Influence of Resveratrol on the Immune Response

Abstract

Resveratrol is the most well-known polyphenolic stilbenoid, present in grapes, mulberries, peanuts, rhubarb, and in several other plants. Resveratrol can play a beneficial role in the prevention and in the progression of chronic diseases related to inflammation such as diabetes, obesity, cardiovascular diseases, neurodegeneration, and cancers among other conditions. Moreover, resveratrol regulates immunity by interfering with immune cell regulation, proinflammatory cytokines’ synthesis, and gene expression. At the molecular level, it targets sirtuin, adenosine monophosphate kinase, nuclear factor-κB, inflammatory cytokines, anti-oxidant enzymes along with cellular processes such as gluconeogenesis, lipid metabolism, mitochondrial biogenesis, angiogenesis, and apoptosis. Resveratrol can suppress the toll-like receptor (TLR) and pro-inflammatory genes’ expression. The antioxidant activity of resveratrol and the ability to inhibit enzymes involved in the production of eicosanoids contribute to its anti-inflammation properties. The effects of this biologically active compound on the immune system are associated with widespread health benefits for different autoimmune and chronic inflammatory diseases. This review offers a systematic understanding of how resveratrol targets multiple inflammatory components and exerts immune-regulatory effects on immune cells.

Full text

nutrients
Review
Influence of Resveratrol on the Immune Response
Lucia Malaguarnera
Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97,
95124 Catania, Italy; lucmal@unict.it
Received: 28 February 2019; Accepted: 19 April 2019; Published: 26 April 2019


Abstract:
Resveratrol is the most well-known polyphenolic stilbenoid, present in grapes, mulberries,
peanuts, rhubarb, and in several other plants. Resveratrol can play a beneficial role in the
prevention and in the progression of chronic diseases related to inflammation such as diabetes,
obesity, cardiovascular diseases, neurodegeneration, and cancers among other conditions. Moreover,
resveratrol regulates immunity by interfering with immune cell regulation, proinflammatory cytokines’
synthesis, and gene expression. At the molecular level, it targets sirtuin, adenosine monophosphate
kinase, nuclear factor-
κ
B, inflammatory cytokines, anti-oxidant enzymes along with cellular processes
such as gluconeogenesis, lipid metabolism, mitochondrial biogenesis, angiogenesis, and apoptosis.
Resveratrol can suppress the toll-like receptor (TLR) and pro-inflammatory genes’ expression.
The antioxidant activity of resveratrol and the ability to inhibit enzymes involved in the production
of eicosanoids contribute to its anti-inflammation properties. The effects of this biologically active
compound on the immune system are associated with widespread health benefits for different
autoimmune and chronic inflammatory diseases. This review offers a systematic understanding of
how resveratrol targets multiple inflammatory components and exerts immune-regulatory effects on
immune cells.
Keywords:
resveratrol; immune response; macrophages; T lymphocytes; natural killer; B lymphocytes
1. Introduction
Resveratrol (trans-3,4,5-trihydroxystilbene) is a natural polyphenol found in red wine [
1
],
rhubarb [
2
], and fruits such as blueberries [
3
], many red grape varieties [
4
], and peanuts [
5
] to name a
few, that plays an important role in a large variety of biological activities [
6
,
7
]. Resveratrol can exhibit
antioxidative, anti-inflammatory, anticancer, antimicrobial, anti-neurodegenerative, and estrogenic
properties [
8
,
9
]. The immunomodulatory role of resveratrol was proposed 18 years ago, with an
investigation that demonstrated how it inhibits the proliferation of spleen cells induced by concanavalin
A (ConA), interleukin-2 (IL-2), or alloantigens, and more efficiently prevents the production of IL-2 and
interferon-gamma (IFN
γ
) by lymphocytes and the production of tumor necrosis factor alpha (TNF-
α
)
or IL-12 by macrophages [
10
]. By interacting with several molecular targets, resveratrol regulates innate
and adaptive immunity [
11
]. Nevertheless, sometimes its properties seem to be contrasting. It has
been reported that resveratrol modulates immune function in a dose dependent manner, at low doses
resveratrol stimulates the immune system, whereas at high doses it induces immunosuppression [
12
].
Its effect as an immunomodulator has been demonstrated in various animal models and in different cell
lines. In rodents, resveratrol reduces inflammatory responses in peritonitis, reverses immunosenescence
in elder rats, and improves immunologic activity against cancer cells [
13
,
14
]. Regarding the immune
system, it has been found that resveratrol participates in the activation of macrophage, T cell and natural
killer (NK), and is involved in CD4
+
CD25
+
regulatory T cell suppressive functions [
11
,
15
]. Its effects
are the result of its ability to remove reactive oxygen species (ROS) [
16
], to inhibit cyclooxygenase
(COX) [
17
,
18
], and to activate many anti-inflammatory pathways, including among others Sirtuin-1
Nutrients 2019,11, 946; doi:10.3390/nu11050946 www.mdpi.com/journal/nutrients

Nutrients 2019,11, 946 2 of 24
(Sirt1) [
19
]. Sirt1 disrupts the TLR4/NF-
κ
B/STAT signal which in turn decreases cytokines production
from inactivated immune cells [
20
], or macrophage/mast cell-derived pro-inflammatory factors, such as
platelet-activating factor (PAF), TNF-
α
, and histamine [
21
]. For its benefits to human health (Figure 1)
and for showing promising properties in immunologic disorders, it is increasingly proposed as a
dietary supplement for human consumption [
22
]. However, the pharmacokinetic analysis reveals
that resveratrol undergoes rapid metabolism in the body. Its bioavailability after oral administration
is very low, despite absorption reaching 70%, this impacts the physiological significance of the high
concentrations used in vitro studies [23].
In the present review, we aim to outline the molecular mechanisms of action, the role in the
immunological function, and the therapeutic use of resveratrol in many diseases characterized
by inflammation.
Nutrients 2019, 11, 946 2 of 25
TLR4/NF-κB/STAT signal which in turn decreases cytokines production from inactivated immune
cells [20], or macrophage/mast cell-derived pro-inflammatory factors, such as platelet-activating
factor (PAF), TNF-α, and histamine [21]. For its benefits to human health (Figure 1) and for showing
promising properties in immunologic disorders, it is increasingly proposed as a dietary supplement
for human consumption [22]. However, the pharmacokinetic analysis reveals that resveratrol
undergoes rapid metabolism in the body. Its bioavailability after oral administration is very low,
despite absorption reaching 70%, this impacts the physiological significance of the high
concentrations used in vitro studies [23].
In the present review, we aim to outline the molecular mechanisms of action, the role in the
immunological function, and the therapeutic use of resveratrol in many diseases characterized by
inflammation.
Figure 1. Activity of resveratrol against different human diseases based on experimental studies.
2. Resveratrol Pathways in Immune Function
A key function of resveratrol is to inhibit the production of inflammatory factors through the
activation of Sirt1 [24]. Sirt1 is an important deacetylase involved in numerous molecular events,
including metabolism [25], cancer [26], embryonic development [27], and immune tolerance [28,29].
Sirt1 maintains periphery T cell tolerance. The ablation of Sirt1 leads to the enhancement of T cell
activation and the occurrence of spontaneous autoimmune disease [30]. Structural studies indicate
that resveratrol binding to Sirt1 modulates the Sirt1 structure and enhances binding activity to its
substrates [31]. Due to its aptitude to activate Sirt1 and suppress inflammation, resveratrol is able to
alleviate inflammatory symptoms in several experimental autoimmune disease models, such as
colitis, type I diabetes, encephalomyelitis, and rheumatoid arthritis [32,33] (Figure 1). One of the
principal substrates of Sirt1 is p65/RelA [34], a NF-κB member, which is the major regulator of
leukocyte activation and inflammatory cytokines signaling [35]. The activation of Sirt1 by resveratrol
generates the inhibition of RelA acetylation, which in turn decreases NF-κB-induced expression of
inflammatory factors such as TNF-α, IL-1β, IL-6, metalloproteases (MMP)-1 and MMP3, and Cox-2
[36] (Figure 2). Resveratrol-treated cells are less responsive to TNF-α-induced NF-κB signaling and
apoptosis initiation, acting as a double block on the NF-κB signaling pathway [37]. Moreover,
resveratrol inhibits p300 expression and promotes inhibitor protein-κBα (IkBα) degradation,
nevertheless, it is unknown whether this process occurs through Sirt1 activation [38]. The targets of
resveratrol include AMP-activated protein kinase (AMPK), an essential energy sensor in cells, which
controls the activity of Sirt1 by regulating the cellular levels of available nicotinamide adenine
dinucleotide (NAD+) [39] (Figure 2). Cyclic adenosine monophosphate (cAMP) levels trigger protein
kinase A (PKA), which in turn phosphorylates and activates Sirt1 [40]. The evidence that the function
of resveratrol is mediated, in part by Sirt1, is confirmed by the observation that the anti-inflammatory
properties of resveratrol are abolished by the genetic deletion of Sirt1, or by the addition of Sirt1
Figure 1. Activity of resveratrol against different human diseases based on experimental studies.
2. Resveratrol Pathways in Immune Function
A key function of resveratrol is to inhibit the production of inflammatory factors through the
activation of Sirt1 [
24
]. Sirt1 is an important deacetylase involved in numerous molecular events,
including metabolism [
25
], cancer [
26
], embryonic development [
27
], and immune tolerance [
28
,
29
].
Sirt1 maintains periphery T cell tolerance. The ablation of Sirt1 leads to the enhancement of T cell
activation and the occurrence of spontaneous autoimmune disease [
30
]. Structural studies indicate
that resveratrol binding to Sirt1 modulates the Sirt1 structure and enhances binding activity to its
substrates [
31
]. Due to its aptitude to activate Sirt1 and suppress inflammation, resveratrol is able
to alleviate inflammatory symptoms in several experimental autoimmune disease models, such as
colitis, type I diabetes, encephalomyelitis, and rheumatoid arthritis [
32
,
33
] (Figure 1). One of the
principal substrates of Sirt1 is p65/RelA [
34
], a NF-
κ
B member, which is the major regulator of leukocyte
activation and inflammatory cytokines signaling [
35
]. The activation of Sirt1 by resveratrol generates
the inhibition of RelA acetylation, which in turn decreases NF-
κ
B-induced expression of inflammatory
factors such as TNF-
α
, IL-1
β
, IL-6, metalloproteases (MMP)-1 and MMP3, and Cox-2 [
36
] (Figure 2).
Resveratrol-treated cells are less responsive toTNF-
α
-induced NF-
κ
B signaling and apoptosis initiation,
acting as a double block on the NF-
κ
B signaling pathway [
37
]. Moreover, resveratrol inhibits p300
expression and promotes inhibitor protein-
κ
B
α
(IkB
α
) degradation, nevertheless, it is unknown whether
this process occurs through Sirt1 activation [
38
]. The targets of resveratrol include AMP-activated
protein kinase (AMPK), an essential energy sensor in cells, which controls the activity of Sirt1 by
regulating the cellular levels of available nicotinamide adenine dinucleotide (NAD
+
) [
39
] (Figure 2).
Cyclic adenosine monophosphate (cAMP) levels trigger protein kinase A (PKA), which in turn
phosphorylates and activates Sirt1 [
40
]. The evidence that the function of resveratrol is mediated, in
part by Sirt1, is confirmed by the observation that the anti-inflammatory properties of resveratrol are

Nutrients 2019,11, 946 3 of 24
abolished by the genetic deletion of Sirt1, or by the addition of Sirt1 inhibitors such as Sirtinol [
39
–
41
].
In the downstream activation of AMPK, an increase of nicotinamide adenine dinucleotide (NAD
+)
levels
induces Sirt1 activation, which promotes beneficial metabolic changes primarily through deacetylation
and activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1
α
)
(Figure 2).
Nutrients 2019, 11, 946 3 of 25
inhibitors such as Sirtinol [39–41]. In the downstream activation of AMPK, an increase of
nicotinamide adenine dinucleotide (NAD+) levels induces Sirt1 activation, which promotes beneficial
metabolic changes primarily through deacetylation and activation of peroxisome proliferator-
activated receptor gamma coactivator 1-alpha (PGC-1α) (Figure 2).
Figure 2. Resveratrol pathways in immune function: resveratrol activates Sirtuin-1 (Sirt1) inhibiting
RelA acetylation and promotes inhibitor protein-κBα (IkBα) degradation, which decreases nuclear
factor kappa B (NF-κB)-induced expression of tumor necrosis-alpha (TNF-α), interrleukin (IL)-1β, IL(-
6), metalloproteases (MMPs), and cyclooxygenase Cox-2. Cyclic adenosine monophosphate (cAMP)
levels trigger protein kinase A (PKA), which activates Sirt1. AMP-activated protein kinase (AMPK)
controls the activity of Sirt1 by regulating the cellular levels of nicotinamide adenine dinucleotide
(NAD+). In the downstream activation of AMPK, an increase of NAD+ levels induces Sirt1 activation,
which promotes deacetylation and activation of peroxisome proliferator-activated receptor gamma
coactivator 1-alpha (PGC-1α).
3. Resveratrol and Macrophages
Resveratrol exhibits an anti-inflammatory profile in macrophages [35]. Macrophages
differentiate from blood monocytes and participate in both innate and adaptive immunity. These
cells constitute a heterogeneous pool of cells with a wide range of biological activities depending on
their physical location and on external signals received from the tissue microenvironment [19]. Many
of these activities appear to be divergent in nature: pro- versus anti-inflammatory effects,
immunogenic versus tolerogenic activities, and tissue destruction versus tissue repair [42]. With a
wide range of pattern recognition receptors (PRRs), these immune cells can specifically identify
conserved pathogen-associated molecular patterns (PAMPs), which are exclusively present on
microbes such as viruses, bacteria, parasites, and fungi [43]. The main members of PRR families are
transmembrane TLRs, C-type lectin receptors (CLRs), cytoplasmic nucleotide oligomerization
domain (NOD)-like receptors (NLRs), and RNA helicase retinoic acid inducible gene I (RIG-I)-like
receptors (RLRs). Thus, the activated intracellular signaling induces the expression of genes involved
in inflammatory and/or immune response and the recruitment of phagocytic cells to the site of
infection. Because of their abilities to recognize pathogens and activate bactericidal activities,
macrophages are always operating at the site of immune defense [44]. They produce anti-
inflammatory cytokines, such as interleukin-10 (IL10) and transforming growth factor-beta (TGF β),
and inhibit the inflammatory pathways mediated by TLRs [45]. TLRs initiate signaling in innate and
adaptive immune pathways. This highly conserved family of transmembrane proteins comprises an
extracellular domain that recognizes exogenous and endogenous danger molecules and an
ectodomain that activates downstream pathways. Several lines of evidence suggest that continuous
activation or dysregulation of TLRs signaling may contribute to the occurrence of chronic
Figure 2.
Resveratrol pathways in immune function: resveratrol activates Sirtuin-1 (Sirt1) inhibiting
RelA acetylation and promotes inhibitor protein-
κ
B
α
(IkB
α
) degradation, which decreases nuclear
factor kappa B (NF-
κ
B)-induced expression of tumor necrosis-alpha (TNF-
α
), interrleukin (IL)-1
β
,
IL(-6), metalloproteases (MMPs), and cyclooxygenase Cox-2. Cyclic adenosine monophosphate (cAMP)
levels trigger protein kinase A (PKA), which activates Sirt1. AMP-activated protein kinase (AMPK)
controls the activity of Sirt1 by regulating the cellular levels of nicotinamide adenine dinucleotide
(NAD
+
). In the downstream activation of AMPK, an increase of NAD
+
levels induces Sirt1 activation,
which promotes deacetylation and activation of peroxisome proliferator-activated receptor gamma
coactivator 1-alpha (PGC-1α).
3. Resveratrol and Macrophages
Resveratrol exhibits an anti-inflammatory profile in macrophages [
35
]. Macrophages differentiate
from blood monocytes and participate in both innate and adaptive immunity. These cells constitute
a heterogeneous pool of cells with a wide range of biological activities depending on their physical
location and on external signals received from the tissue microenvironment [
19
]. Many of these
activities appear to be divergent in nature: pro- versus anti-inflammatory effects, immunogenic
versus tolerogenic activities, and tissue destruction versus tissue repair [
42
]. With a wide range
of pattern recognition receptors (PRRs), these immune cells can specifically identify conserved
pathogen-associated molecular patterns (PAMPs), which are exclusively present on microbes such as
viruses, bacteria, parasites, and fungi [
43
]. The main members of PRR families are transmembrane
TLRs, C-type lectin receptors (CLRs), cytoplasmic nucleotide oligomerization domain (NOD)-like
receptors (NLRs), and RNA helicase retinoic acid inducible gene I (RIG-I)-like receptors (RLRs). Thus,
the activated intracellular signaling induces the expression of genes involved in inflammatory and/or
immune response and the recruitment of phagocytic cells to the site of infection. Because of their
abilities to recognize pathogens and activate bactericidal activities, macrophages are always operating
at the site of immune defense [
44
]. They produce anti-inflammatory cytokines, such as interleukin-10
(IL10) and transforming growth factor-beta (TGF
β
), and inhibit the inflammatory pathways mediated
by TLRs [
45
]. TLRs initiate signaling in innate and adaptive immune pathways. This highly conserved
family of transmembrane proteins comprises an extracellular domain that recognizes exogenous and
endogenous danger molecules and an ectodomain that activates downstream pathways. Several lines

Nutrients 2019,11, 946 4 of 24
of evidence suggest that continuous activation or dysregulation of TLRs signaling may contribute
to the occurrence of chronic pathological conditions [
46
]. Resveratrol regulates the expression of
TLR4 [
47
]. Hence, resveratrol can be employed for TLR-mediated inflammatory responses and
chronic diseases linked to TLR activation including obesity, type 2 diabetes mellitus (T2DM), fatty
liver disease, Crohn’s disease, rheumatoid arthritis, cardiovascular and neurodegenerative disorders
(Figure 1) [
48
]. The molecular regulation of inflammatory response is substantially modulated by
transcription factors. It has been demonstrated that resveratrol decreases NF-
κ
B activation and
COX-2 expression in lipopolysaccharide (LPS)-induced RAW264.7 (Figure 3). Moreover, it inhibits
TANK-binding kinase1 (TBK1) and receptor-interacting protein 1 (RIP1) in a toll-interleukin-1 receptor
domain-containing adaptor inducing an interferon (TRIF) complex in myeloid differentiation factor 88
(MyD88)-independent signaling pathways (Figure 3) [
49
]. Additional studies showed that resveratrol
exerts anti-inflammatory effects by attenuating TLR4-TRAF6, mitogen-activated protein kinase (MAPK),
and AKT pathways in LPS-induced macrophages [
50
]. Another signaling pathway that has been
linked to inflammation is the endoplasmic reticulum (ER) response [
51
]. ER stress leads to the
activation of inositol-requiring enzyme 1 (IRE1), which splices X-box binding protein 1 (Xbp-1) into its
functional message, and ultimately leads to suppressed global translation and increased chaperone
activity. If the cells fail to reduce the ER load, they will undergo apoptosis [
52
]. It has been suggested
that the IRE1
α
-Xbp-1 pathway is critical for TLR-induced inflammatory cytokines production by
macrophages [
53
]. Xbp-1 is regulated by post-translational acetylation and deacetylation mediated
by the acetyltransferase p300 and deacetylase Sirt1, respectively [
54
]. More recently it was shown
that resveratrol prevents the increase of acetylated
α
-tubulin caused by mitochondrial damage in
macrophages stimulated with inducers of the nod-like receptor family, pyrin domain containing 3
(NLRP3) inflammasome (Figure 3). As result, since resveratrol influences the generation of an optimal
site for the assembly of NLRP3 and ASC and, in turn, inhibits NLRP3-inflammasome activation, it could
be an effective medication for the treatment of NLRP3-related inflammatory diseases [
55
]. Resveratrol
not only influences the transcription of NF-
κ
B elements but also the transcription of STAT1 and cyclic
adenosine monophosphate (cAMP)-responsive element binding protein 1 (CREB1) [
56
]. TNF-
α
-induced
activation of the NF-
κ
B elements is modulated by resveratrol. Interestingly, a study reported that LPS
dose-dependently increased extracellular malondialdehyde (MDA) and nitric oxide without affecting
their intracellular level, whereas resveratrol abolished all these deleterious effects. LPS-activation
of monocytes and macrophages induces the NF-
κ
B dependent transcription of chemokines such as
CXCL8/IL-8, CXCL10/IP-10, CCL2/MCP1, and CCL5/RANTES [
45
]. LPS increased CD14 expression,
interleukin-1 receptor-associated kinase (IRAK1), and a phosphorylated form of p38 MAPK protein.
Resveratrol prevented LPS effect by decreasing CD14 and IRAK1 (Figure 3) expression but, surprisingly,
increased the p38 MAPK protein phosphorylation [
57
]. Further investigation showed that resveratrol
decreased LPS-induced pro-oxidant effect in the AR42J cell line via a Myd88-dependent signaling
pathway. This data indicated that resveratrol exerted antioxidant properties by a Myd88-dependent way
not involving IRAK1 or by a TRIF dependent pathway [
57
] (Figure 3). Sirt1 has a direct regulatory role
in macrophages functions during inflammation. The production of pro-inflammatory cytokines TNF-
α
,
IL-6, and IL-1
β
by macrophages from the myeloid-specific Sirt1 knockout mice is dramatically increased
in response to infection and inflammation. In addition to pro-inflammatory cytokines, Sirt1 is involved
in the expression of cell surface molecules such as intercellular cell adhesion molecule1 (ICAM-1) to
facilitate macrophage trafficking during the inflammatory response (Figure 3) [
58
]. Hyperacetylation
of NF-
κ
B transcription factor RelA/p65 has been detected in macrophages from myeloid-specific Sirt1
knockout mice, indicating that the anti-inflammatory activity of Sirt1 in macrophages occurs, at least
partially, through NF-κB suppression [59].
Remarkably, resveratrol also stronglyreduces the production of granulocyte-macrophage
colony-stimulating factor (GM-CSF) [
60
] (Figure 3), a pro-inflammatory cytokine that acts at the
interface between innate and adaptive immunity essential for survival/differentiation/activation of
pro-inflammatory macrophages [
61
] and a key marker of atheroma formation [
62
]. Several evidences

Nutrients 2019,11, 946 5 of 24
indicate that resveratrol modifies cell morphology, gene expression, ligand-receptor interactions,
signaling pathways, and foam-cell formation [
63
–
65
]. Additionally, resveratrol modulates the immune
response by influencing cellular prostaglandin E2 (PGE
2
) levels (Figure 3). PGE
2
plays an important role
in the regulation of the immune response [
66
]. Resveratrol up-regulates COX-2 in various inflammatory
diseases [
66
,
67
]. The cell-specific effect on interleukin production is another important function of
resveratrol. In fact, resveratrol was found to enhance the expression of IL-1
β
and IL-6 in the peripheral
blood lymphocytes (PBLs), but it had opposite effects in macrophages [
60
]. The enhanced production
of IL-1
β
and IL-6 characterizes a pro-inflammatory status contributing to T helper lymphocytes
differentiation and function [
68
], but it is also involved in tissue regeneration [
69
]. The immune cells
exposed to resveratrol in the vascular compartment expressing significant levels of IL-1
β
or IL-6 are
triggered for the adaptive immune response. Nevertheless, resveratrol affects the immune cells only
for a limited time because of its short half-life in the blood [
70
]. These findings suggest that resveratrol
facilitates the systemic response to injuries [
10
,
45
] and restrains the low-grade inflammatory status
related to chronic diseases in tissues.
Nutrients 2019, 11, 946 5 of 25
immune response by influencing cellular prostaglandin E2 (PGE2) levels (Figure 3). PGE2 plays an
important role in the regulation of the immune response [66]. Resveratrol up-regulates COX-2 in
various inflammatory diseases [66,67]. The cell-specific effect on interleukin production is another
important function of resveratrol. In fact, resveratrol was found to enhance the expression of IL-1β
and IL-6 in the peripheral blood lymphocytes (PBLs), but it had opposite effects in macrophages [60].
The enhanced production of IL-1β and IL-6 characterizes a pro-inflammatory status contributing to
T helper lymphocytes differentiation and function [68], but it is also involved in tissue regeneration
[69]. The immune cells exposed to resveratrol in the vascular compartment expressing significant
levels of IL-1β or IL-6 are triggered for the adaptive immune response. Nevertheless, resveratrol
affects the immune cells only for a limited time because of its short half-life in the blood [70]. These
findings suggest that resveratrol facilitates the systemic response to injuries [10,45] and restrains the
low-grade inflammatory status related to chronic diseases in tissues.
Figure 3. Effects of resveratrol on immune cells: Breg, regulatory B cell; COX2, cyclooxygenase;
FOXP3, forkhead box P-3; GM-CSF, granulocyte–macrophage colony-stimulating factor; IL-10,
interleukin-10; IL-17, interleukin 17; IRAK, interleukin-1 receptor-associated kinase; LPS,
lipopolysaccharide; MΦ, macrophage; MCP1, monocyte chemoattractant protein-1; NF-κB, nuclear
factor-Kappa B; NLRP3, nod-like receptor family, pyrin domain containing 3; Nrf2, nuclear factor
erythroid 2-related factor 2; RIP, receptor-interacting protein; PCs, plasma cells; PGE2, prostaglandin
E2; Sirt1, silent mating type information regulation 2 homolog; STAT3, signal transducer and activator
of transcription; TAMs, tumor associated macrophages; TBK1, TANK-binding kinase1; TGF-β1,
transforming growth factor-β1; Treg, regulatory T cell; Th17, T helper 17; TRIF, toll-interleukin-1
receptor domain-containing adaptor inducing interferon; TLR-2, toll-like receptor-2; VEGF, vascular
endothelial growth factor.
Resveratrol and Tumor Associated Macrophages (TAMs)
Clinical and experimental evidence reports that high infiltration of macrophages in most human
cancers is associated with tumor malignancy, poor prognosis, and tumor relapse. Macrophages show
plasticity in their activation profile under different cytokines stimulation. They are capable of both
inhibiting and promoting the growth and spread of cancers, depending on their activation state.
Macrophages can be classically activated (M1), in the presence of IFN-γ and LPS, while in the
presence of IL-4 and IL-13, or indirectly through Th2 cells induction toward alternatively activated
macrophages (M2). Macrophage polarization deeply alters the immune properties of these cells [44].
Figure 3.
Effects of resveratrol on immune cells: Breg, regulatory B cell; COX2, cyclooxygenase; FOXP3,
forkhead box P-3; GM-CSF, granulocyte–macrophage colony-stimulating factor; IL-10, interleukin-10;
IL-17, interleukin 17; IRAK, interleukin-1 receptor-associated kinase; LPS, lipopolysaccharide; M
Φ
,
macrophage; MCP1, monocyte chemoattractant protein-1; NF-
κ
B, nuclear factor-Kappa B; NLRP3,
nod-like receptor family, pyrin domain containing 3; Nrf2, nuclear factor erythroid 2-related factor
2; RIP, receptor-interacting protein; PCs, plasma cells; PGE2, prostaglandin E2; Sirt1, silent mating
type information regulation 2 homolog; STAT3, signal transducer and activator of transcription; TAMs,
tumor associated macrophages; TBK1, TANK-binding kinase1; TGF-
β
1, transforming growth factor-
β
1;
Treg, regulatory T cell; Th17, T helper 17; TRIF, toll-interleukin-1 receptor domain-containing adaptor
inducing interferon; TLR-2, toll-like receptor-2; VEGF, vascular endothelial growth factor.
Resveratrol and Tumor Associated Macrophages (TAMs)
Clinical and experimental evidence reports that high infiltration of macrophages in most human
cancers is associated with tumor malignancy, poor prognosis, and tumor relapse. Macrophages show
plasticity in their activation profile under different cytokines stimulation. They are capable of both
inhibiting and promoting the growth and spread of cancers, depending on their activation state.
Macrophages can be classically activated (M1), in the presence of IFN-
γ
and LPS, while in the presence

Nutrients 2019,11, 946 6 of 24
of IL-4 and IL-13, or indirectly through Th2 cells induction toward alternatively activated macrophages
(M2). Macrophage polarization deeply alters the immune properties of these cells [
44
]. The M1 polarized
macrophages manifest high levels of proinflammatory cytokines and promote Th1 responses, which
contributes to tumoricidal activity and antitumor immunity [
42
]. The polarization of M1 macrophages
is mainly regulated by distinct transcriptional networks consisting of an interferon regulatory factor
(IRF-1/5), STAT-1/4, and NK-
κ
B [
71
,
72
]. Alternatively, M2-like polarization of macrophages, which
produce secretory factors to promote tissue remodeling, immune tolerance, and angiogenesis may be
linked with tumor progression. M2 polarization is induced by Th2 cytokines, like IL-13 and IL-4 [
72
],
and is regulated by transcription factors such as IRF-4, STAT-3/6, PPAR-
γ
, and Krüppel-like factor
4 (KLF-4) [
73
–
75
]. An accumulating line of evidence indicates that macrophages ruling to execute
tumor-promoting or tumor-suppressing activities depend on their sub-phenotype, which is dynamically
switched [
76
,
77
]. TAMs in malignant tumors resemble alternatively activated macrophages (M2-like).
They enhance tumor-associated angiogenesis, promote tumor migration and invasion, and lack in
anti-tumor immune responses [
78
]. A high density of TAMs, particularly the M2 subset, matches to
worse overall survival (OS) in patients with lung cancer, gastric cancer, or breast cancer [
79
–
81
]. TAMs
infiltrated in primary tumors or metastatic sites have a critical role in directing tumor cells from the
primary site to distant tissues in different murine models [
82
,
83
]. TAMs in the peripheral blood may
mediate circulating tumor cells migration and aid their achieving into distant metastatic sites [
84
].
In an experimental
in vitro
model investigating macrophage morphology and functions in relation to
the tumor microenvironment, it was observed that treatment with a synthetic resveratrol analogue
HS-1793 significantly increased IFN-
γ
, which reprogrammed the M2 phenotype (Table 1). Therefore,
it was proved that HS-1793 powerfully counteracted the immunosuppressive and tumor progressive
influences of TAMs [85]. STATs are cytoplasmic transcription factors that act as intracellular effectors
of cytokine and growth factor signaling pathways. STAT3, a member of STAT family, plays a key
role in promoting proliferation, differentiation, anti-apoptosis, or cell cycle progression. Constitutive
activation of STAT3 is involved in a variety of tumor cells [
86
]. As mentioned before, activation of
STAT3 in the M2 subset leads to tumor-induced immunosuppression and constitutively activates STAT3
inhibiting the expression of mediators required for immune activation against tumor cells. In several
murine models of carcinogenesis, tumor progression is frequently associated with a phenotypic switch
from M1 to M2 in TAMs [
76
]. The inhibition of STATs signaling pathways can suppress tumor growth
and metastasis by inhibiting M2-like polarization of macrophages, further suggesting that TAMs
are a possible target in cancer therapy [
87
]. To date, many studies have been carried out about the
roles of STAT3 in cancer and therapeutic applications. In lung cancer cells resveratrol treatment
decreases the activity of STAT3 and inhibits lung cancer progression by suppressing the pro-tumor
activation of TAMs [
88
] (Figure 3). In addition, in a mouse lung cancer xenograft model, resveratrol
significantly inhibits the tumor growth, decreasing cell proliferation and expression of p-STAT3 in
tumor tissues [
88
]. Other studies demonstrated that both antitumor and antimetastatic effects of
resveratrol were partly due to anti-lymphangiogenesis through the regulation of M2 macrophage
activation and differentiation [
89
]. In fact, resveratrol inhibited the production of IL-10 of monocyte
chemoattractant protein-1 (MCP-1) in M2 macrophages, whereas it promoted TGF
β
1 production.
Nevertheless, resveratrol inhibited the phosphorylation of STAT3 without affecting its expression in the
differentiation process of M2 macrophages. Furthermore, a resveratrol-treated condition medium of
M2 macrophages inhibited vascular endothelial growth factor C (VEGFC)-induced human lymphatic
endothelial cells (HLECs) migration, invasion, and lymphangiogenesis (Figure 3).
In vivo
resveratrol
inhibited tumor growth and metastasis to the lung, and reduced the area of lymphatic endothelial cells
in tumors [89].
4. Resveratrol and T Lymphocytes
The improvement of effective adaptive immunity is much more persistent and reliant on the
responses of T and B lymphocytes cooperating with antigen presenting cells (APC) in peripheral

Nutrients 2019,11, 946 7 of 24
lymphoid tissue over the course of days and weeks. However, once the adaptive immune responses
occur, Th1 and Th17, subsets of effector T helper cells, migrate from lymphoid tissue into circulation,
infiltrate infected sites, and produce their own cytokines enriching macrophages and neutrophils
activity, respectively. Both innate and adaptive immunity possess the ability to control inflammation and
develop self and non-self-discrimination. During development, immature T cell populations acquire the
ability to express antigen-specific receptors that distinguish self or non-self-macromolecules [
90
]. In the
thymus, developing T lymphocytes with T cell receptors (TCRs) are capable of high affinity recognition
of self-peptides in the context of self, and major histocompatibility complex (MHC) proteins undergo
apoptosis in a negative selection [
91
]. As a safeguard against self-reactive T cells entry into periphery
lymphoid tissue, regulatory T cells (Tregs) are produced naturally (nTregs) during central development
of T cells in the thymus [92] and are induced peripherally (iTregs) during the progression of immune
responses [
93
]. Failures of tolerance within the adaptive immune system are uncommon. But, when
central and/or induced peripheral tolerance fail, autoimmune diseases can arise. Abnormal T cell
activation is involved in many autoimmune diseases, such as insulin-dependent diabetes, rheumatoid
arthritis, systemic lupus erythematosus, and multiple sclerosis [
94
]. Given that resveratrol can inhibit
T cell activation and reduce cytokine production, it is conceivable that it can prevent autoimmune
disease progression. It has been reported that resveratrol-treated mice displayed significantly reduced
disease incidence and footpad thickness. Histological analysis demonstrated that infiltrated cells in
the joint were clearly reduced in the resveratrol-treated mice compared with the control mice. This
observation indicated that resveratrol can prevent the development of collagen-induced arthritis [
33
].
The Th17 cells are CD4+T subsets, their development depends on signals mediated by IL-6, TGF-
β
,
IL-21, and IL-23, and by induction of the lineage-specifying transcription factor, retinoic acid-related
orphan nuclear receptor (ROR
γ
T). Unlike Th1 and Th2 cells, which after differentiation are secretory
cells, Th17 cells maintain their stem cell–like properties, which allows them to persist for a long
time while retaining the aptitude to produce functionally divergent progeny when reactivated by
antigen [
95
]. The Th17 cells are key initiators of proinflammatory responses, by recruiting neutrophils
and macrophages to injured tissues, and via their production of IL-17 play an important role in host
defense against infection to extracellular pathogens. An additional cytokine produced by Th17 is IL23,
which controls survival and maintenance of the Th17 phenotype and is responsible for the crosstalk
between innate and adaptive immunity [
96
]. Moreover, Th17 cells produce IL-22 which, similar to IL-17,
is beneficial to the host in many infectious and inflammatory disorders. Nevertheless, synergistically
with IL-17, it can play an important role in disease due to its proinflammatory properties [
97
]. Th17
cells are powerful inducers of chronic inflammatory responses. Th17 cells play very important roles in
autoimmune disease [
96
]. Resveratrol could modulate murine collagen-induced arthritis by inhibiting
Th17 and B-cells function [
33
]. The arthritis-protective effects of resveratrol are also associated with the
reduced numbers of Th17 cells and the production of IL-17 in the draining lymph node (Figure 3) [
33
].
Resveratrol protection against experimental autoimmune encephalomyelitis (EAE) is not associated
with declines in IL-17
+
T cells but is associated with rises in IL-17
+
/IL-10
+
T cells and CD4-IFN-
γ+
and with repressed macrophage IL-6 and IL-12/23 p40 expression [
98
]. Interestingly, the function
of resveratrol on Treg cells seems to benefit from T cell activation. CD4
+
CD25
+
Foxp3
+
cells were
found significantly reduced in the total splenocytes as in tumor tissues from HS-1793-administered
mice, and the production of TGF-
β
inducing Treg showed a similar pattern [
99
]. The administration
of resveratrol suppresses the CD4
+
CD25
+
cell population among CD4
+
cells, down-regulates the
secretion of TGF-
β
, and enhances IFN
γ
expression in CD8+T cells both ex vivo and
in vivo
, leading
to immune stimulation [
16
]. Other findings established that resveratrol decreases the expressions
of CD28 and CD80 and increases the production of IL-10, but does not influence the percentage of
CD4
+
CD25
+
Treg cells [
11
] (Figure 3). Therefore, the studies reporting the effects of resveratrol on
T cells and its specific molecular mechanisms are in some cases controversial. Sirt1 is involved in
periphery T cell tolerance [
23
], ablation of Sirt1 in T cells could induce hyper-activation of T cells and
lead to spontaneous autoimmune disease (Figure 3) [
30
]. It has been reported that resveratrol inhibits

Nutrients 2019,11, 946 8 of 24
T cell activation and production of antigen-specific antibody
in vivo
. The inhibition of T cell activation
by resveratrol is mediated by Sirt1 as demonstrated by the observation that the inhibitory effect of
resveratrol on T cell activation disappeared in Sirt1 knockdown T cells. Moreover, Sirt1 expression
was up-regulated in activated T cells and was higher in resveratrol-treated T cells than in naïve T
cells. Other data demonstrated that resveratrol maintains T-cell tolerance in mice by regulating the
function of Sirt1 which inhibits activation of self-reactive T cells that escape negative selection in the
thymus [
100
]. The mechanism by which resveratrol modulates T cell activation has been, in part
clarified. Resveratrol increased Sirt1 acetylase activity on c-Jun, but not on the nuclear factor of
activated T cells (NFAT) and NF
κ
b in T cells [
101
]. However, resveratrol cannot decrease the acetylation
of c-Jun in Sirt1
-/-
T cells, strongly suggesting that acetylation change of c-Jun is totally dependent
on Sirt1. Once T cells are activated, c-Jun translocate into the nucleus. Nevertheless, the action of
c-Jun is suppressed in resveratrol-treated T cells (Figure 3). Thus, resveratrol can clearly inhibit T cell
activation by increasing the expression of Sirt1 and the deacetylase activity of Sirt1 on c-Jun, which in
turn blocks the translocation of c-Jun into the nucleus [
102
]. Additionally, resveratrol represses the
protein kinase Cθin peripheral blood T lymphocytes in a rat liver transplantation model [103].
Obesity has deleterious effects on cell-mediated immunity and increases the risk of infectious
diseases. In facts, obesity dysregulates T-cell generation and function impairing the ability to
promote a peripheral T-cell-mediated protective immune response and damages wound healing
and infection [
104
,
105
]. Several studies in murine models have elucidated how resveratrol can
reverse the deleterious effects of T-cell function in diet-induced obesity. Interestingly, resveratrol as a
supplement for a high-fat diet (HFD) relieves oxidative stress, inhibits inflammatory genes expression,
and increases Tregs number via aryl hydrocarbon receptor activation in HFD-induced obese mice [
106
].
Furthermore, resveratrol decreases the fasting blood glucose and fasting plasma insulin and increased
the CD3
+
CD4
+
/CD
3
+CD8
+
subsets percentages in the obese model of C57BL/6 mice [
106
] (Figure 1).
Interestingly, the reduction in CD3
+
CD4
+
/CD
3
+CD8
+
ratio is usually associated with malignancies
or the attack of the virus such as HIV infection [
107
] (Figure 1). This reduction also existed in the
mouse model of systemic lupus erythematosus [
108
], suggesting that resveratrol may act in these
diseases inducing CD3
+
CD4
+
/CD
3
+CD8
+
. Moreover, resveratrol activates the nuclear factor erythroid
2-related factor 2 (Nrf2) signaling pathway-mediated antioxidant enzyme expression and alleviates
the inflammation by protecting against oxidative damage and T-lymphocyte subset-related chronic
inflammatory response in the development of HFD-induced obesity [
106
] (Figure 1). The data suggested
that resveratrol supplement-maintained glucose homeostasis by activating the phosphatidylinositol
3’-kinase (PI3K) and SIRT1 signaling pathways. Overall, these evidence indicate that resveratrol can be
used in clinic for treating inflammation induced by T cell activation and other T cell-related diseases.
Resveratrol acts on T cells activation in a bidirectional way: for autoimmune disease model it exerts an
inhibitory function, whereas for tumor model resveratrol reduces the suppressive function of Tregs
inhibiting the tumor growth.
5. Resveratrol and Natural Killer Cells
NK cells comprise about 15% of all circulating lymphocytes [
109
] and are able to lyse cancer
cells
in vitro
without prior immune sensitization [
110
]. Their main importance resides in early host
defense against both allogenic and autologous cells after virus infection [
111
], infection with bacteria
or parasites, or against tumor cells [
112
]. NK cells express various PRRs like TLRs, NLRs, and RLRs.
They respond to PAMPs in a suitable milieu in the presence of cytokines like IL-2, IL-12, IL-15, or
IL-18. Consequently, activated NK cells release IFN-
γ
, GM-CSF, TNF-
α
or cytotoxic granules directed
toward a target cell. NKs kill target cells through different mechanisms. Firstly, NK cells form immune
synapses. Afterward, they release cytoplasmic granules, organelles containing perforin (Prf1), the
saposin-like family member granulysin, and serin-proteases such as granzyme B (GzmB) to cleave
several pro-caspases, which trigger apoptosis in the target cell [
113
]. As well, the expression of
members of the tumor necrosis factor (TNF)-family such as FAS ligand (FASL), TNF, and TNF-related

Nutrients 2019,11, 946 9 of 24
apoptosis inducing ligand (TRAIL) induce tumor-cell apoptosis upon formation of immune synapses.
Another mechanism of action to kill target cells is the secretion of a number of effector cytokines such
as IFN-
γ
, IL-5, IL-10, IL-13, and GM-CSF after achievement of distinct stages of NK-cell differentiation.
NK cells secrete also a variety of chemokines including chemokine C-C motif ligand (CCL) such as
CCL2, CCL3, CCL4, CCL5, monocyte-chemoattractant protein (MCP-1), macrophage inflammatory
protein (MIP-1
α
), and (MIP-1
β
), RANTES, chemokine X-C motif ligand 1 (XCL1, lymphotactin), and
IL-8. NKs interacting with other immune cells like dendritic cells in areas of inflammation modulate
the innate and adapatative immune response and promote T-cell response against tumors [
114
].
Their killing capacity against malignant cells depends on stimulation of two main structural classes
of NK cell surface receptors such as receptors of the C-type lectin-like family and the killer cell
immunoglobulin-like receptors (KIRs), which inhibit and/or activate signaling cascades. Certain
human activating receptors like different KIRs or natural cytotoxicity receptors (NCRs) such as
NKp30, NKp44, NKp46, and NKp80 activate signal via protein tyrosine kinase-dependent pathways.
To antagonize NK cell activation, inhibitory surface receptors like different KIRs in humans are present,
which act through protein tyrosine phosphatase-dependent pathways [
115
]. Resveratrol exerts a direct
influence on the ability of killing of NK cells and simultaneously affects other immune cells like CD8
+
-
and CD4
+
-T-cells [
116
]. Resveratrol possesses therapeutic potential in boosting NKs activity against
aggressive cell leukemia and lymphomas by inhibiting constitutively active signal transducers and
activators of transcription 3 (STAT3) signaling [
117
]. NK cell killing capacity has been detected in
human immortalized myelogenous leukemia K562 cells. NK cell cytotoxic activity was enhanced at
low resveratrol concentration whereas at high concentration it was suppressed (Table 1) [116].
Other findings demonstrated inhibition of viability and increased apoptosis of NK cells upon
incubation with high resveratrol concentrations, whereas low concentrations induced an upregulation
of NKG2D and IFN-
γ
and increased NK cell killing towards leukemia K562 target cells [
118
] (Figure 3).
These data suggest a concentration-dependent biphasic effect of resveratrol, which is caused by
stimulating cell apoptosis via caspase signaling pathways in high concentration ranges. As supported
by a significantly reduced rate apoptotic/necrotic cells after pre-treatment with the caspase inhibitor
z-VAD-FMK. In addition, this study showed a higher cytotoxic susceptibility of Jurkat cells, a human
lymphoblastoid T cells line, towards resveratrol. A similar dose-dependent enhancement of cytotoxic
NK cell killing activity was also observed against tumor cell lines derived from solid tumors, such as
HepG2 and A549 cells after pre-stimulation of immortalized NK cells (NK-92 cells) with resveratrol at
low concentrations [
13
] (Table 1). Further, has been reported that in NK-92 resveratrol-treatment induces
phosphorylation of ERK-1/2 and JNK and a dose-dependent upregulation of perforin expression [
119
].
An increase NK cell killing activity with a consequent anticancer effect was observed in a study
evaluating the anti-infectious properties of resveratrol in a murine acute pneumonia model [
120
].
The resveratrol-treated group showed an increased alveolar macrophage infiltration, an elevated
NK cell activity, a decreased bacterial burden in the lungs and a decreased mortality. Remarkably,
isolated spleen NK cells of rats pre-treated with resveratrol displayed an enhanced killing efficacy
against YAC-1 target cells. As well, resveratrol treatment makes promyeloblastic leukemia KG-1a cells
susceptible to cytokine-induced killer-mediated cytolysis via an increase in cell-surface expression of
natural group 2, member D (NKG2D) ligands and receptor DR4, combined with a downregulation of
cell-surface expression of DcR1 in KG-1a cells, and an activation of the TNF-related apoptosis-inducing
ligand (TRAIL) pathway [
121
] (Figure 2). Resveratrol upregulates the agonistic receptors DR4 and
DR5 in androgen-insensitive human prostate carcinoma cells PC-3 and DU-145 [
122
], enhancing
TRAIL sensitivity and possibly facilitating NK cell-mediated killing. Similar results were obtained
in human prostate adenocarcinoma LNCaP cells and on PC-3 prostate cancer cells TRAIL-resistant
that after treatment with resveratrol showed an enhancement of DR4 and DR5 surface expression.
A dose-dependent activation of caspase-3 for resveratrol treatment alone, and caspase-8 activation for
combined treatment with resveratrol and TRAIL was observed as well. Human 1205 LU metastatic
melanoma cells show a resveratrol-dependent enhanced sensitivity to TRAIL through downregulation

Nutrients 2019,11, 946 10 of 24
of the antiapoptotic proteins cellular FLICE-like inhibitory protein (cFLIP) and Bcl-xL [
123
]. Moreover,
resveratrol sensitizes to TRAIL-induced apoptotic cell death various other cancer cells types such as
pancreatic, breast, colon cancers, T-cell leukemia, melanoma neuroblastoma, medulloblastoma, and
glioblastoma [
124
]. Resveratrol is able to increase CD95L expression on HL60 human leukemia cells
and on T47D breast carcinoma cells [
125
] (Figure 3) facilitating NK cells to trigger signaling-dependent
apoptosis. Because of tumor cell-platelet aggregation, circulating tumor cells coated by aggregated
platelets could escape the immune response aiding the occurrence of metastasis. Cancer cells can activate
platelets and their aggregation, which correlates with their metastatic potential [
126
]. A connection
of platelet aggregation and the susceptibility of cancer cells to NK cell-mediated lysis has been
reported [
127
]. Remarkably, resveratrol inhibits platelet aggregation via reduction of integrin gpIIb/IIIa
on the platelet membrane, which acts as a fibrinogen receptor involved in clot formation that generates
bridges between platelets. Resveratrol reduces the production of TxA2, which activates platelets and
so exacerbates aggregation, through inhibition of COX1-dependent pathways [128].
6. Resveratrol and B Lymphocytes
B cells are characterized by their capacity to produce antibodies. As well, they release cytokines
and act as secondary APCs. B cells possess distinct subpopulations that accomplish both regulatory
and pathogenic functions. Regulatory B cells (Bregs) are a rare B cell subpopulation (less than
10% of total B-cells in circulation) with regulatory/suppressor functions and are important for the
peripheral tolerance mechanisms [
129
]. Their regulatory activity is generally, but not exclusively
performed through IL-10 production. Less than 20% of these cells from the different subsets are
IL-10 producers after stimulation [
130
]. Inflammation induces potently Bregs development and
differentiation. A combination of different molecules including TLRs, CD40, the B cell receptor, CD80,
CD86, and cytokines are required to activate Bregs [
129
]. Three different types for Breg cells have
been characterized on the basis of activation pathways: innate Breg cells requiring signaling via innate
receptors, such as TLRs; immature Breg cells requiring CD40 stimulation; antigen-specific Breg cells
requiring both B-cell receptor and CD40 signaling. Bregs prevent inflammation by inhibition of Th1
cells activation, maintenance of the Treg cell population and Th17 proliferation and differentiation [
131
].
Although IL-10 is a key player in Breg inhibition of inflammation, new investigations have shown that
some Breg subsets perform their suppressive function through additional factors. It has been reported
that cancer metastasis needs the involvement of regulatory immune cells, such as FoxP3
+
CD4
+
Tregs
and TGF
β
-expressing tBregs [
132
]. Tregs and tBregs need to be controlled to efficaciously prevent lung
metastasis. Low doses and non-cytotoxic doses of resveratrol prevents progression of B16 melanoma
and of 4T1.2 breast cancer cells and abrogates lung metastasis by inactivating tBregs, thereby disabling
tBregs ability to convert FoxP3
+
Tregs, a process that requires TGF
β
expression (Figure 2) [
133
].
Moreover, resveratrol at a low and non-cytotoxic dose inhibits the generation and function of tBregs by
inactivating Stat3 (Table 1). This inactivation of Stat3 in tBregs probably causes the inhibition of TGF
β
expression, a downstream target of Stat3 [133] (Figure 3).
This study suggested that low doses of resveratrol can be used to induce antitumor effector and to
combat cancer escape mediated by tBregs. [
133
]. Recently it has been demonstrated that resveratrol
treatment can ameliorate lupus nephritis in MRL/lpr mice by upregulating Fc
γ
RIIB, leading to a
selective reduction of B cells in the spleen and bone marrow [
134
]. Moreover, plasma cells, expressing
the highest levels of Fc
γ
RIIB were significantly reduced in both spleen and bone marrow in response
to resveratrol (Figure 3). Depletion of autoreactive plasma cells caused a decrement of autoantibody
production, thereby leading to decreased immune complexes deposition in the kidney [
135
]. This result
is of clinical importance because neither anti-proliferative agents, for example, cyclophosphamide, nor
anti-CD20 mAbs, such as rituximab, can efficiently eliminate plasma cells from the bone marrow of
systemic lupus erythematosus (SLE) patients [
134
] (Figure 3). Moreover, it was shown that Sirt1 induced
by resveratrol inhibits B cells proliferation and autoantibody production (Figure 3) ameliorating SLE in
a mouse model with constitutive and continued activation of Th1 cells [136].

Nutrients 2019,11, 946 11 of 24
Lupus nephritis is characterized by glomerular and tubulointerstitial inflammation and mesangial
cell proliferation, followed by progressive glomerulosclerosis and interstitial fibrosis between tubules.
Resveratrol significantly reduced fibrosis in both glomeruli and tubulointerstitial space, and significantly
restored glomerular morphology [
136
]. In addition, the degree of immunocomplexes deposition in
the glomerulus was markedly reduced. The inhibitory effects of enhanced Fc
γ
RIIB expression on
B cells
in vivo
may allow Fc
γ
RIIB to execute a self-regulatory feedback loop to control the number
of plasma cells via immunocomplex-dependent apoptosis. This effect is of clinical relevance in that
reduced surface Fc
γ
RIIB expression on memory B cells and PCs is often observed in SLE patients,
leading to a limited capacity to restrain B cells from activation and to induce apoptosis of PCs
(Figure 3) [
137
]. Therefore, the pharmacological upregulation of Fc
γ
RIIB expression by resveratrol
can produce a significant decrease of PCs and autoantibody production. This data indicated that the
depletion of autoreactive PCs in the bone marrow after resveratrol treatment is mainly mediated by
the Fc
γ
RIIB-dependent apoptotic pathway rather than inhibition of B cell receptor (BC)R-dependent
activation [
136
]. Other studies have corroborated the idea that elimination of PCs, mainly long-lived
PCs in the bone marrow, is crucial in the treatment for SLE patients [
137
] (Figure 1). Clinically, the
upregulation of Fc
γ
RIIB in B cells could be of particular benefit for improving the outcome of SLE
patients who manifest downregulation of surface Fc
γ
RIIB on their memory B cells and PCs [
134
].
In addition, it was demonstrated that NF-
κ
B is a critical regulator of resveratrol in the upregulation
of Fc
γ
RIIB expression [
134
]. Because neither T cells nor NK cells express Fc
γ
RIIB, the selective
modulation on humoral immunity via Fc
γ
RIIB, emphasize an exclusive therapeutic strategy for SLE,
without affecting other immune functions and avoiding the side effects of systemic immunosuppression
induced by current treatments [137].

Nutrients 2019,11, 946 12 of 24
Table 1. Activity and effects of resveratrol in immune cells and in mice models.
Study Type Subjects Dose Effect Ref.
In vitro Splenic lymphocytes, CTLs and
LAKs 25–50 µM
Suppresses mitogen-, IL-2-, and alloantigen-induced proliferation of splenic
lymphocytes; development of antigen-specific CTLs; LAK cells were
less sensitive.
[10]
In vitro T lymphocytes and
Macrophages 1–20 µM
Suppresses: T cells proliferation and secretion of IFN-γand IL-4; B cells
proliferation and production of IgG1 and IgG2a isotypes; IL-1, IL-6, TNF-α.
Enhances: IL-10; down-regulates the expression of CD28 on CD4
+
T cells and
of CD80 on macrophages.
[13]
In vitro NK92 cell line 1.5 µMEnhances perforin expression and cytotoxic activity acting via
NKG2D-dependent JNK and ERK-1/2 pathways. [12]
Ex vivo
In vivo
Splenocytes
C57BL/6 and BALB/c mice
25–75 µM
4 mg/kg, i.p.
Suppresses the CD4+CD25+subsets; downregulated secretion of TGF-β.
Enhances IFN-γexpression in CD8+T cells. [15]
In vitro RAW 264.7 cell line and BV-2
cell line 50 µM
Suppresses IL-6, M-CSF, MCP-1, MCP-5, CD54, IL-1ra, IL-27, and TNF-αin
both cell lines.
Inhibits the TLR4/NF-κB/STAT signaling cascade
[20]
In vivo NOD mice were given 250 mg/kg
Decreases in expression of CCR-6. Inhibits CD11b+F4/80hi macrophages.
It reduces CCR6+IL-17-producing cells and CD11b+F4/80hi in the pancreas.
It reduces migration of splenocytes toward media containing CCL20. Prevents
type 1 diabetes in NOD mice.
[32]
In vitro
U-937
Jurkat
HeLa and H4 cells lines
0.5–25 µM
Suppresses TNF-induced phosphorylation and nuclear translocation of the p65
subunit of NFκB, and NFκB-dependent reporter gene transcription. It
suppresses TNF-induced NFκB activation. Blocks NFκB activation induced
by PMA, LPS, H2O2, and okadaic acid. Suppresses AP-1. Inhibits the
TNF-induced activation of MEK and JNK. Abrogates TNF-induced cytotoxicity
and caspase activation. Suppresses ROI generation and lipid peroxidation.
[37]
In vitro Bone-derived cell cultures and
MC3T3-E1 cell lines 5µM
Inhibits RANKL-induced acetylation and nuclear translocation of NFκB.
Induces Sirt1-p300 association in bone-derived and preosteoblastic cells,
leading to deacetylation of RANKL-induced NFκB, inhibition of NFκB
transcriptional activation, and osteoclastogenesis. It activates the bone
transcription factors Cbfa-1 and Sirt1 and induces the formation of Sirt1-Cbfa-1
complexes. It regulates the balance between the osteoclastic versus osteoblastic
activity. It could exert a therapeutic potential for treating osteoporosis and
rheumatoid arthritis-related bone loss.
[38]

Nutrients 2019,11, 946 13 of 24
Table 1. Cont.
Study Type Subjects Dose Effect Ref.
In vitro MH7A cell lines 100 µM
Induces MH7A cell apoptosis by activating caspase-9 and the effector
caspase-3, reduces Bcl-XL expression, allowing cytochrome c release from the
mitochondria into the cytosol, in a sirtuin 1-dependent manner. It could
suppress hyperplasia of synovial cells, a critical factor of rheumatoid arthritis.
[40]
In vitro RAW264.7 and HEK 293T cell
lines 30, 50, 75, 100 µM
Inhibits TRIF signaling in the TLR3 and TLR4 pathway by targeting
TANK-binding kinase 1 and RIP1 in TRIF complex. Modulates TLR-derived
signaling and inflammatory target gene expression. It could alter susceptibility
to microbial infection and chronic inflammatory diseases.
[46]
In vitro RAW 264.7 cell line 50 µM
Suppresses LPS-induced TRAF6 expression and ubiquitination, attenuates the
LPS-induced TLR4–TRAF6, MAPK, and AKT pathways. It could exert
anti-inflammatory effects.
[47]
In vitro Mouse bone-marrow cells
J774 cell line 5µM
Inhibits the accumulation of acetylated α-tubulin and suppressing
NLRP3-inflammasome assembly. It prevents the NLRP3-related
inflammatory diseases.
[53]
In vitro AR42J cell line 10–100 µM
It decreases CD14 and IRAK1 expression and increases the p38 MAPK protein
phosphorylation. It exerts antioxidant properties either by a
Myd88-dependent way not involving IRAK1 or by a TRIF dependent pathway.
[55]
In vitro
RAW 264.7
THP-1
HUVEC cell lines and PBLs
6.25–12.5–25–50 µM
3.13–6.25–12.5–25 µM
10–20–30 µM
6.25–12.5–25 µM
Modulates many mediators of the inflammatory response. Its effects are
context-dependent, influencing chemokines and cytokines in opposite ways in
different cells.
[58]
In vitro Macrophages 2.5 µM
Suppresses LPS-induced phosphorylation of FoxO3a. Blocks the LPS-induced
PI3K-AKT pathway and affects FoxO3a phosphorylation. Inhibits Nox1 and
MCP-1 expression. Could modulate the activations of important macrophage
functions associated with atherosclerosis.
[61]
In vitro TPH1 cell line 25 µM
Promotes apoA-1 and HDL-mediated efflux, downregulates oxLDL uptake,
and diminishes foam cell formation. Regulates expression of the cholesterol
metabolizing enzyme CYP27A1, and helps cholesterol elimination.
[62]
In vitro TPH1 cell line 2.5 µM
Inhibits foam cells formation by regulating the expression of the inflammatory
cytokine, MCP-1, and by activating the AMPK-Sirt1-PPAR signaling pathway.
[63]

Nutrients 2019,11, 946 14 of 24
Table 1. Cont.
Study Type Subjects Dose Effect Ref.
In vitro
Granulocytes
Monocytes
RAW 264.7 cell line
5–100 µM
Inhibits oxidative burst and CD11b expression in granulocytes and monocytes.
Inhibits the production of NO and PGE2, but did not reduce iNOS, TNFα, or
IL-1βgene expression in LPS-stimulated RAW 264.7.
Induces NRf2 nuclear translocation and reduced miR-146a expression in LPS
treated RAW 264.7.
[64]
In vitro Human rheumatoid arthritis
synovial fibroblasts 20 µM
Suppresses the bradykinin-induced COX-2/PGE2. Inhibits the
phosphorylation and acetylation of p65, c-Jun, and Fos and reduces the
binding to the COX-2 promoter, thereby attenuated the COX-2 expression.
Could be used for inflammatory arthritis therapy.
[65]
In vivo
In vitro
C3H/He mice
Splenocytes
1.5 mg/Kg
1.25–2.5–5 µM
Reprograms M-2 phenotype (TAM) countering the immunosuppressive and
tumor progressive influences of TAM. [83]
In vitro M2 polarization of human
monocyte derived macrophages
20 µMDecreases STAT3. It inhibits F4/80 positive expressing cells and M2
polarization in the tumors. [86]
In vivo C3H/He mice 0.5, 1 and 1.5 mg/kg
Reduces Tregs (CD4 +CD25 +Foxp3 +cells) and the production of TGF-β.
Increases IFN-
γ
-expressing CD8
+
T cells. Upregulates IFN-
γ
production and
enhances the cytotoxicity of splenocytes against FM3A tumor cells.
[97]
In vitro
In vivo
T cell
C57/BL6 and DBA1 mice
0.5 µM or 25 µM
25 mg/kg
Upregulates Sirt1 expression. Decreases c-Jun acetylation and its translocation.
Reduces the incidence and severity of collagen-induced arthritis in mice. [100]
In vivo Wistar rats 100 mg kg-1 ml Downregulates PKC9 level in T lymphocytes [101]
In vivo C57BL/6 mice HFD supplemented
with 0.06% resveratrol
Activates the PI3K and Sirt1 signaling transduction. Activates the
Nrf2-regulated adaptive response.
Increases the CD3+CD4+/CD3+CD8+subsets percentages and the Tregs.
Maintains glucose homeostasis alleviating inflammation.
[104]
In vitro PBMCs 0.625–2.5–5–10 µM
Modulates the functional activities of both T and NK effector cells, with
stimulation at low concentrations and suppression at high concentrations.
Affects cytokine-production by activated CD41 and CD81 T cells.
[114]
In vitro KHYG-1, NKL, NK-92, and
NK-YS cell lines
3.125–6.25–12.5–
25–50 µM
Suppresses STAT3 and inhibits JAK2 phosphorylation. Induces
downregulation of the anti-apoptotic proteins MCL1 and survivin. Induces
apoptotic and antiproliferative activities of L-asparaginase against KHYG-1,
NKL and NK-92 cells.
[115]

Nutrients 2019,11, 946 15 of 24
Table 1. Cont.
Study Type Subjects Dose Effect Ref.
In vitro Human NKs
Jurkat cell line 0.5−50 µM
At high concentration promotes apoptosis of NK cells and of Jurkat cells.
At low concentration increases the NK cells cytotoxicity via up-regulating the
expression of NKG2D and IFN-γ.
[116]
In vitro KG-1a cells
PBMCs 25–100 µM
Inhibits KG-1a cell growth but has the least growth-inhibition effect PBMCs.
Makes KG-1a cells susceptible to CIKs-mediated cytolysis correlated with an
increase in cell-surface expression of NKG2D ligands and DR4, coupled with a
downregulation of cell-surface expression of DcR1.
[13]
In vitro DU145, and PC3 cells 5–30 µM
Induces apoptosis in prostate cancer cells. Downregulates Bcl-2, Bcl-XL, and
surviving. Upregulates Bax, Bak, PUMA, Noxa, and Bim, TRAIL-R1/DR4 and
TRAIL-R2/DR5 expression.
Activates caspase-3 and caspase-9 and induces apoptosis.
[119]
In vitro cell lines LU120 cell line 25–100 µM
Decreases STAT3 and NF-κB activation. Suppresses expression of cFLIP and
Bcl-xL proteins and increases sensitivity to exogenous TRAIL in
DR5-positive melanomas.
In combination with TRAIL it could have a significant efficacy in the treatment
of human melanomas.
[121]
In vitro HL60
T47D cell line 32 µM
Induces cell death mediated by intracellular caspases
Dose-dependent increase in proteolytic cleavage of caspase substrate PARP.
Enhances CD95L expression on both HL60 cells T47D breast carcinoma cells.
[123]
In vivo
In vitro
BALB/c or C57BL/6 mice
tBregs
20 or 50 mg/mouse
12.5 mM
Inhibits lung metastasis in mice. Inactivates Stat3, preventing the generation
and function of tBregs, including expression of TGF-β. It reduces antitumor
effector immune responses by disabling tBreg-induced conversion of Foxp3+
Tregs. Could control cancer escape-promoting tBregs/Tregs without
nonspecific inactivation of effector immune cells.
[131]
In vivo MRL/lpr mice
BJAB B cells 20 mg kg−1per day
Increases the expression of FcγRIIB in B cells. Decreases serum autoantibody
titers in MRL/lpr mice. The upregulation of Fc
γ
RIIB causes an increase of Sirt1
protein and deacetylation of p65 NF-κB.
Reduces plasma cells in MRL/lpr mice, leading to improvement of nephritis
and prolonged survival.
[132]

Nutrients 2019,11, 946 16 of 24
Table 1. Cont.
Study Type Subjects Dose Effect Ref.
In vivo BALB/c mice 20 mg/kg
Reduces proteinuria, immunoglobulin deposition in kidney, and in serum in
pristane-induced lupus mice.
Inhibits CD69 and CD71 expression on CD4+T cells and CD4+T cell
proliferation. Induces CD4+T cell apoptosis, and decreased CD4 IFNc+Th1
cells and the ratio of Th1/Th2 cells in vitro. Inhibits antibody production and
proliferation of B cells in vitro.
[134]
Abbreviations:
AKT, protein kinase B; AMPK, AMP-activated protein kinase; AP-1, activator protein 1; apoA-1, apolipoprotein (Apo) A-I; Bax, Bcl-2-associated X protein; Bak, Bcl-2
homologous antagonist killer; Bcl-2, B-cell lymphoma; Bcl-xL, B-cell lymphoma-extra-large; Bim, Bcl-2-like 11; Cbfa-1, core-binding factor a1; CCL20, chemokine (C-C motif) ligand 20;
CCR 6 chemokine (C-C motif) receptor 6; cFLIP, cellular FLICE-inhibitory protein; CIKs, cytokine-induced killer cells; COX-2, cyclooxygenase-2; CTLs, cytotoxic T lymphocytes; CYP27A1,
cytochrome P450 27-hydroxylase; DR, death receptor; DcR1, decoy receptor 1; ERK1/2, extracellular signal–regulated kinases; Fc
γ
RIIB, Fc gamma receptor IIb; FoxO3a, forkhead box O3A;
Foxp3, forkhead box P3; HDL, high-density lipoprotein cholesterol; HFD, high-fat diet; IFN-
γ
interferon-gamma; IL, interleukin; iNOS, inducible nitric oxide synthase; IRAK1, interleukin-1
receptor-associate kinase 1; JAK2, janus activated kinase; JNK, c-Jun N-terminal kinase; LAKs, lymphokine activated killer cells; LPS, lipopolysaccharide; MAPK, mitogen-activated protein
kinase; M-CSF, macrophage colony stimulating factor; MCP, monocyte chemoattractant protein; MEK, mitogen-activated protein kinase; Myd88, myeloid differentiation factor 88; NK,
natural killer; NLRP3, NOD-like receptor family pyrin domain containing 3; NKG2D, natural killer group 2 member D; Nrf2, nuclear factor (erythroid-derived 2)-related factor-2; NF-
κ
B,
nuclear factor-kappa B; NOD, nucleotide oligomerization domain; PARP poly (ADP-ribose) polymerase; PBMCs, peripheral blood mononuclear cells; PGE2, prostaglandin E2; PI3K,
phosphoinositide 3-kinase; PKC
ϑ
, protein kinase c-delta; PMA, phorbol 12-myristate13-acetate; PPAR, peroxisome proliferator-activated receptors; PUMA, p53 upregulated modulator
of apoptosis; RANKL, receptor activator of nuclear factor kB ligand; RIP, receptor interacting protein; ROI, reactive oxygen intermediate, Sirt1, Sirtuin-1; STAT, signal transducer and
activator; TAMs, tumor associated macrophages; TANK, TRAF family member-associated NF-
κ
B activator; tBregs, TGF
β
-expressing regulatory B cells; Tregs, regulatory T cells; TRAF6,
tumor necrosis factor receptor-associated factor 6; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TNF-related apoptosis inducing ligand; TRIF, TIR-domain-containing
adapter-inducing interferon; TLR, toll-like receptor; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis alpha.

Nutrients 2019,11, 946 17 of 24
7. Conclusions
There is an abundance of experimental studies highlighting the regulatory mechanisms and the
immunomodulatory role of resveratrol both
in vivo
and
in vitro
. These data reveal the promising role of
resveratrol in the prevention and therapy of a wide variety of chronic diseases including cardiovascular,
inflammatory, metabolic, neurological and skin diseases, and various infectious diseases (Figure 1).
There are also increasing lines of evidence suggesting it has a potent chemosensitizing effect in various
cancers. These studies show that resveratrol modulates many cellular and molecular mediators of the
inflammatory response. Nevertheless, a few studies have reported that resveratrol can function as an
antagonistic as well. Its effects are context-dependent (i.e., resveratrol might influence chemokines and
cytokines in opposite ways in different tissues). Although, preclinical studies produced exciting results,
nowadays many questions remain unanswered about the usage of resveratrol in the clinical setting
just because the clinical evidence indicating that resveratrol is an effective therapeutic in humans are
still lacking. Moreover, some official systematic clinical trials using resveratrol treatment in humans
had some disappointing outcomes and the difficulties of the clinical application of resveratrol are
enormous, such as its poor water solubility, bioavailability, and dosage. Therefore, various strategies
are being implemented, which include the development of resveratrol analogues [
138
] and formulations
such as adjuvants, nanoparticles, liposomes, micelles, and phospholipid complexes, to improve its
bioavailability. In addition, several other approaches have been employed to enhance its bioavailability,
which include altering the route of administering resveratrol and obstructing the metabolic pathways
via co-treatment with other agents. In fact, since resveratrol has multiple intracellular targets, additional
data is needed to determine the consequences of the interaction or the synergistic effects between
other polyphenols and vitamins, amino acids and other micronutrients or ordinarily used drugs.
More detailed and well-controlled preclinical and clinical trials are inevitable to evaluate the efficacy
of these new formulations as compared with the parental compound. Therefore, further studies in
humans are required to improveits bioavailability and to clarify the mechanisms of action of resveratrol
in several physiological conditions in order to make this agent a cutting-edge therapeutic strategy for
the prevention and treatment of a wide variety of autoimmune and inflammatory chronic diseases.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Jeandet, P.; Bessis, R.; Maume, B.F.; Meunier, P.; Peyron, D.; Trollat, P. Effect of enological practices on the
resveratrol isomer content of wine. J. Agric. Food Chem. 1995,43, 316–319. [CrossRef]
2.
Raal, A.; Pokk, P.; Arend, A.; Aunapuu, M.; J
õ
gi, J.; Okva, K.; Püssa, T. Trans-resveratrol alone and
hydroxystilbenes of rhubarb (Rheum rhaponticum L.) root reduce liver damage induced by chronic ethanol
administration: A comparative study in mice. Phytother. Res. 2009,23, 525–532. [CrossRef] [PubMed]
3.
Lyons, M.M.; Yu, C.; Toma, R.B.; Cho, S.Y.; Reiboldt, W.; Lee, J.; van Breemen, R.B. Resveratrol in raw and
baked blueberries and bilberries. J. Agric. Food Chem. 2003,51, 5867–5870. [CrossRef]
4.
Jeandet, P.; Bessis, R.; Gautheron, B. The production of resveratrol (3,5,4’-trihydroxystilbene) by grape berries
in different developmental stages. Am. J. Enol Viticult. 1991,42, 41–46.
5.
Sales, J.M.; Resurreccion, A.V.A. Resveratrol in peanuts. Crit. Rev. Food Sci. Nutr.
2014
,54, 734–770.
[CrossRef] [PubMed]
6.
Harikumar, K.B.; Aggarwal, B.B. A multitarget agent for age-associated chronic diseases. Cell Cycle
2008
,15,
1020–1035. [CrossRef]
7.
Pennisi, M.; Bertino, G.; Gagliano, C.; Malaguarnera, M.; Bella, R.; Borz
ì
, A.M.; Madeddu, R.; Drago, F.;
Malaguarnera, G. Resveratrol in Hepatitis C Patients Treated with Pegylated-Interferon-
α
-2b and Ribavirin
Reduces Sleep Disturbance. Nutrients 2017,9, 897. [CrossRef] [PubMed]
8.
Piotrowska, H.; Kucinska, M.; Murias, M. Biological activity of piceatannol: Leaving the shadow of
Resveratrol. Rev. Mutat. Rese. 2012,750, 60–82. [CrossRef]

Nutrients 2019,11, 946 18 of 24
9.
Malaguarnera, G.; Pennisi, M.; Bertino, G.; Motta, M.; Borz
ì
, A.M.; Vicari, E.; Bella, R.; Drago, F.;
Malaguarnera, M. Resveratrol in Patients with Minimal Hepatic Encephalopathy. Nutrients
2018
,10,
329. [CrossRef]
10.
Gao, X.; Xu, Y.X.; Janakiraman, N.; Chapman, R.A.; Gautam, S.C. Immunomodulatory activity of Resveratrol:
Suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production.
Biochem. Pharmacol. 2001,62, 1299–1308. [CrossRef]
11.
Švajger, U.; Jeras, M. Anti-inflammatory effects of Resveratrol and its potential use in therapy of
immune-mediated diseases. Int. Rev. Immunol. 2012,31, 202–222. [CrossRef]
12.
Sharma, S.; Chopra, K.; Kulkarni, S.K.; Agrewala, J.N. Resveratrol and curcumin suppress immune response
through CD28/CTLA-4 and CD80 co-stimulatory pathway. Clin. Exp. Immunol.
2007
,147, 155–163. [CrossRef]
[PubMed]
13.
Lu, C.C.; Chen, J.K. Resveratrol enhances perforin expression and NK cell cytotoxicity through
NKG2D-dependent pathways. J. Cell. Physiol. 2010,223, 343–351. [CrossRef] [PubMed]
14.
Yuan, Y.; Xue, X.; Guo, R.B.; Sun, X.L.; Hu, G. Resveratrol enhances the antitumor effects of temozolomide
in glioblastoma via ROS-dependent AMPK-TSC-mTOR signaling pathway. CNS Neurosci. Ther.
2012
,18,
536–546. [CrossRef] [PubMed]
15.
Yang, Y.; Paik, J.H.; Cho, D.; Cho, J.A.; Kim, C.W. Resveratrol induces the suppression of tumor-derived
CD4+CD25+regulatory T cells. Int. Immunopharmacol. 2008,8, 542–547. [CrossRef] [PubMed]
16.
Mahal, H.S.; Mukherjee, T. Scavenging of reactive oxygen radicals by Resveratrol: Antioxidant effect.
Res. Chem. Intermed. 2006,32, 59–71. [CrossRef]
17.
Subbaramaiah, K.; Chung, W.J.; Michaluart, P.; Telang, N.; Tanabe, T.; Inoue, H.; Jang, M.; Pezzuto, J.M.;
Dannenberg, A.J. Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated
human mammary epithelial cells. J. Biol. Chem. 1998,273, 21875–21882. [CrossRef] [PubMed]
18.
Szewczuk, L.M.; Forti, L.; Stivala, L.A.; Penning, T.M. Resveratrol is a peroxidase mediated inactivator of
COX-1 but not COX-2: A mechanistic approach to the design of COX-1 selective agents. J. Biol. Chem.
2004
,
279, 22727–22737. [CrossRef]
19.
Saiko, P.; Szakmary, A.; Jaeger, W.; Szekeres, T. Resveratrol and its analogs: Defense against cancer, coronary
disease and neurodegenerative maladies or just a fad? Mutat. Res. Rev. 2008,658, 68–94. [CrossRef]
20.
Capiralla, H.; Vingtdeux, V.; Zhao, H.; Sankowski, R.; Al-Abed, Y.; Davies, P.; Marambaud, P. Resveratrol
mitigates lipopolysaccharide-and A
β
-mediated microglial inflammation by inhibiting the TLR4/NF-
κ
B/STAT
signaling cascade. J. Neurochem. 2012,120, 461–472. [CrossRef]
21.
Alarcon De La Lastra, C.; Villegas, I. Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms
and clinical implications. Mol. Nutr. Food Res. 2005,49, 405–430. [CrossRef] [PubMed]
22.
Mei, Y.Z.; Liu, R.X.; Wang, D.P.; Wang, X.; Dai, C.C. Biocatalysis and biotransformation of Resveratrol in
microorganisms. Biotechnol. Lett. 2015,37, 9–18. [CrossRef]
23.
Baur, J.A.; Sinclair, D.A. Therapeutic potential of Resveratrol: The
in vivo
evidence. Nat. Rev. Drug Discov.
2006,5, 493. [CrossRef] [PubMed]
24.
Saqib, U.; Kelley, T.T.; Panguluri, S.K.; Liu, D.; Savai, R.; Baig, M.S.; Schürer, S.C. Polypharmacology or
Promiscuity? Structural Interactions of Resveratrol with Its Bandwagon of Targets. Front. Pharmacol.
2018
,9,
1201. [CrossRef] [PubMed]
25.
Chalkiadaki, A.; Guarente, L. Sirtuins mediate mammalian metabolic responses to nutrient availability.
Nat. Rev. Endocrinol. 2012,8, 287–296. [CrossRef] [PubMed]
26.
Lee, C.W.; Wong, L.L.; Tse, E.Y.; Liu, H.F.; Leong, V.Y.; Lee, J.M.; Hardie, D.G.; Ng, I.O.; Ching, Y.P. AMPK
promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells. Cancer Res.
2012,72, 4394–4404. [CrossRef]
27.
Lin, Z.; Yang, H.; Kong, Q.; Li, J.; Lee, S.M.; Gao, B.; Dong, H.; Wei, J.; Song, J.; Zhang, D.D.; et al. USP22
antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required
for mouse embryonic development. Mol. Cell 2012,46, 484–494. [CrossRef]
28.
Kwon, H.S.; Lim, H.W.; Wu, J.; Schnölzer, M.; Verdin, E.; Ott, M. Three novel acetylation sites in the Foxp3
transcription factor regulate the suppressive activity of regulatory T cells. J. Immunol.
2012
,188, 2712–2721.
[CrossRef]

Nutrients 2019,11, 946 19 of 24
29.
Gao, B.; Kong, Q.; Kemp, K.; Zhao, Y.S.; Fang, D. Analysis of sirtuin 1 expression reveals a molecular
explanation of IL-2-mediated reversal of T-cell tolerance. Proc. Natl. Acad. Sci. USA
2012
,109, 899–904.
[CrossRef]
30.
Zhang, J.; Lee, S.M.; Shannon, S.; Gao, B.; Chen, W.; Chen, A.; Divekar, R.; McBurney, M.W.; Braley-Mullen, H.;
Zaghouani, H.; et al. The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in
mice. J. Clin. Investig. 2009,119, 3048–3058. [CrossRef]
31.
Borra, M.T.; Smith, B.C.; Denu, J.M. Mechanism of human SIRT1 activation by Resveratrol. J. Biol. Chem.
2005,280, 17187–17195. [CrossRef]
32. Lee, S.M.; Yang, H.; Tartar, D.; Gao, B.; Luo, X.; Ye, S.; Zaghouani, H.; Fang, D. Prevention and treatment of
diabetes with Resveratrol in a non-obese mouse model of type 1 diabetes. Diabetologia
2011
,54, 1136–1146.
[CrossRef] [PubMed]
33.
Xuzhu, G.; Komai-Koma, M.; Leung, B.P.; Howe, H.S.; McSharry, C.; McInnes, I.B.; Xu, D. Resveratrol
modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function. Ann. Rheum. Dis.
2012
,
71, 129–135. [CrossRef]
34.
Yeung, F.; Hoberg, J.E.; Ramsey, C.S.; Keller, M.D.; Jones, D.R.; Frye, R.A.; Mayo, M.W. Modulation of
NF-
κ
B-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J.
2004
,23, 2369–2380.
[CrossRef]
35.
Bonizzi, G.; Karin, M. The two NF-
κ
B activation pathways and their role in innate and adaptive immunity.
Trends Immunol. 2004,25, 280–288. [CrossRef] [PubMed]
36.
Yamamoto, Y.; Gaynor, R.B. Therapeutic potential of inhibition of the NF-
κ
B pathway in the treatment of
inflammation and cancer. J. Clin. Investig. 2001,107, 135–142. [CrossRef]
37.
Manna, S.K.; Mukhopadhyay, A.; Aggarwal, B.B. Resveratrol suppresses TNF-induced activation of nuclear
transcription factors NF-
κ
B, activator protein-1, and apoptosis: Potential role of reactive oxygen intermediates
and lipid peroxidation. J. Immunol. 2000,164, 6509–6519. [CrossRef]
38. Shakibaei, M.; Buhrmann, C.; Mobasheri, A. Resveratrol-mediated SIRT-1 interactions with p300 modulate
receptor activator of NF-
κ
B ligand (RANKL) activation of NF-
κ
B signaling and inhibit osteoclasto-genesis in
bone-derived cells. J. Biol. Chem. 2011,286, 11492–11505. [CrossRef] [PubMed]
39.
Price Nathan, L.; Gomes Ana, P.; Ling Alvin, J.Y.; Duarte Filipe, V.; Martin-Montalvo, A.; North Brian, J.;
Agarwal, B.; Ye, L.; Ramadori, G.; Teodoro Joao, S.; et al. SIRT1 is required for AMPK activation and the
beneficial effects of Resveratrol on mitochondrial function. Cell Metab. 2012,15, 675–690. [CrossRef]
40.
Nakayama, H.; Yaguchi, T.; Yoshiya, S.; Nishizaki, T. Resveratrol induces apoptosis MH7A human rheumatoid
arthritis synovial cells in a sirtuin 1-dependent manner. Rheumatol. Int. 2012,32, 151–157. [CrossRef]
41.
Pallar
è
s, V.; Calay, D.; Ced
ó
, L.; Castell-Auv
í
, A.; Raes, M.; Pinent, M.; Ard
é
vol, A.; Arola, L.; Blay, M.
Enhanced anti-inflammatory effect of Resveratrol and EPA in treated endotoxin-activated RAW 264.7
macrophages. Br. J. Nutr. 2012,108, 1562–1573. [CrossRef]
42.
Stout, R.D.; Suttles, J. Functional plasticity of macrophages: Reversible adaptation to changing
microenvironments. J. Leukoc. Biol. 2004,76, 509–513. [CrossRef]
43.
Akira, S.; Uematsu, S.; Takeuchi, O. Pathogen recognition and innate immunity. Cell
2006
,124, 783–801.
[CrossRef]
44.
David, M.; Jonathan, B.; David, B.R.; Ivan, M.R. Mononuclear Phagocytes in Immune Defense. In Immunology,
8th ed.; David, M., Jonathan, B., David, B.R., Ivan, M.R., Eds.; Elsevier Saunders: Philadelphia, PA, USA,
2013; pp. 125–126.
45.
Arango Duque, G.; Descoteaux, A. Macrophage cytokines: Involvement in immunity and infectious diseases.
Front. Immunol. 2014,5, 491. [CrossRef]
46.
Thompson, M.R.; Kaminski, J.J.; Kurt-Jones, E.A.; Fitzgerald, K.A. Pattern recognition receptors and the
innate immune response to viral infection. Viruses 2011,3, 920–940. [CrossRef]
47.
Yang, Y.; Li, S.; Yang, Q.; Shi, Y.; Zheng, M.; Liu, Y.; Chen, F.; Song, G.; Xu, H.; Wan, T.; et al. Resveratrol
reduces the proinflammatory effects and lipopolysaccharide- induced expression of HMGB1 and TLR4 in
RAW264.7 cells. Cell. Physiol. Biochem. 2014,33, 1283–1292. [CrossRef]
48.
Narayanankutty, A. Toll like receptors as a novel therapeutic target for natural products against chronic
diseases. Curr. Drug Target 2019. [CrossRef]

Nutrients 2019,11, 946 20 of 24
49.
Youn, H.S.; Lee, J.Y.; Fitzgerald, K.A.; Young, H.A.; Akira, S.; Hwang, D.H. Specific inhibition of
MyD88-independent signaling pathways of TLR3 and TLR4 by Resveratrol: Molecular targets are TBK1 and
RIP1 in TRIF complex. J. Immunol. 2005,175, 3339–3346. [CrossRef]
50.
Jakus, P.B.; Kalman, N.; Antus, C.; Radnai, B.; Tucsek, Z.; Gallyas, F., Jr.; Sumegi, B.; Veres, B. TRAF6 is
functional in inhibition of TLR4-mediated NF-
κ
B activation by Resveratrol. J. Nutr. Biochem.
2013
,24,
819–823. [CrossRef]
51.
Hu, P.; Han, Z.; Couvillon, A.D.; Kaufman, R.J.; Exton, J.H. Autocrine tumor necrosis factor a links
endoplasmic reticulum stress to the membrane death receptor pathway through IRE1
α
-mediated NF-
κ
B
activation and down-Regulation of TRAF2 expression. Mol. Cell. Biol. 2006,26, 3071–3084. [CrossRef]
52.
Calfon, M.; Zeng, H.; Urano, F.; Till, J.H.; Hubbard, S.R.; Harding, H.P.; Clark, S.G.; Ron, D. IRE1 couples
endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature
2002
,415, 92–96.
[CrossRef] [PubMed]
53.
Martinon, F.; Chen, X.; Lee, A.H.; Glimcher, L.H. TLR activation of the transcription factor XBP1 regulates
innate immune responses in macrophages. Nat. Immunol. 2010,11, 411–418. [CrossRef]
54.
Wang, F.M.; Chen, Y.J.; Ouyang, H.J. Regulation of unfolded protein response modulator XBP1s by acetylation
and deacetylation. Biochem. J. 2010,433, 245–252. [CrossRef] [PubMed]
55.
Misawa, T.; Saitoh, T.; Kozaki, T.; Park, S.; Takahama, M.; Akira, S. Resveratrol inhibits the acetylated
α
-tubulin-mediated assembly of the NLRP3-inflammasome. Int. Immunol.
2015
,27, 425–434. [CrossRef]
[PubMed]
56.
Whitlock, N.C.; Baek, S.J. The anticancer effects of Resveratrol: Modulation of transcription factors.
Nutr. Cancer 2012,64, 493–502. [CrossRef] [PubMed]
57.
Sebai, H.; Ristorcelli, E.; Sbarra, V.; Hovsepian, S.; Fayet, G.; Aouani, E.; Lombardo, D. Protective effect of
Resveratrol against LPS-induced extracellular lipoperoxidation in AR42J cells partly via a Myd88-dependent
signaling pathway. Arch. Biochem. Biophys. 2010,495, 56–61. [CrossRef] [PubMed]
58.
Stein, S.; Schafer, N.; Breitenstein, A.; Besler, C.; Winnik, S.; Lohmann, C.; Heinrich, K.; Brokopp, C.E.;
Handschin, C.; Landmesser, U.; et al. SIRT1 reduces endothelial activation without affecting vascular function
in ApoE−/−mice. Aging (Albany N. Y.) 2010,2, 353. [CrossRef]
59.
Schug, T.T.; Xu, Q.; Gao, H.; Peres-da-Silva, A.; Draper, D.W.; Fessler, M.B.; Purushotham, A.; Li, X. Myeloid
deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol. Cell. Biol.
2010
,
30, 4712–4721. [CrossRef]
60.
Schwager, J.; Richard, N.; Widmer, F.; Raederstorff, D. Resveratrol distinctively modulates the inflammatory
profiles of immune and endothelial cells. BMC Complement Altern. Med. 2017,17, 309. [CrossRef]
61.
Murray, P.J.; Allen, J.E.; Biswas, S.K.; Fisher, E.A.; Gilroy, D.W.; Goerdt, S.; Gordon, S.; Hamilton, J.A.;
Ivashkiv, L.B.; Lawrence, T.; et al. Macrophage activation and polarization: Nomenclature and experimental
guidelines. Immunity 2014,41, 14–20. [CrossRef]
62.
Fossati, G.; Mazzucchelli, I.; Gritti, D.; Ricevuti, G.; Edwards, S.W.; Moulding, D.A.; Rossi, M.L.
In vitro
effects of GM-CSF on mature peripheral blood neutrophils. Int. J. Mol. Med. 1998,1, 943–951. [CrossRef]
63.
Park, D.W.; Baek, K.; Kim, J.R.; Lee, J.J.; Ryu, S.H.; Chin, B.R.; Baek, S.H. Resveratrol inhibits foam cell
formation via NADPH oxidase 1- mediated reactive oxygen species and monocyte chemotactic protein-1.
Exp. Mol. Med. 2009,41, 171–179. [CrossRef]
64.
Voloshyna, I.; Hai, O.; Littlefield, M.J.; Carsons, S.; Reiss, A.B. Resveratrol mediates anti-atherogenic effects
on cholesterol flux in human macrophages and endothelium via PPAR
γ
and adenosine. Eur. J. Pharmacol.
2013,698, 299–309. [CrossRef] [PubMed]
65.
Dong, W.; Wang, X.; Bi, S.; Pan, Z.; Liu, S.; Yu, H.; Lu, H.; Lin, X.; Wang, X.; Ma, T.; et al. Inhibitory effects
of Resveratrol on foam cell formation are mediated through monocyte chemotactic protein-1 and lipid
metabolism-related proteins. Int. J. Mol. Med. 2014,33, 1161–1168. [CrossRef] [PubMed]
66.
Bigagli, E.; Cinci, L.; Paccosi, S.; Parenti, A.; D’Ambrosio, M.; Luceri, C. Nutritionally relevant concentrations
of Resveratrol and hydroxytyrosol mitigate oxidative burst of human granulocytes and monocytes and the
production of pro-inflammatory mediators in LPS-stimulated RAW 264.7 macrophages. Int. Immunopharmacol.
2017,43, 147–155. [CrossRef] [PubMed]
67.
Yang, C.M.; Chen, Y.W.; Chi, P.L.; Lin, C.C.; Hsiao, L.D. Resveratrol inhibits BK-induced COX-2 transcription
by suppressing acetylation of AP-1 and NF-
κ
B in human rheumatoid arthritis synovial fibroblasts.
Biochem. Pharmacol. 2017,132, 77–91. [CrossRef]

Nutrients 2019,11, 946 21 of 24
68.
Mauer, J.; Chaurasia, B.; Goldau, J.; Vogt, M.C.; Ruud, J.; Nguyen, K.D.; Theurich, S.; Hausen, A.C.; Schmitz, J.;
Brönneke, H.S.; et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia
and obesity-associated resistance to insulin. Nat. Immunol. 2014,15, 423–430. [CrossRef] [PubMed]
69.
Karin, M.; Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature
2016
,529, 307–315.
[CrossRef] [PubMed]
70. Walle, T.; Hsieh, F.; DeLegge, M.H.; Oatis, J.E., Jr.; Walle, U.K. High absorption but very low bioavailability
of oral Resveratrol in humans. Drug Metab. Dispos. 2004,32, 1377–1382. [CrossRef] [PubMed]
71.
Krausgruber, T.; Blazek, K.; Smallie, T.; Alzabin, S.; Lockstone, H.; Sahgal, N.; Hussell, T.; Feldmann, M.;
Udalova, I.A. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat. Immunol.
2011,12, 231–238. [CrossRef] [PubMed]
72.
Hagemann, T.; Lawrence, T.; McNeish, I.; Charles, K.A.; Kulbe, H.; Thompson, R.G.; Robinson, S.C.;
Balkwill, F.R. “Re-educating” tumor-associated macrophages by targeting NF-kappa B. J. Exp. Med.
2008
,
205, 261–268. [CrossRef] [PubMed]
73.
Satoh, T.; Takeuchi, O.; Vandenbon, A.; Yasuda, K.; Tanaka, Y.; Kumagai, Y.; Miyake, T.; Matsushita, K.;
Okazaki, T.; Saitoh, T.; et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses
against helminth infection. Nat. Immunol. 2010,11, 936–944. [CrossRef] [PubMed]
74.
Szanto, A.; Balint, B.L.; Nagy, Z.S.; Barta, E.; Dezso, B.; Pap, A.; Szeles, L.; Poliska, S.; Oros, M.; Evans, R.M.;
et al. STAT6 transcription factor is a facilitator of the nuclear receptor PPARgamma-regulated gene expression
in macrophages and dendritic cells. Immunity 2010,33, 699–712. [CrossRef]
75.
Liao, X.; Sharma, N.; Kapadia, F.; Zhou, G.; Lu, Y.; Hong, H.; Paruchuri, K.; Mahabeleshwar, G.H.; Dalmas, E.;
Venteclef, N.; et al. Krüppel-like factor 4 regulates macrophage polarization. J. Clin. Investig.
2011
,121,
2736–2749. [CrossRef]
76.
Qian, B.Z.; Pollard, J.W. Macrophage diversity enhances tumor progression and metastasis. Cell
2010
,14,
139–151. [CrossRef]
77.
Biswas, S.K.; Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a
paradigm. Nat. Immunol. 2010,11, 889–896. [CrossRef] [PubMed]
78.
Sica, A.; Schioppa, T.; Mantovani, A.; Allavena, P. Tumor-associated macrophages are a distinct M2 polarised
population promoting tumor progression: Potential targets of anti-cancer therapy. Eur. J. Cancer
2006
,427,
17–727.
79.
Wu, P.; Wu, D.; Zhao, L.; Huang, L.; Chen, G.; Shen, G.; Huang, J.; Chai, Y. Inverse role of distinct subsets
and distribution of macrophage in lung cancer prognosis: A meta-analysis. Oncotarget
2016
,7, 40451–40460.
[CrossRef]
80.
Mei, J.; Xiao, Z.; Guo, C.; Pu, Q.; Ma, L.; Liu, C.; Lin, F.; Liao, H.; You, Z.; Liu, L. Prognostic impact of
tumor-associated macrophage infiltration in non-small cell lung cancer: A systemic review and meta-analysis.
Oncotarget 2016,7, 34217–34228. [CrossRef]
81.
Yin, S.; Huang, J.; Li, Z.; Zhang, J.; Luo, J.; Lu, C.; Xu, H.; Xu, H. The Prognostic and Clinicopathological
Significance of Tumor-Associated Macrophages in Patients withGastric Cancer: A Meta-Analysis. PLoS ONE
2017,12, e0170042.
82.
Qian, B.Z.; Zhang, H.; Li, J.; He, T.; Yeo, E.J.; Soong, D.Y.; Carragher, N.O.; Munro, A.; Chang, A.; Bresnick, A.R.;
et al. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes
breast cancer metastasis. J. Exp. Med. 2015,212, 1433–1448. [CrossRef] [PubMed]
83.
Kitamura, T.; Qian, B.Z.; Soong, D.; Cassetta, L.; Noy, R.; Sugano, G.; Kato, Y.; Li, J.; Pollard, J.W. CCL2-induced
chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated
macrophages. J. Exp. Med. 2015,212, 1043–1059. [CrossRef]
84.
Wang, J.; Cao, Z.; Zhang, X.M.; Nakamura, M.; Sun, M.; Hartman, J.; Harris, R.A.; Sun, Y.; Cao, Y. Novel
mechanism of macrophage-mediated metastasis revealed in a zebrafish model of tumor development.
Cancer Res. 2015,75, 306–315. [CrossRef] [PubMed]
85.
Jeong, S.K.; Yang, K.; Park, Y.S.; Choi, Y.J.; Oh, S.J.; Lee, C.W.; Lee, K.Y.; Jeong, M.H.; Jo, W.S. Interferon
gamma induced by Resveratrol analog, HS-1793, reverses the properties of tumor associated macrophages.
Int. Immunopharmacol. 2014,22, 303–310. [CrossRef] [PubMed]
86. Gkouveris, I.; Nikitakis, N.; Sauk, J. STAT3 signaling in cancer. J. Cancer Ther. 2015,6, 709–726. [CrossRef]

Nutrients 2019,11, 946 22 of 24
87.
Ries, C.H.; Cannarile, M.A.; Hoves, S.; Benz, J.; Wartha, K.; Runza, V.; Rey-Giraud, F.; Pradel, L.P.; Feuerhake, F.;
Klaman, I.; et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for
cancer therapy. Cancer Cell 2014,25, 846–859. [CrossRef]
88.
Sun, L.; Chen, B.; Jiang, R.; Li, J.; Wang, B. Resveratrol inhibits lung cancer growth by suppressing M2-like
polarization of tumor associated macrophages. Cell Immunol. 2017,311, 86–93. [CrossRef]
89.
Kimura, Y.; Sumiyoshi, M. Resveratrol Prevents Tumor Growth and Metastasis by Inhibiting
Lymphangiogenesis and M2 Macrophage Activation and Differentiation in Tumor-associated Macrophages.
Nutr. Cancer 2016,68, 667–678. [CrossRef]
90.
Hengartner, H.; Odermatt, B.; Schneider, R.; Schreyer, M.; Walle, G.; MacDonald, H.R.; Zinkernagel, R.M.
Deletion of self-reactive T cells before entry into the thymus medulla. Nature
1988
,336, 388–390. [CrossRef]
91.
Jenkinson, E.J.; Kingston, R.; Smith, C.A.; Williams, G.T.; Owen, J.J. Antigen-induced apoptosis in developing
T cells: A mechanism for negative selection of the T cell receptor repertoire. Eur. J. Immunol.
1989
,19,
2175–2177. [CrossRef]
92.
Shimon, S.; Noriko, S.; Jun, S.; Sayuri, Y.; Toshiko, S.; Misako, I.; Kuniyasu, Y.; Nomura, T.; Toda, M.;
Takahashi, T. Immunologic tolerance maintained by CD25+CD4+regulatory T cells: Their common role in
controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 2001,182, 18–32.
93.
Fu, S.; Zhang, N.; Yopp, A.C.; Chen, D.; Mao, M.; Zhang, H.; Ding, Y.; Bromberg, J.S. TGF-beta induces Foxp3
+T-regulatory cells from CD4 +CD25—Precursors. Am. J. Transplant. 2004,4, 1614–1627. [CrossRef]
94.
Tai, Y.; Wang, Q.; Korner, H.; Zhang, L.; Wei, W. Molecular Mechanisms of T Cells Activation by Dendritic
Cells in Autoimmune Diseases. Front. Pharmacol. 2018,9, 642. [CrossRef]
95.
Caza, T.; Landas, S. Functional and Phenotypic Plasticity of CD4(+) T Cell Subsets. Biomed. Res. Int.
2015
,
521957. [CrossRef]
96.
Astry, B.; Venkatesha, S.H.; Moudgil, K.D. Involvement of the IL-23/IL-17 axis and the Th17/Treg balance in
the pathogenesis and control of autoimmune arthritis. Cytokine 2015,74, 54–61. [CrossRef]
97.
Tesmer, L.A.; Lundy, S.K.; Sarkar, S.; Fox, D.A. Th17 cells in human disease. Immunol. Rev.
2008
,223, 87–113.
[CrossRef]
98.
Petro, T.M. Regulatory role of Resveratrol on Th17 in autoimmune disease. Int. Immunopharmacol.
2011
,11,
310–318. [CrossRef]
99.
Jeong, M.H.; Yang, K.M.; Choi, Y.J.; Kim, S.D.; Yoo, Y.H.; Seo, S.Y.; Lee, S.H.; Ryu, S.R.; Lee, C.M.; Suh, H.;
et al. Resveratrol analog, HS-1793 enhance anti-tumor immunity by reducing the CD4+CD25+regulatory T
cells in FM3A tumor bearing mice. Int. Immunopharmacol. 2012,14, 328–333. [CrossRef] [PubMed]
100.
Lopez-Pastrana, J.; Shao, Y.; Chernaya, V.; Wang, H.; Yang, X.F. Epigenetic enzymes are the therapeutic
targets for CD4+CD25+/highFoxp3+regulatory T cells. Transl. Res. 2015,165, 221–240. [CrossRef]
101.
Chen, X.; Lu, Y.; Zhang, Z.; Wang, J.; Yang, H.; Liu, G. Intercellular interplay between Sirt1 signalling and cell
metabolism in immune cell biology. Immunology 2015,145, 455–467. [CrossRef]
102.
Zou, T.; Yang, Y.; Xia, F.; Huang, A.; Gao, X.; Fang, D.; Xiong, S.; Zhang, J. Resveratrol Inhibits CD4+T cell
activation by enhancing the expression and activity of Sirt1. PLoS ONE 2013,8, e75139. [CrossRef]
103.
Wu, S.L.; Yu, L.; Jiao, X.Y.; Meng, K.W.; Pan, C.E. The suppressive effect of Resveratrol on protein kinase
C theta in peripheral blood T lymphocytes in a rat liver transplantation model. Transplant. Proc.
2006
,38,
3052–3054. [CrossRef]
104.
Karlsson, E.A.; Sheridan, P.A.; Beck, M.A. Diet-induced obesity impairs the T cell memory response to
influenza virus infection. J. Immunol. 2010,184, 3127–3133. [CrossRef]
105.
Eliakim, A.; Schwindt, C.; Zaldivar, F.; Casali, P.; Cooper, D.M. Reduced tetanus antibody titers in overweight
children. Autoimmunity 2006,39, 137–141. [CrossRef]
106.
Wang, B.; Sun, J.; Li, L.; Zheng, J.; Shi, Y.; Le, G. Regulatory effects of Resveratrol on glucose metabolism
and T-lymphocyte subsets in the development of high-fat diet-induced obesity in C57BL/6 mice. Food Funct.
2014,5, 1452–1463. [CrossRef]
107.
Liu, L.L.; Chao, P.L.; Zhang, H.L.; Tong, M.L.; Liu, G.L.; Lin, L.R.; Su, Y.H.; Wu, J.Y.; Dong, J.; Zheng, W.H.;
et al. Analysis of lymphocyte subsets in HIV-negative neurosyphilis patients. Diagn. Microbiol. Infect. Dis.
2013,75, 165–168. [CrossRef] [PubMed]

Nutrients 2019,11, 946 23 of 24
108.
Andrade, D.; Redecha, P.B.; Vukelic, M.; Qing, X.; Perino, G.; Salmon, J.E.; Koo, G.C. Engraftment of
peripheral blood mononuclear cells from systemic lupus erythematosus and antiphospholipid syndrome
patient donors into BALB-RAG-2
−/−
IL-2R
γ−/−
mice: A promising model for studying human disease.
Arthr. Rheum. 2011,63, 2764–2773. [CrossRef]
109.
Robertson, M.J.; Ritz, J. Biology and clinical relevance of human natural killer cells. Blood
1990
,76, 2421–2438.
110.
Kiessling, R.; Klein, E.; Wigzell, H. “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for
mouse moloney leukemia cells. Specificity and distribution according to genotype. Eur. J. Immunol.
1975
,5,
112–117. [CrossRef]
111.
Lee, S.-H.; Miyagi, T.; Biron, C.A. Keeping NK cells in highly regulated antiviral warfare. Trends Immunol.
2007,28, 252–259. [CrossRef]
112.
Biron, C.A.; Brossay, L. NK cells and NKT cells in innate defense against viral infections. Curr. Opin. Immunol.
2001,13, 458–464. [CrossRef]
113.
Krzewski, K.; Strominger, J.L. The killer’s kiss: The many functions of NK cell immunological synapses.
Curr. Opin. Cell. Biol. 2008,20, 597–605. [CrossRef]
114.
Walzer, T.; Dalod, M.; Robbins, S.H.; Zitvogel, L.; Vivier, E. Natural-killer cells and dendritic cells: ‘l’union
fait la force’. Blood 2005,106, 2252–2258. [CrossRef] [PubMed]
115. Narni-Mancinelli, E.; Ugolini, S.; Vivier, E. Tuning the threshold of natural killer cell responses. Curr. Opin.
Immunol. 2013,25, 53–58. [CrossRef]
116.
Falchetti, R.; Fuggetta, M.P.; Lanzilli, G.; Tricarico, M.; Ravagnan, G. Effects of Resveratrol on human immune
cell function. Life Sci. 2001,70, 81–96. [CrossRef]
117.
Quoc Trung, L.; Espinoza, J.L.; Takami, A.; Nakao, S. Resveratrol induces cell cycle arrest and apoptosis in
malignant NK cells via JAK2/STAT3 pathway inhibition. PLoS ONE 2013,8, e55183. [CrossRef]
118.
Li, Q.; Huyan, T.; Ye, L.-J.; Li, J.; Shi, J.-L.; Huang, Q.-S. Concentration-dependent biphasic effects of
Resveratrol on human natural killer cells
in vitro
.J. Agric. Food Chem.
2014
,62, 10928–10935. [CrossRef]
[PubMed]
119.
Chen, X.; Trivedi, P.P.; Ge, B.; Krzewski, K.; Strominger, J.L. Many NK cell receptors activate ERK2 and JNK1
to trigger microtubule organizing center and granule polarization and cytotoxicity. Proc. Natl. Acad. Sci. USA
2007,104, 6329–6334. [CrossRef] [PubMed]
120.
Lu, C.-C.; Lai, H.-C.; Hsieh, S.-C.; Chen, J.-K. Resveratrol ameliorates Serratia marcescens-induced acute
pneumonia in rats. J. Leukoc. Biol. 2008,83, 1028–1037. [CrossRef] [PubMed]
121.
Hu, L.; Cao, D.; Li, Y.; He, Y.; Guo, K. Resveratrol sensitized leukemia stem cell-like KG-1a cells to
cytokine-induced killer cells-mediated cytolysis through NKG2D ligands and TRAIL receptors. Cancer Biol.
Ther. 2012,13, 516–526. [CrossRef]
122.
Shankar, S.; Siddiqui, I.; Srivastava, R. Molecular mechanisms of Resveratrol (3,4,5-trihydroxy-trans-stilbene)
and its interaction with TNF-related apoptosis inducing ligand (TRAIL) in androgen-insensitive prostate
cancer cells. Mol. Cell. Biochem. 2007,304, 273–285. [CrossRef]
123.
Ivanov, V.N.; Partridge, M.A.; Johnson, G.E.; Huang, S.X.L.; Zhou, H.; Hei, T.K. Resveratrol sensitizes
melanomas to TRAIL through modulation of antiapoptotic gene expression. Exp. Cell Res.
2008
,314,
1163–1176. [CrossRef]
124.
Jacquemin, G.; Shirley, S.; Micheau, O. Combining naturally occurring polyphenols with TNF-related
apoptosis-inducing ligand: A promising approach to kill resistant cancer cells? Cell. Mol. Life Sci.
2010
,67,
3115–3130. [CrossRef]
125.
Clement, M.V.; Hirpara, J.L.; Chawdhury, S.H.; Pervaiz, S. Chemopreventive agent Resveratrol, a natural
product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood
1998,92, 996–1002.
126.
Van Es, N.; Sturk, A.; Middeldorp, S.; Nieuwland, R. Effects of cancer on platelets. Semin. Oncol.
2014
,41,
311–318. [CrossRef]
127.
Nieswandt, B.; Hafner, M.; Echtenacher, B.; Männel, D.N. Lysis of tumor cells by natural killer cells in mice is
impeded by platelets. Cancer Res. 1999,59, 1295–1300. [PubMed]
128.
Toliopoulos, I.K.; Simos, Y.V.; Oikonomidis, S.; Karkabounas, S.C. Resveratrol diminishes platelet aggregation
and increases susceptibility of K562 tumor cells to natural killer cells. Indian J. Biochem. Biophys.
2013
,50,
14–18.

Nutrients 2019,11, 946 24 of 24
129.
Mauri, C.; Menon, M. Human regulatory B cells in health and disease: Therapeutic potential. J. Clin. Investig.
2017,127, 772–779. [CrossRef]
130.
Ray, A.; Basu, S.; Williams, C.B.; Salzman, N.H.; Dittel, B.N. A novel IL-10-independent regulatory role for B
cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand. J. Immunol.
2012
,
188, 3188–3198. [CrossRef]
131.
Bodogai, M.; Lee-Chang, C.; Wejksza, K.; Lai, J.P.; Merino, M.; Wersto, R.P.; Gress, R.E.; Chan, A.C.;
Hesdorffer, C.; Biragyn, A. Anti-CD20 antibody promotes cancer escape via enrichment of tumor-evoked
regulatory B cells expressing low levels of CD20 and CD137L. Cancer Res. 2013,73, 2127–2138. [CrossRef]
132.
Olkhanud, P.B.; Damdinsuren, B.; Bodogai, M.; Gress, R.E.; Sen, R.; Wejksza, K.; Malchinkhuu, E.; Wersto, R.P.;
Biragyn, A. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4 T
cells to T-regulatory cells. Cancer Res. 2011,71, 3505–3515. [CrossRef] [PubMed]
133.
Lee-Chang, C.; Bodogai, M.; Martin-Montalvo, A.; Wejksza, K.; Sanghvi, M.; Moaddel, R.; de Cabo, R.;
Biragyn, A. Inhibition of breast cancer metastasis by Resveratrol-mediated inactivation of tumor-evoked
regulatory B cells. J. Immunol. 2013,191, 4141–4151. [CrossRef] [PubMed]
134.
Jhou, J.P.; Chen, S.J.; Huang, H.Y.; Lin, W.W.; Huang, D.Y.; Tzeng, S.J. Upregulation of Fc
γ
RIIB by Resveratrol
via NF-
κ
B activation reduces B-cell numbers and ameliorates lupus. Exp. Mol. Med.
2017
,49, e381. [CrossRef]
[PubMed]
135.
Hiepe, F.; Radbruch, A. Plasma cells as an innovative target in autoimmune disease with renal manifestations.
Nat. Rev. Nephrol. 2016,12, 232–240. [CrossRef]
136.
Wang, Z.L.; Luo, X.F.; Li, M.T.; Xu, D.; Zhou, S.; Chen, H.Z.; Gao, N.; Chen, Z.; Zhang, L.L.; Zeng, X.F.
Resveratrol possesses protective effects in a pristane-induced lupus mouse model. PLoS ONE
2014
,9, e114792.
[CrossRef]
137.
Isa
á
k, A.; Gergely, P., Jr.; Szekeres, Z.; Prechl, J.; Po
ó
r, G.; Erdei, A.; Gergely, J. Physiological up-regulation of
inhibitory receptors Fc
γ
RII and CR1 on memory B cells is lacking in SLE patients. Int. Immunol.
2008
,20,
185–192. [CrossRef]
138.
Jeandet, P.; Sobarzo-S
á
nchez, E.; Cl
é
ment, C.; Nabavi, S.F.; Habtemariam, S.; Nabavi, S.M.; Cordelier, S.
Engineering stilbene metabolic pathways in microbial cells. Biotechnol. Adv.
2018
,36, 2264–2283. [CrossRef]
©
2019 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).