and suppress antigen-specific IgE (Immunoglobulin E) antibody formation [73].
Flavonoids are known to inhibit histamine release from human basophils and murine mast
cells [
71
,
72
]. Flavonoids inhibit the release of chemical mediators; further suppress interleukin
(IL)-4 and IL-13 synthesis (Th2 type cytokines) by allergen- or anti-IgE antibody-stimulated
receptor-expressing cells (e.g., peripheral blood basophils or mast cells). They can also affect the
differentiation of naïve glycoprotein CD4 (cluster of differentiation 4) T cells (white blood cells) due to
the inhibitory effect on the activation of the aryl hydrocarbon receptor [
1
,
74
]. The inhibitory activity of
flavonoids on IL-4 and CD40 ligand expression is probably related through their inhibitory action on
activation of nuclear factors of activated T cells and AP-1 (activator protein-1) [1].

Molecules 2016,21, 623 5 of 15
Flavonols extracted from plants inhibit histamine and some cytokines release from rodent
basophils and mast cells. Basophils are more responsible for this balance than tissue mast cells,
therefore they could be considered as the potent natural substances for allergy cure [75].
Nowadays, the attention is focused on immunomodulation and anti-inflammatory properties of
quercetin such as stimulation of immune system, antiviral activity (anti-herpes virus type I), inhibition
of histamine release, inhibition of nuclear factor activation (NF-
κ
B), pro-inflammatory cytokines and
leukotrienes [8,76].
Quercetin induces significant gene expression and production of Th-1-derived interferon (IFN)-g,
as well as downregulating Th-2-derived IL-4 production by normal peripheral blood mononuclear
cells [
77
]. The anti-inflammatory profile of quercetin is known to impact on the recruitment of immune
cells to the skin and in preventing the development of secondary infections following disruption of the
skin barrier [3].
The anti-inflammatory action of quercetin is caused by the inhibition of enzymes such as
lipoxygenase, and the inhibition of inflammatory mediators. Quercetin affects immunity and
inflammation by acting mainly on leukocytes and targeting many intracellular signaling kinases
and phosphatases, enzymes and membrane proteins often crucial for a cellular specific function [
78
].
Quercetin inhibits the production and release of histamine and other allergic and inflammatory
substances, possibly by stabilizing cell membranes of mast cells [
79
,
80
]. In particular, quercetin is
an inhibitor of allergic (IgE-mediated) mediator release from mast cells and basophils, another type
of white blood cell involved in immune reactions. Quercetin is also an inhibitor of human mast cell
activation through the inhibition of Ca
2+
influx, histamine, leukotrienes and prostaglandins release and
proteinkinase activation [
27
]. Mast cells are influential immune cells important for the pathogenesis of
allergic responses and autoimmune disorders. They also affect release of many cytokines involved
in the inflammatory reactions such as IL-8 and Tumor necrosis factor (TNF) [
81
,
82
]. It is a reason
why quercetin is suitable for the treatment of mast cell-derived allergic inflammatory diseases such as
asthma, sinusitis, and rheumatoid arthritis [8].
The anti-allergic and anti-inflammatory properties of quercetin have been proved by several
studies, in animal models and in vitro, as presented in Table 1.
4.1. Quercetin and Respiratory Allergic Diseases: In Vitro and Animal Studies
Nowadays, the most studied food products in relation to their anti-allergic properties are onions
and their extracts. The anti-allergic activity (type I hypersensitivity) of different onion cultivars (eight
cultivars from three geographical origins) were determined by Sato et al. [
29
] using rat mast cells
(RBL-2H3 cells). Extensive variation of anti-allergic effectiveness was ascertained between the cultivars.
Between the studied types, Satsuki cultivar demonstrated the highest activity due to inhibitory
concentration value (IC
50
= 89.1 mg/mL). The positive correlation (r = 0.91) was exhibited between
compounds of onion extracts, such as quercetin 41-glucoside, and anti-allergic response.

Molecules 2016,21, 623 6 of 15
Table 1. Summarization of quercetin and its anti-allergic effect—in vitro studies.
Effect Studied Models Mechanism of Action References
Inhibition of mast
cell activation
rats
Stabilization of mast cell membrane Johri et al. [83]
Inhibition of leucotriens release, prostaglandin D2,
Ca2+ influx Kimata et al. [72]
Human cultured mast cells Release of IL-6, IL-8, TNF-2, inhibition of tryptase release,
activation of NF-κB
Kempuraj et al. [81],
Min et al. [84]
Inhibition of
histamine release
In vitro malignant cells Decrease of tryptase, MCP-1, IL-6, histidine
decarboxylase (HDC) Shaik et al. [85]
Antigen sensitized human mast cells Normal path of Ca2+ entry to cells, inhibition of
leucotrienes, PGD-2
Fewtrell and Gomperts [
86
],
Kimata et al. [72],
Weng et al. [82]
Rats mast cells Release of immunologically induced cells, inhibition of
anaphylactic histamine
Haagag et al. [87]
Pearce et al. [88]
ovalbumin-challenged mice
release from mucosal cells, inhibited eosinophil peroxidase
activity and protein content in bronchoalveolar lavage
fluid (BALF)
Kaiser et al. [89]
Suppression of
eosinophilic inflammation
OVA-induced asthma model rats Reduction of eosinophil peroxidase activity, level of IL-4,
Th2 cytokine production
Park et al. [90]
Chirumbolo [27]
Jurikova et al. [8]
Murine model of asthma Decrease in eosinophil counts in bronchoalveolar lavage
fluid, inhibition of NF-kappa B
Roger et al. [91]
Roger et al. [92]
Relaxation of muscles
Male A/J mice Isoproterenol induced relaxation Towsend and Emala [93]
Smoth muscle murine model of asthma Reduction of production of inflammatory cytokines Oliveira et al. [94]
(OVA)-sensitized conscious guinea pigs
Inhibitory activity of quercetin inhalation on sRaw (specific
airway resistance)
Jung et al. [95]
Moon et al. [96]
Isolated tracheal tissue Concentration-dependent inhibition of contractions
induced by both carbachol and electrical field stimulation Capasso et al. [97]
Suppression of
immunoglobulin E against
peanuts proteins
Wister rats
Plasma histamine levels in the quercetin-treated rats were
lower significantly, regulate mucosal immunity during
hypersensitivity reaction
Shiseboar et al. [98]
Wei et al. [99]

Molecules 2016,21, 623 7 of 15
Oliveira et al. [
94
] investigated the effect of onion extract and quercetin on cytokines and on
smooth muscle contraction
in vitro
and its effectiveness in a murine model of asthma. After a treatment
with onion extract or quercetin, they examined a decrease in inflammatory cytokines creation, a release
of tracheal rings and a lowering of cells quantity in bronchoalveolar lavage and eosinophil peroxidase
in lungs.
An herbal fraction from onion bulb can inhibit histamine release and reduce intracellular calcium
levels in induced rat peritoneal mast cells. Eosinophil peroxidase activity and protein amount in
bronchoalveolar lavage fluid of ovalbumin-challenged mice were also inhibited [89].
The effect of quercetin on pro-inflammatory mediator release and its probable principles of action
in human mast cells was investigated by Kempuraj et al. [
81
]. Human umbilical cord blood-derived
cultured mast cells grown in the presence of stem cell factor and interleukin (IL)-6 were incubated
for 15 min with quercetin (0.01
µ
M), followed by activation with anti-IgE. Release of IL-6, IL-8 and
TNF-
α
was inhibited by 82%, tryptase release by 79%–96%, and histamine release by 52%–77% at
100
µ
M concentration of quercetin, Min et al. [
84
] also investigated the effect of quercetin on the
expression of pro-inflammatory cytokines in human mast cell line. These cells were stimulated with
phorbol 12-myristate 13-acetate (PMA) and calcium ionophore. Results of the experiment showed that
quercetin decreased the gene expression and production of tumor necrosis factor-
α
, interleukin-1
β
,
IL-6, and IL-8 in human mast cells. Quercetin reduced phorbol calcium ionophore-induced activation
of NF-κB and p38 mitogen-activated protein kinase.
Quercetin has a significant inhibitory effect on histamine release. The effect of quercetin on
histamine secretion from antigen sensitized mast cells was examined by Fewtrell and Gomperts
already in 1977 at
µ
M concentrations [
86
]. Quercetin had an inhibitory effect on histamine secretion
mediated by antigen, but it had little effect on release induced by the ionophores. Quercetin exerts its
effect after the binding of the releasing ligands and the distinction between its effect on ligand induced
and A23187 induced secretion. That suggests that it influences the path of Ca2+ entry into the cell.
Like histamine and most cyclin-dependent kinases, quercetin restrains the
in vitro
growth of
some malignant cells and thus indicates considerable anti-cancer effects. Quercetin could restrain
compounds responsible for allergy response due to the inhibition action of mast cell secretion, effecting
regress in the release of tryptase, monocyte chemoattractant protein 1 (MCP-1) and IL-6 [85].
Haggag et al. [
87
] tested inhibitory effect of herbs infusion (chamomile, saffron, anise, fennel,
caraway, licorice, cardamom and black seed) on histamine that was relinquished from stimulated
rat peritoneal mast cells by immunoglobulin E and anti-immunoglobulin E. The results of the
experiment showed that the herbs infusion restrained histamine released from chemically- and
immunologically-induced cells by 81% and 85%, respectively. In comparison, quercetin appears
to be more effective, as it affected histamine release by 95% and 97%, respectively.
Animal studies conducted in rats showed that more than 25% of the absorbed quercetin is
localized in the lung tissue, an added benefit to combat allergy and associated asthma [
8
]. Addition
of quercetin already in the concentration of 100 nM may relax airway rings precontracted with
acetylcholine. The cure with quercetin in the concentration of 100
µ
M avoided a force creation upon
exposure to acetylcholine. Moreover, quercetin in the concentration of 50
µ
M notably augmented
isoproterenol-induced relaxations. In addition, dispersion of quercetin, in the concentration of 100
µ
M,
in an
in vivo
model of airways perception notably inhibited methacholine-induced progress in airways
resistance [93].
Quercetin inhibits rat tracheal contractility through a presynaptic (involving nitric oxide) and a
postsynaptic site of action. The results of Capasso et al. [
97
] study showed that quercetin produced a
concentration-dependent inhibition of contractions induced by carbachol. However, quercetin was
more active in inhibiting the contractions produced by electrical field stimulation than those induced
by carbachol, suggesting a presynaptic site of action (in addition to a postsynaptic effect, as revealed
by the inhibitory action of quercetin on carbachol-induced contractions).

Molecules 2016,21, 623 8 of 15
Long ago, in the experiment of Johri et al. [
83
], a stabilization effect of quercetin, isolated from
onions, on mast cell membrane of rats was shown. In the study of Kimata et al. [
72
], human cultured
mast cells were sensitized with IgE, and then treated with flavonoids before challenge with antihuman
IgE. Results showed that quercetin inhibited the release of histamine, leukotrienes, prostaglandin
D
2
, and granulocyte macrophage-colony stimulating factor from human cultured mast cells in a
concentration-dependent manner. Moreover, quercetin inhibited Ca
2+
influx strongly. The activation
of extracellular signal-regulated kinases and c-Jun NH
2
-terminal kinase were clearly suppressed
by quercetin.
Quercetin is effective eosinophilic inflammation suppressor for diseases like allergic rhinitis and
asthma. Rogerio et al. [
91
] investigated the anti-inflammatory effect of quercetin and isoquercitrin in a
murine model of asthma. In mice feeding with these flavonoids, the amount of white blood cells and
eosinophil in the bronchoalveolar lavage fluid, blood and lung parenchyma was detected in lower
quantities [91,92].
In another study of Rogerio et al. [
92
], the anti-inflammatory effect of quercetin-loaded
microemulsion and quercetin suspension in an experimental model of airways allergic inflammation
have been compared. Oral administration of quercetin suspension failed to interfere with leukocyte
recruitment, while quercetin-loaded microemulsion inhibited in a dose-dependent way, the eosinophil
recruitment to the bronchoalveolar lavage fluid. The microemulsion considerably reduced IL-5
and IL-4 levels too, but has not be capable to interfere with CCL11, IFN-gamma and LTB(4) levels.
Oral treatment with microemulsion also decreased the nuclear transcription factor
κ
B activation, and
the mucus production in the lung.
Park et al. [
90
] examined whether quercetin could influence eosinophil peroxidase activity.
They demonstrated that asthmatic reactions in mice, sensitized by ovalbumin injection, could be
notably inhibited by their feeding with quercetin. In another experiment, Sakai-Kashiwabara [
100
]
examined peripheral blood eosinophils and IgE levels after infection by Mesocestoides corti.
The experiment was designed to examine the influence of quercetin on eosinophil activation induced
by SCF stimulation
in vitro
. The addition of quercetin into cell cultures could suppress eosinophil
activation induced by SCF stimulation. The minimum concentration of quercetin that caused significant
suppression of factor secretion was 5 µM.
Chirumbolo et al. [
27
] studied the anti-allergic effect in the Th1/Th2 immune response.
They attempted to determine whether quercetin regulates Th1/Th2 cytokine production, T-bet and
GATA binding protein 3 gene expression in ovalbumin-induced asthma model mice. Results of
experiment showed that quercetin reduced the increased levels of IL-4, Th2 cytokine production in
ovalbumin-sensitized and challenged mice. During the experiment the elevation of interferon-gamma,
Th1 cytokine production occurred in quercetin administrated mice. Therefore, quercetin is able to
regulate Th1/Th2 balance.
Quercetin is an inhibitor of enzymes responsible for inflammatory reaction, naturally derived
PDE4-selective (cyclic nucleotide phosphodiesterases) inhibitor. Chan et al. [
101
] attempted to
determine the PDE4(H)/PDE4(L) ratios of different quercetin forms in relation to phosphodiesterase
(PDE)-4 activity. The anti-inflammatory effects of PDE4 inhibitors were reported to be associated with
inhibition of PDE4 catalytic activity. To reduce inflammation, an inhibition of lipolytic enzyme, human
secretory phospholipase A2 group IIA, could be effective as it leads to a decrease in eicosanoids levels.
This lipolytic enzyme is therefore of high pharmacological interest in treatment of chronic diseases
such as asthma [102]. Good inhibitory activity was shown for quercetin and kaempferol.
Quercetin is structurally related to the anti-allergic drug disodium cromoglycate. Weng et al. [
82
]
compared effect of quercetin and cromolyn on cultured human mast cells. Both compounds at the
concentration of 100
µ
M can effectively inhibit secretion of histamine and leukotrienes from primary
human cord blood-derived cultured mast cells stimulated by IgE/Anti-IgE. Quercetin is more effective
than cromolyn in inhibiting IL-8; reduces IL-6 in a dose-dependent manner; and inhibits cytosolic
calcium level increase.

Molecules 2016,21, 623 9 of 15
Quercetin is useful in the treatment of immediate (IP), late-phase (LP), and late-late-phase
(LLP) asthma responses via inhibition of histamine and protein release, phospholipase A2 activity.
It also reduces recruitment of neutrophils and eosinophils into the lung. Jung et al. [
95
] studied
this effect for IP and LP on the asthmatic responses in ovalbumin-sensitized conscious guinea pigs.
The results of experiment showed that quercetin (7.5 mg/kg) significantly and dose-dependently
inhibited immediate and late-phase in asthma responses but less efficiently than dexamethasone and
salbutamol. Analogously, Moon et al. [
96
] studied the effects of quercetin inhalation into asthmatic
responses by exposure to aerosolized-ovalbumin in conscious sensitized guinea pigs. Results showed
that quercetin inhalation decreased IP, LP and LLP in asthma responses, compared with the control.
Inhibitory activity of quercetin inhalation on specific airway resistance was similar to effect of its oral
administration (10 mg/kg) in asthmatic responses.
4.2. Quercetin and Respiratory Allergic Diseases—Epidemiological Evidence
The results of several epidemiological studies suggest that an increase of flavonoid intake is
beneficial for asthma [
90
,
103
]. Moreover, clinical trials with flavonoids have shown their ameliorative
effects on symptoms related to asthma [
74
]. A protective effect of quercetin consumption on asthma
incidence have been demonstrated by epidemiological- and population-based case-control studies
in Finland by Knekt et al. [
104
], where higher quercetin intake was associated with lower asthma
incidence. In the Netherlands, Willers et al. [
105
] ascertained that consummation of apples during
pregnancy may have a protective effect against the development of childhood asthma and allergic
diseases. In the Shaheen et al. [
106
] survey of the United Kingdom, about 600 persons with asthma and
900 healthy subjects were investigated due to their diet habits and lifestyle. Total fruit and vegetable
intake was only weakly associated with asthma. Apple intake showed a stronger inverse relationship
with asthma. This was mostly clear in subjects who consumed at least two apples per week. Onion,
tea, and red wine consumption were not related to asthma incidence, suggesting a beneficial effect of
apple flavonoids, especially quercetin.
Tabak et al. [
107
] deduced a positive association between fruit (such as apples) consumption and
general pulmonary health. Scientists in their study with over 13,000 individuals proved a positive link
of fruit consumption with pulmonary function, probably due to the high quercetin content. However,
they also assessed the lack of association between chronic obstructive pulmonary disease (COPD) and
flavonol intake. A profitable result of apple consummation on lung function was also demonstrated in
another study with about 2500 middle-aged men. More than four apples consumed weekly notably
boosted forced expiratory volume compared to subjects who did not eat apples [
38
,
108
]. In the study of
Woods et al. [
109
] involving 1600 adults in Australia, they discovered that apple and pear intake could
be associated with a decreased risk of asthma and a decrease in bronchial hypersensitivity. However,
total fruit and vegetable intake is not associated with asthma risk or severity.
4.3. Quercetin and Food Allergies
Food allergies are a relevant and common health complaint with an increasing prevalence. Actual
allergy therapy is reduced to an avoidance of problematic foods [
110
]. Studies of this problem are
aimed especially at prevention, as the enormous burden is in early childhood [111].
For food allergies, there is a very important practice in an inhibition of dendric cells function.
Quercetin together with kaempferol and isoflavones are able to regulate mucosal immunity during
hypersensitivity reaction [99].
In the study of Shiseboar et al. [
98
], the effects of quercetin on peanut-induced anaphylactic
reactions were investigated in a rat model with rats sensitized by peanut infusion. After daily-intake
of quercetin for four weeks, entirely restricted peanut-induced anaphylactic reactions. The comparison
with positive control rat group showed that the plasma histamine values in rats with quercetin
ingestion were substantially decreased.

Molecules 2016,21, 623 10 of 15
Quercetin is therefore a potent suppressor of the on-going immunoglobulin E responses against
peanut proteins, and can be introduced as an alternative medicine like a defender against IgE-mediated
food allergies.
5. Conclusions
Allergic disorders (skin, food and respiratory allergies) have been rapidly increasing worldwide
during the last three decades. Therefore, there is a demand for new sources of anti-allergic bioactive
compounds. Nowadays, most attention has been focused on flavonoids, especially quercetin. Quercetin
displays high antioxidant and anti-inflammatory properties that have been proven by many
in vivo
and
in vitro
studies. Quercetin’s anti-allergic mechanism of action through the inhibition of enzymes
and inflammatory mediators has also been extensively studied. It is well known that quercetin is an
inhibitor of human mast cell activation through the inhibition of Ca
2+
influx, histamine, leukotrienes
and prostaglandins release. This review also summarizes the role of quercetin in relation to respiratory
allergic diseases (
in vitro
, animal and epidemiological studies) and food allergies. The results of the
studies prove a unique position of quercetin in the treatment of allergic disorders and the possibility of
using phytochemicals such as quercetin for an efficient cure.
Acknowledgments:
This study was funded by internal grant agency of Tomas Bata University in Zlín, project no.
IGA/FT/2016/008 and IGA ZF 2016.
Author Contributions:
All authors designed review. Tunde Jurikova, Jiri Mlcek, Sona Skrovankova and Jiri Sochor
contributed to the writing of the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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