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-γ and 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 µM	Enhances 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-γ expression 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-α in 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 NFκ B, and NFκ B-dependent reporter gene transcription. It suppresses TNF-induced NFκ B activation. Blocks NFκ B 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	5 μM	Inhibits RANKL-induced acetylation and nuclear translocation of NFκ B. Induces Sirt1-p300 association in bone-derived and preosteoblastic cells, leading to deacetylation of RANKL-induced NFκ B, inhibition of NFκ B 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]
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	5 μM	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]
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-1β gene 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 μM	Decreases 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]
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−1 per day	Increases the expression of FcγRIIB in B cells. Decreases serum autoantibody titers in MRL/lpr mice. The upregulation of FcγRIIB 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]
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; FcγRIIB, 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-κB, 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; PKCϑ, 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-κB activator; tBregs, TGFβ-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.