Curcumin (diferuloylmethane) is an orange-yellow component of turmeric (Curcuma longa), a spice often found in curry powder. Traditionally known for its an antiinflammatory effects, curcumin has been shown in the last two decades to be a potent immunomodulatory agent that can modulate the activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells. Curcumin can also downregulate the expression of various proinflammatory cytokines including TNF, IL-1, IL-2, IL-6, IL-8, IL-12, and chemokines, most likely through inactivation of the transcription factor NF-κB. Interestingly, however, curcumin at low doses can also enhance antibody responses. This suggests that curcumin’s reported beneficial effects in arthritis, allergy, asthma, atherosclerosis, heart disease, Alzheimer’s disease, diabetes, and cancer might be due in part to its ability to modulate the immune system. Together, these findings warrant further consideration of curcumin as a therapy for immune disorders.
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INTRODUCTION
Turmeric (called Haldi in Hindi language) and named by British as curry spice, is the dried rhizome powder of Curcuma longa, a perennial herb of the Zingiberaceae (ginger) family, which is 3–5 ft tall bearing oblong, pointed, short-stemmed leaves and funnel-shaped yellow flowers. The rhizome of turmeric is a valuable cash crop, which is widely cultivated in Asia, India, China, and other tropical countries (1). Turmeric, is commonly used as a spice in curries, food additive and also, as a dietary pigment. It has been used to treat various illnesses in the Indian subcontinent from the ancient times. Turmeric finds its use in one form or the other in the textile and pharmaceutical industries (2). It is used in Hindu religious ceremonies and Hindus also apply a mixture of turmeric and sandalwood powder on their foreheads. Turmeric has been used as a nontoxic drug in Ayurveda for centuries to treat a wide variety of disorders including rheumatism, bodyache, skin diseases, intestinal worms, diarrhea, intermittent, fevers, hepatic disorders, biliousness, urinary discharges, dyspepsia, inflammations, constipation, leukoderma, amenorrhea, and colic (3). Turmeric has been considered as an emmenagogue, diuretic, and carminative when taken orally, whereas topical application is commonly used to treat bruises, pains, sprains, boils, swellings, sinusitis, and various skin disorders (4). Turmeric is used to treat angina pectoris, stomachache, postpartum abdominal pain, and gallstones in the Chinese system of medicine (5). It seems to promote the qi flow, “stimulates menstrual discharge,” and relieves menstrual pain (6). The poultices prepared from turmeric are topically applied to relieve pain and inflammation (7). A mixture of turmeric powder and slaked lime is applied topically as a household remedy to cure injury-related sprains and swelling. Turmeric is also an effective household remedy for sore throat, cough, and common cold, where it is taken orally with tea or hot milk.
The major chemical principles of turmeric are curcuminoids, which impart characteristic yellow color to it. The curcuminoids can be separated from turmeric by ethanol extraction and it usually contains 0.3–5.4% curcumin (one of the major curcuminoids) depending on the season of its harvest (7). Vogel and Pellatier (8) first reported molecular formula of curcumin as C21H20O6, which was later identified as diferuloylmethane (8). The IUPAC name of curcumin is (1,7-bis (4-hydroxy-3-methoxy-phenyl) hepta-1, 6-diene-3, 5-dione) and its chemical structure (9) is depicted in Fig. 1. Curcumin is an orange-yellow, crystalline powder and does not dissolve in water; however, it readily goes into solution in ethanol and dimethylsulfoxide.
Chemical structure of curcumin.
Curcumin as such does not possess any nutritive value however; it has been in constant use by humans as turmeric powder since Vedic times or even earlier and could be considered as pharmacologically safe. Human consumption of curcumin as a dietary spice ranges up to 100 mg/day (10) and recent phase I clinical trials indicate that humans can tolerate a dose of curcumin as high as 12 g/day, without any toxic side effects (11). The latest report has indicated safe dose of curcumin up to 12 g/day in humans (12).
The degradation kinetics of curcumin have been worked out under various pH conditions (13). Ninety percent of curcumin gets decomposed within 30 min in 0.1 M phosphate buffer and serum-free medium (pH 7.2 at 37°C). The decomposition of curcumin is pH-dependent (pH 3–10) and the rate of decomposition is higher under neutral-basic conditions. Curcumin is comparatively more stable in cell culture media containing 10% fetal calf serum and in human blood. Less than 20% of curcumin gets degraded after 1 h and approximately 50% decomposes after 8 h. The trans-6-(4′-hydroxy-3′-methoxyphenyl)-2,4-dioxo-5-hexenal has been reported as a major degradation product of curcumin, whereas vanillin, ferulic acid, and feruloyl methane were found to be the minor degradation products. Among all the major degradation products reported, the quantity of vanillin increases with time (13). Levels as low as 0.017 ng/mL of curcumin can be detected in aqueous solution in vitro by flurometric methods using mixed micelle of sodium dodecyl benzene sulfonate (SDBS) and cetyltrimethylammonium bromide (CTAB) surfactants (14).
Curcumin reportedly possesses several pharmacological properties including antiinflammatory, antimicrobial, antiviral, antifungal, antioxidant, chemosensitizing, radiosensitizing, and wound healing activities (2, 15–33). Curcumin can suppress tumor initiation, promotion, and metastasis in experimental models (34–44). It can also act as an antiproliferative agent by interrupting the cell cycle, disrupting mitotic spindle structures, and inducing apoptosis and micronucleation (45–48). Apparently, curcumin is a pluripotent pharmacological agent that utilizes multiple molecular pathways to leave its imprint on biological systems (47). This review is mainly focused on curcumin’s immunomodulatory activities.
EFFECT OF CURCUMIN ON IMMUNE CELLS
Curcumin has been found to modulate the growth and cellular response of various cell types of the immune system (Fig. 2). How this agent affects T cells, B cells, macrophages, neutrophils, NK cells, and dendritic cells is discussed in the following text.
Action of curcumin on different types of immune cells.
Effect of Curcumin on T Cells
Numerous lines of evidence suggest that curcumin can modulate both the proliferation and the activation of T cells. Curcumin inhibited the proliferation induced by concanavalin A (Con A), phytohemagglutinin (PHA), and phorbol-12-myristate-13-acetate (PMA) of lymphocytes derived from fresh human spleen ((49); Table I). During these studies, curcumin also suppressed IL-2 synthesis; and IL-2 induced proliferation of lymphocytes. This correlated with suppression of NF-κB activation. Thus, these results suggest that curcumin exhibits immunosuppressive effects mediated through regulation of IL-2. In another study, the same group reported that curcumin inhibits the proliferation induced by PMA and anti-CD28 antibody or that induced by PHA of T lymphocytes isolated from healthy donors (50). In comparison, cyclosporine A was found to suppress PHA-induced T-cell proliferation but not that induced by PMA and anti-CD28 antibody. Thus, curcumin can overcome the resistance of PMA and CD28 pathway to cyclosporine A. These results suggest that curcumin exhibits immunosuppressive properties that are superior than cyclosporine A. Yadav and his group also reported that curcumin can suppress the PHA-induced proliferation of human peripheral blood mononuclear cells (PBMCs) and inhibit IL-2 expression and NF-κB (51). In still another report, curcumin inhibited the activation of human V γδT cells induced by phosphoantigens (52).
A study by Sikora et al., reported that curcumin treatment completely abolished the proliferation of Con A stimulated rat thymocytes and it also suppressed the dexamethasone-induced apoptosis in stimulated as well as nonstimulated rat thymocytes. This inhibition of apoptosis is accompanied by partial or complete oppression of AP-1 activity in nonstimulated or Con-A-stimulated thymocytes, respectively. A similar effect was also observable in rat thymocytes treated with dexamethasone; however, curcumin per se did not have any adverse effect on AP-1 activity (53). The immunomodulatory role of curcumin has been studied in HTLV-1-infected T-cells and primary ATL cells, where curcumin treatment preferentially inhibited the growth of HTLV-1-infected T-cells and primary ATL cells, but spared the normal PMBCs. This antiproliferative effect of curcumin on HTLV-1-infected T-cells and primary ATL cells was directly correlated to its ability to induce cell cycle arrest by downregulating the expression of cyclin D1, Cdk1, and Cdc25C and induce apoptosis by reducing the expression of XIAP and survivin. In addition, it also suppressed the constitutive AP-1 DNA-binding and transcriptional activity in these cells (54, 55).
Another study on mouse lymphocytes has reported that a low-dose curcumin increased the proliferation of splenic lymphocytes, whereas high-dose curcumin depressed it indicating its ability to differentially regulate the proliferation of splenic lymphocytes (56). In yet another study, curcumin treatment increased the proliferation of intestinal mucosal CD3+ T cells due to change in CD4+ T subsets in C57BL/6J-Min/+ (Min/+) mice bearing a germline mutation in Apc tumor suppressor gene (57). These studies further demonstrate the ability of curcumin to modulate immune functions in T cells.
The studies by Gerstch et al. on PMA-stimulated PBMCs have revealed that the low concentrations of curcumin significantly downregulated the expression of PMA-induced granulocyte macrophage colony stimulating factor (GM-CSF) mRNAs, whereas high concentrations upregulated interferon gamma (IFN-γ) mRNAs. These effects of curcumin were linked with the suppression of PMA-induced activation of NF-κB and downregulation of PMA-induced cyclin D1 mRNA expression in PMBCs (58). The experiments on rat splenic lymphocytes showed that curcumin treatment enhances the immune response of the lymphocytes by increasing IgG production (59).
The studies of ion transport enzyme activity in stimulated T cells revealed a marked regulatory activity of turmeric and its active principles, turmerin or curcumin. Treatment of Con A-stimulated and control human blood mononuclear T cells with different concentrations of turmeric, curcumin, and turmerin reduced ATPase levels on 3 and 5 days after treatment than the control. On the contrary, a three and twofold elevation in Ca2+ATPase and Na/K+ ATPase activities were observed on day 7, respectively (60). This could be one of the mechanisms of immunomodulation by curcumin in T cells.
Curcumin not only plays an important role in the immunomodulation of normal but also transformed T cells, where it adversely affects the cell proliferation of these cells by suppression of IL-2 gene expression and by inhibiting the activation of NF-κB (58). These results indicate that the antiproliferative activity of curcumin against T cells may be relevant for T-cell leukemia.
Effect of Curcumin on B Cells
In addition to affecting T cells, curcumin can also influence the proliferation of B cells and B lymphocyte-mediated immune function. Curcumin has been reported to block Epstein-bar virus (EBV) induced immortalization of human B cells. This effect of curcumin appears to be mediated through downregulation of oxidative stress induced by cyclosporine and hydrogen peroxide. Thus, posttransplant lymphoproliferative disorder (PLTD) associated with the use of cyclosporine during organ transplantation, can be reversed by curcumin (61). Churchill et al., have reported that curcumin treatment stimulates proliferation of B cells in the mucosa of intestine of C57BL/6J-Min/+ (Min/+) mice indicating its immunostimulatory activity (57).
Apart from affecting normal B-cells, curcumin has been found to differentially reduce the proliferation of immature B-cell lymphoma (BKS-2) cells, but not of normal cells, by inducing apoptosis and this is associated with downregulation of egr-1, c-myc, bcl-XL, and the tumor suppressor gene p53, and almost complete inhibition of NF-κB activity (62). These studies indicate that curcumin differentially regulates the immune function in normal as well as tumor cells, which could confer advantage in a therapeutic setting.
Effect of Curcumin on Macrophages
Many studies have shown curcumin’s ability to modulate the activation of macrophages. For example, curcumin seems to regulate the immune function of mice in a dose-dependent fashion as curcumin treatment enhanced the phagocytosis of peritoneal macrophages and differentially regulates the proliferation of splenocytes (56). Apart from cell proliferation, a daily diet of curcumin (30 mg/kg body weight/day) for 2 weeks in rats reportedly attenuated the ability of macrophages to generate ROS, (63) and secrete lysosomal enzymes collagenase, elastase, and hyaluronidase (64). The ability of curcumin to downregulate Th1 and NO production has been directly correlated to its ability to differentially activate the host macrophages (65).
Effect of Curcumin on Natural Killer Cells
Curcumin can also apparently modulate the activation of natural killer (NK) cells. Studies by South and his colleagues, in rats showed that curcumin at a dose of 1 and 20 mg/kg body weight could not enhance the IgG levels in the NK cells, whereas a higher dose (40 mg/kg) did elevate IgG levels significantly. More importantly, none of the three doses of curcumin significantly enhanced either delayed-type hypersensitivity or NK cell activity (66). The extended studies by these authors on YAC-1 and EL4 tumor cells and normal splenocytes in vitro showed that curcumin treatment exerted differential effects on cell viability and proliferation. Treatment with low-dose curcumin (1.25 μg/mL) enhanced the proliferation of YAC-1 cells but not that of either splenocytes or EL4 cells (66). A similar differential effect has been reported on NK cells by curcumin and it was linked to its ability to upregulate Th1 and NO production (65). In yet another study, curcumin treatment retarded the proliferation of splenic lymphocytes, cytotoxic T lymphocytes (CTLs), lymphokine-activated killer (LAK) cells, and macrophages (67). In one of the investigations, curcumin has been found to augment NK-cell cytotoxicity (51). All these studies indicate that curcumin acts like a good immunomodulatory agent.
In addition to its immunomodulation of normal NK cells, curcumin could also increase cell death of refractory natural killer/T-cell lymphoma (NKTL) cell lines (i.e., NKL, NK-92, and HANK1), which are resistant to other therapies. This was directly linked to the suppression of the NF-κB activation including the constitutively expressed NF-κB and also blockage of Bcl-xL, cyclin D1, XIAP, and c-FLIP expression and the subsequent cleavage and activation of caspase-8 and poly (ADP-ribose) polymerase (68). These observations indicate its potential as an antiproliferative agent that could play an important and decisive role in cancer chemotherapy.
Effect of Curcumin on Dendritic Cells
Dendritic cells are professional antigen-presenting cells that play a key role as immune sentinels in the initiation of T-cell responses to microbial pathogens, tumors, and inflammation (69, 70). Peripheral DCs are generally immature both phenotypically and functionally (71). They nevertheless have clinical potential as cellular adjuvants in the treatment of chronic infectious diseases and tumors (72). There is only one report to date on immune modulation of murine DCs using curcumin by Kim et al., who found that curcumin significantly depressed the expression of CD80, CD86, and MHC class II antigens in GM-CSF/IL-4 stimulated DCs without affecting MHC class I antigens. They also found that curcumin efficiently blocked the LPS-induced expression of IL-12 and inflammatory cytokines including IL-1β, IL-6, and TNF-α. Curcumin treatment enhanced the Ag capturing ability of DCs via mannose receptor-mediated endocytosis. However, their Th1 and normal cell-mediated immune response was very poor. Further studies showed that treatment of DCs with curcumin before LPS stimulation completely suppressed the LPS-induced phosphorylation of MAPK and NF-κB nuclear translocation (73). The direct suppression of these activities by curcumin in DCs may lead to the attenuated T-cell-mediated immune responses by interfering with handling and presentation of antigens by DCs.
Effect of Curcumin on Other Immune Cells
Apart from affecting T cells, B cells, macrophages, and NK cells, curcumin has also been reported to affect other immune cells such as neutrophils, etc. In one of the studies, curcumin inhibited the FMLP (a chemotactic peptide) and zymosan-activated plasma (ZAP)-induced aggregation of monkey neutrophils. However, such an action was absent in serum-treated zymosan (STZ) and arachidonic acid (AA) treated neutrophils. Curcumin also blocked the production of O2 − radicals, and myeloperoxidase, in AA-, STZ-, and fmlp-stimulated cells, except lysozymes, which were mildly affected (74). The studies on Balb/c mice spleen immunized with sheep red blood cells have shown several immunostimulatory actions of curcumin including increase in total white blood cell count, circulating antibody titer, and plaque-forming cells (75). In addition, curcumin also raised bone marrow cellularity, α-esterase-positive cells, and phagocytic activity of macrophages (75).
Moreover, curcumin has been found to induce reaginic antibody in β-lactoglobulin-challenged brown Norway rats maintained on diets comprising 10% coconut oil (CO), high oleic safflower oil, safflower oil (SO), or fish oil. Curcumin also reduced the secretion of rat chymase II (RChyII) in rats fed with SO and 0.5% curcumin, indicating variable effect on the synthesis of immunoglobulin E and the degranulation of intestinal mast cells (76). Curcumin treatment has been reported to inhibit 5-hydroxyeicosatetraenoic acid in human neutrophils in one of the studies (77).
In yet another study, curcumin caused cell death by apoptosis in both normal and transformed human (HL 60) and rodent cells despite the lack of oligonucleosomal DNA fragmentation (DNA “ladder”). However, curcumin blocked HL-60 in sub-G1 and increased caspase-3 activity (78). These results indicate that curcumin exerts its immunomodulatory action on other immune cells described earlier.
EFFECT OF CURCUMIN ON IMMUNE CYTOKINES
Effect of Curcumin on Expression and Action of TNF/TRAIL and Their Receptors
Cytokines are autocrine, paracrine, and acrine cell signaling molecules that play a crucial role in acquired as well as innate immunity. TNF-α is one of the most versatile pleiotropic cytokine that induces growth stimulation as well as inhibition by self-regulatory mechanisms of its own and plays a crucial role as an immunostimulant and mediator of host resistance to many infectious agents. Curcumin exerts its profound effects on various cytokines of the TNF superfamily. Curcumin can modulate the expression of both TNF and TNF-induced signaling and can also inhibit LPS-induced expression of TNF-α (79–81). It has also been reported to inhibit LPS or PMA-induced TNF-α in dendtritic cells, macrophages, monocytes, alveolar macrophages, and endothelial and bone marrow cells (73, 82, 83). An almost identical observation has been made in rats, where curcumin treatment attenuated TNF-α in sodium taurocholate-induced acute pancreatitis (84).
In another study, curcumin treatment blocked the expression of TNF-α mRNA in the rat model of hemorrhage and resuscitation (85). Studies by Siddiqui et al., on septic rats revealed that curcumin treatment both before and after the onset of sepsis could reduce tissue injury, mortality, and decrease TNF-α expression (86). The analysis of molecular pathways revealed that curcumin restores PPAR-γ expression in the liver of septic rats within 20 h. Similar results were obtained in endotoxin-treated cultured RAW 264.7 cells, where curcumin suppressed endotoxin-indued TNF-α expression and markedly elevated PPAR-γ expression (86).
Experiments on HT29 intestinal epithelial cells (IECs) stimulated with TNF-α and IL-1β, showed that curcumin can block the binding of Shiga-like toxins (Stx) to IECs by inhibiting Gb3 synthase (GalT6) mRNA expression (83). In another set of experiments, three major active principles namely, 1,7-bis (4-hydroxyphenyl)-1,4,6-heptatrien-3-one, procurcumenol, and epiprocurcumenol isolated from the crude methanol extract of the rhizomes of Curcuma zedoaria were reported to suppress the production of TNF-α in LPS-stimulated macrophages (87). These studies suggest that antiinflammatory activity of curcumin could well be correlated to its ability to inhibit inflammatory cytokines at protein as well as mRNA levels.
TNF-related apoptosis-inducing ligand (TRAIL) is another member of TNF superfamily that has been found to be markedly influenced by curcumin treatment in various investigations. Experiments conducted on the androgen-sensitive human prostate cancer cell line LNCaP have shown that curcumin increases cell death-promoting activity of TRAIL by inducing DNA fragmentation even though neither agent alone is significantly cytotoxic to LNCaP cells at low concentrations (10 μM curcumin and 20 ng/mL TRAIL). Further analysis of molecular mechanisms showed that combination treatment resulted in cleavage of procaspase-3, procaspase-8, and procaspase-9; truncation of Bid, and release of cytochrome c from the mitochondria (88, 89) and could be responsible for the observed increase in cytotoxicity.
Another study has reported the effect of curcumin on death receptor DR5 (DR5/TRAIL-R2) in Caki, HCT 116, HT 29, HepG2, and Hep 3B cells. This study clearly demonstrated that curcumin and TRAIL treatment synergistically increased the death of TRAIL-resistant Caki cells in a curcumin concentration-dependent manner, which could be directly correlated to the upregulated expression of DR5 and proapoptotic gene, C/EBP homologous protein (CHOP), at both the mRNA and protein levels in HCT 116, HT29, and HepG2 cell lines after curcumin treatment. This upregulation of DR5 and CHOP and cytotoxic effect of curcumin were due to its ability to generate ROS (90, 91). The combination studies on curcumin and TRAIL point that curcumin enhances the effect of TRAIL and could make TRAIL-resistant cells amenable to TRAIL therapy.
Effect of Curcumin on Interleukins
Interleukins are a group of cytokines that are secreted by leukocytes and act as communication channels between them. Curcumin can also alter the expression and activity of a variety of interleukins, especially IL-1, IL-2, IL-6, IL-8, IL-10, and IL-12 and thus can influence functions of different cells in a variety of ways (Table II). For example, treatment of PMBCs with curcumin inhibited LPS-induced IL-1β, IL-6, and TNF-α. Similarly, in rabbit experiments, curcumin reduced LPS-induced fever by attenuating the expression of IL-1β, IL-6, and TNF-α in the serum (81). This action of curcumin was mediated by suppression of NF-κB activation and downstream events that blocked these cytokines (81). Curcumin reportedly reduced PMA- or LPS-stimulated production of IL-1 and IL-8 in human peripheral blood monocytes and alveolar macrophages in a concentration- and time-dependent manner (79). A similar effect was observed for IL-2 production in PHA-stimulated human PMBCs (51).
In endothelial cell-based experiments, curcumin significantly retarded the transcriptional upregulation of IL-1α and TNF-α-induced HO-1 (an inducible form of hemeoxygenase that is upregulated in oxidant and inflammatory settings) mRNA (92). Curcumin can also reportedly block the activity of interleukin-1 (IL-1) receptor-associated kinase (IRAK) thiols in murine EL4 thymoma cells. It also abrogates the recruitment of IRAKs to the IL-1RI followed by the phosphorylation of IRAK and IL-1RI-associated proteins (93). In other studies, the production of IL-8 was abolished by curcumin in a dose and time-dependent fashion (93, 94). In experiments with SV40-transformed embryonic (WI-38 VA13) cells, dendritic cells and sodium taurocholate-induced pancreatitic rats, curcumin was able to arrest the expression of IL-6 (73, 84, 95). The studies conducted on IEC-6, HT-29, and Caco-2 cells showed that curcumin treatment represses the IL-1β-mediated ICAM-1 and IL-8 gene expression (96) and this action of curcumin was a result of suppression of NF-κB activation, RelA nuclear translocation, IκBα degradation, IκB serine 32 phosphorylation, and IκB kinase activity (96).
In still another study, curcumin depressed IL-2 synthesis in Con A-, PHA-, and PMA-stimulated human splenocytes in a concentration-dependent manner by blocking NF-κB activation (49). Similarly, curcumin successfully blocked the IL-1β-stimulated IL-8 gene expression in human bone marrow stromal cells (97). A study on a rat model of hemorrhage and resuscitation reported that curcumin treatment suppresses the production of multiple mRNA transcripts of IL-1α, IL-β, IL-2, IL-6, and IL-10 at 2 and 24 h after hemorrhage/resuscitation and this action is mediated through the inhibition of NF-κB activation and AP-1 (85). In another study, curcumin was found to exert a repressive effect on IL-12 p40 promoter activation in RAW264.7 monocytic cells transfected with p40 promoter/reporter constructs by blocking the activation of NF-κB (98). Similarly, curcumin pretreatment significantly suppressed IL-12 production and Th1 cytokine profile (i.e., decreased IFN-γ and increased IL-4 production) in CD4+ T cells stimulated with either LPS or heat-killed Listeria monocytogenes and ability of macrophages to induce IFN-γ (99). These studies show that one of the most important mechanisms of immunoregulation by curcumin is suppression of activation of NF-κB.
Effect of Curcumin on Toll-Like Receptors
Toll-like receptors (TLRs) are, type I transmembrane proteins that are key regulators of innate and adaptive immune responses in mammals that can recognize distinct pathogen-associated molecular signatures (100). A few studies have reported the influence of curcumin on TLRs. In one such study with Ba/F3 cells, curcumin abated LPS-induced IRF3 activation and LPS-induced TLR4 signaling by arresting both myeloid differentiation factor 88 (MyD88)- and the TIR domain containing adaptor inducing IFN-β (TRIF)-dependent pathways. However, curcumin could not abrogate the IRF3 activation in 293T cells caused by increased expression of TRIF, indicating that curcumin also targets the TLR4 receptor complex in addition to IKKβ (101). In studies using peritoneal mesothelial cells from C3H/HeN mice, curcumin has been shown to suppress lipid A-induced NF-κB, MCP-1, and MIP-2 mRNA, implying its role in TLR4 signaling (102). In still another experiment, treatment of C3H/HeN mouse splenic macrophages with curcumin was found to abrogate LPS-induced mRNA expression of TLR2 and block NF-κB activation (103). Studies on TLRs indicate that immunomodulatory activity of curcumin may also be due to its ability to target TLRs.
Effect of Curcumin on Chemokines
Chemokines are small, chemotactic cytokines, which direct leukocyte migration, activate inflammatory responses, and help regulate tumor growth. A number of studies in various study systems have confirmed curcumin’s potential to suppress various chemokines. In experiments with human pancreatic carcinoma cell lines, curcumin abated the constitutive production of IL-8 while raising the expression of IL-8 receptors CXCR1 and CXCR2 (93). Similarly, in human colorectal cancer cells, curcumin blocked in a time- and dose-dependent manner the IL-1β-stimulated and neurotensin receptor-induced expression of IL-8 (94). In other studies, curcumin blocked the expression of IL-6 in WI-38 VA13 and dendritic cells and also in sodium taurocholate-induced acute pancreatitis in rats (73, 84, 95, 96). The studies by Mendez-Samperio et al., on Mycobacterium bovis Calmette-Guerin (BCG)-stimulated human monocytes reported that curcumin abated BCG-induced IL-8 secretion by blocking nuclear translocation of NF-κB (104).
Curcumin reportedly arrests the expression of the chemokines MCP-1 (105) and interferon-inducible protein-10 kDa (IP-10) in mouse bone marrow stromal cells. This effect is apparently mediated by curcumin’s ability to prevent TNF, IL-1, and LPS-induced expression of MCP-1 and IP-10 mRNA, and it is completely reversible within 24 h after removing curcumin from the cell culture medium. The inhibition of AP-1 and NF-κB activation are responsible for this activity of curcumin (106, 107).
Studies on human gingival fibroblasts have shown that curcumin impedes the chemotactic activity of monocytes isolated from the culture supernatant of Porphyromonas gingivalis LPS (P-LPS)-treated cells (108). This effect of curcumin seems to be mediated by blocking the P-LPS-induced expression of MCP-1 gene and AP-1 and NF-κB activation in human gingival fibroblasts (108). Experiments by Kobayashi et al. have shown that curcumin arrests in a concentration-dependent manner the proliferation of lymphocytes from common house dust mite (Dermatophagoides jhrinea) atopic asthmatics and also their ability to secrete IL-2, IL-5, GM-CSF, and IL-4 (109). The immunomodulatory activity of curcumin may also be due to its ability to alter chemokine expression as indicated earlier.
Effect of Curcumin on Adhesion molecules
Experiments on human umbilical vein endothelial cells demonstrated that curcumin blocks the steady-state transcription of ICAM-1, VCAM-1, and E-selectin both temporally and reversibly (110).
EFFECT OF CURCUMIN ON INFLAMMATORY ENZYMES
Curcumin can markedly influence the activities of enzymes that are hallmark of inflammation and subsequently various disease states in humans (Table III). Curcumin can differentially block inflammatory enzymes involved in inflammation and extracellular matrix degradation at both the mRNA and protein levels (111–127). In several murine studies, curcumin has been shown to abate TPA-induced epidermal inflammation, and inhibit epidermal lipooxygenase and cyclooxygenase (COX) activities in dose-dependent fashion by downregulating TPA-induced NF-κB activation (111–113). Another study has also reported suppression of TPA-induced COX-2, prostaglandin E2 (PGE2), and MMP-9 expression. This was in direct correlation with the inhibition of ERK1/2 phosphorylation and NF-κB activation (114). A similar effect has been reported in Colo 205 colon carcinoma cells, where curcumin reduced COX-2, PGE2, matrix metalloproteinase (MMP)-2, COX-1, and MMP-9 levels, but had no effect on MMP-7 levels (115). Other studies have reported that curcumin blocked the expression of COX-2 mRNA (116, 117) but had no effect on COX-1 mRNAs (116). Plummer et al. observed that curcumin suppressed the protein levels of LPS-induced COX-2 and PGE2 in human leucocytes in a dose-dependent manner (118). A similar effect was reported in A549 human lung epithelial cells, where curcumin inhibited IL-1β or IFN-α-induced prostaglandin E2 and cyclooxygenase-2 at both the protein and the mRNA levels (119, 120). In rats with TNBS-induced colitis, curcumin blocked the expression of COX-2 and inflammatory cytokines while increasing PGE2 levels (121). Various studies on human lung epithelial cells exposed to cigarette smoke have shown that curcumin inhibited NNK-induced activation of NF-κB and COX-2 expression (122, 123). Similarly, in HaCaT cells, curcumin abolished UVB-induced COX-2 expression by suppressing p38 MAPK and JNK activity (124).
In human colon epithelial cells, curcumin arrested the TNF-α, and fecapentaene-12-induced COX-2 by blocking NF-κB activation and IKK activity (125). A similar effect has been observed in HT-29 colon cancer cells, where curcumin arrested the mRNA and protein expression of COX-2 but not of COX-1 (126). Studies on LPS-stimulated RAW-264.7 cells indicate that curcumin reduces COX-2 expression, PGE2 formation, and the catalytic activities of 5-LOX (127).
The studies on mouse peritoneal exudates have revealed that low-dose curcumin reduces LPS- and IFNγ-induced NO production, whereas higher doses do not (128). In another investigation, curcumin reduced the production of iNOS mRNA in cultured BALB/c mouse peritoneal macrophages ex vivo in a concentration-dependent manner and also iNOS mRNA expression in the livers of mice receiving two oral doses of 0.5 mL of a 10-μM curcumin (92 ng/g of body weight) and LPS (129). Similarly, in studies using activated macrophages, low-dose curcumin inhibited NO production at 24 h (IC50 of 6 μM) and 10 μM curcumin also reduced NOS activity than noncurcumin-treated activated macrophages (130). In another study, curcumin has been reported to reduce LPS-induced NO production in mouse macrophages (51). These studies affirm that curcumin acts as a strong antiinflammatory agent.
EFFECT ON CURCUMIN ON TRANSCRIPTION FACTOR NF-κB
The nuclear factor NF-κB is a ubiquitous transcription factor important for its pleiotropic effects, inducible expression patterns, unique regulatory mechanisms, and involvement in a large number of signaling and gene expression pathways (Table III). The activation of NF-κB is crucial to innate and adaptive immunity and it plays an important role in inflammation, autoimmune diseases, and cancer. As shown in a seminal study performed in our laboratory, curcumin abrogates NF-κB activation induced by TNF-α, PMA, or H2O2, by blocking the phosphorylation of IKKα (131). Moreover, our studies on tobacco smoke-induced NF-κB activation in myeloblastic and mantle cell lymphoma cells revealed that curcumin blocks NF-κB activation by inhibiting the phosphorylation and degradation of IκBα (132). Curcumin also reportedly abrogates LPS-induced MAPK activation and the translocation of NF-κB p65 in DCs (73). In several other experiments, curcumin has been reported to downregulate IL1 or TNF-α or LPS-induced NF-κB activation (51, 99, 133, 134). A study with A549 cells has reported that the ability of curcumin to arrest NF-κB binding activity is reversible within 30 min after IFN-α administration (134). In studies on LNCaP cancer cells, curcumin mediated TRAIL-induced apoptosis by blocking IκBα phosphorylation and degradation and subsequently abrogated NF-κB activation (88, 89). The studies with NCTC 2544 keratinocytes have shown that curcumin can inhibit UVB-induced TNF-α, IL-6, and IL-8 by impeding NF-κB activation (135).
The studies with WI-38 VA13 cells have revealed that curcumin can also inhibit the degradation of IκBα upstream and subsequent NF-κB DNA-binding activity and NF-κB-dependent expression of IL-6 downstream (95). Curcumin treatment also repressed NF-κB and Ap-1 activation induced by hemorrhage/resuscitation injury in rats (85). Similar to this, curcumin has also been found to arrest the TPA-induced NF-κB activation by attenuating the degradation of IκBα and the subsequent translocation of the p65 subunit in cultured HL-60 cells. Alternatively, curcumin also repressed the TPA-induced activation of NF-κB through direct interruption of the binding of NF-κB to its consensus DNA sequences (136). The experiments on EC-6, HT-29, and Caco-2 cells revealed that curcumin blocks cytokine-induced NF-κB DNA binding activity, RelA nuclear translocation, IκBα degradation, IκB serine 32 phosphorylation, and IKK activity (96).
Furthermore, as already mentioned earlier, curcumin can prevent and treat wasting and histopathologic symptoms associated with TNBS-induced intestinal inflammation by simultaneously blocking NF-κB activation, degradation of cytoplasmic IκBα protein, and cytokine mRNA expression (137). The experiments on mouse splenic macrophages have shown that high-dose curcumin can abrogate LPS-mediated TLR2 mRNA induction by inhibiting NF-κB activation (102, 103). The studies by Watanabe et al. have shown that curcumin can also arrest BCG-induced IL-8 production in human monocytes and gingival fibroblasts by inhibiting NF-κB activation (108). Finally, curcumin abolished constitutive activation of NF-κB in HTLV-1 infected T-cell lines and primary ATL cells, by inhibiting phosphorylation of IκBα and Tax-induced NF-κB transcriptional activity (55). The various studies outlined earlier indicate that suppression of NF-κB activity may be one of the most important properties of curcumin that could be responsible for its various immune functions.
EFFECT OF CURCUMIN ON IMMUNE DISEASES
Because of its ability to modulate immune cells and immune cell cytokines, curcumin has been shown to affect several autoimmune diseases (Fig. 3). Inflammation is a critical feature of most autoimmune diseases. Thus, the role of curcumin in the therapy of such disorders is expected.
Immune diseases that may be potentially treated with curcumin.
Alzheimer’s Disease
Several reports suggest that curcumin has potential against Alzheimer’s disease (138–141), a disease characterized by the amyloid-induced inflammation in the brain. The effect of curcumin in Alzheimer’s disease is mediated through the downmodulation of cytokine (i.e., TNF-α and IL-1β) and chemokine (i.e., MIP-1b, MCP-1, and IL-8) activity in peripheral blood monocytes and reduces amyloid-β plaque formation (138–141).
Multiple Sclerosis
There are reports that curcumin may have potential against multiple sclerosis, another autoimmune disease. In animal model of this disease, curcumin was found to inhibit IL-12-induced tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4 transcription factors (142).
Cardiovascular Diseases
Curcumin has established antioxidant and antiinflammatory activities that offer promise in the treatment of cardiovascular diseases. For example, it can inhibit lipid peroxidation; reduce creatinine kinase and lactate dehydrogenase levels; and restore reduced glutathione, glutathione peroxidase, and superoxide dismutase to normal levels. Curcumin can also downregulate the expression of myocardial TNF-α and MMP-2 and upregulate the expression of eNOS mRNA (143–147).
Diabetes
In diabetes, curcumin can suppress blood glucose levels, increase the antioxidant status of pancreatic β-cells, and enhance the activation of PPAR-γ (148–153).
Allergy
As shown in experiments in vivo (in guinea pigs) and in vitro (rat basophilic leukemia cells), curcumin can help clear constricted airways and increase antioxidant levels (154, 155).
Asthma
That curcumin can relieve symptoms of asthma, has been reported. These effects are linked with reduction of the lymphocytic production of IL-2, IL-5, GM-CSF, and IL-4 that is associated with bronchial asthma (110, 154).
Inflammatory Bowel Disease
As shown in vivo in humans and rats, curcumin can ameliorate inflammatory bowel disease by reducing inflammatory cytokine levels, blunting NO and O2 production, and suppressing NF-κB activation in colon epithelium (156, 157).
Rheumatoid Arthritis
In rheumatoid arthritis, curcumin exerts beneficial effects by inhibiting the expression of collagenase and stromelysin and the proliferation of synoviocytes (158, 159).
Renal Ischemia
In renal ischemia, curcumin can exert beneficial effects that include reducing creatine levels; upregulating MnSOD levels; and inhibiting the expression of RANTES, MCP-1, and allograft inflammatory factor (160, 161).
Psoriasis
Clinical evaluation of topical application of 1% curcumin gel in psoriatic areas reduced the density of CD8+ T cells when compared to untreated areas, where density of CD8+ T cells showed an elevation (162). This and other studies suggest that curcumin treatment could be an effective paradigm in the treatment of psoriasis as it could also reduce the activity of phosphorylase kinase (163).
Scleroderma
Because scleroderma is a disease that involves excessive collagen deposition and hyperproliferation of fibroblasts, curcumin may be able to provide a therapeutic benefit through its ability to suppress the proliferation of lung fibroblasts in a process involving the inhibition of protein kinase Cε (164).
Acquired Immunodeficiency Disease (AIDS)
There are several reports indicating that curcumin may have potential against AIDS. These effects of curcumin are mediated through suppression of replication of human immunodeficiency virus (HIV) by inhibition of HIV long terminal repeat (165, 166) and HIV protease (167), inhibits HIV-1 integrase (168, 169), inhibits p300/CREB-binding protein-specific acetyltransferase, and represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription (170). Thus, curcumin has a great potential also against AIDS.
CONCLUSIONS
The curcumin, an orange-yellow polyphenol present in curry spice, Curcuma longa has a long history of therapeutic use in the Ayurvedic and Chinese systems of medicine. The wisdom and scientific credentials of this approach have been corroborated by numerous studies conducted over the past 30 years. Indeed, curcumin has been found to possess antioxidant, antiinflammatory, anticancer, and several other activities listed in this review. Mechanistic studies have not only confirmed beyond doubt that curcumin employs multiple pathways to leave its imprint on biological systems, but also warrants its potential use as a modern nontoxic chemotherapy for numerous disorders. Curcumin primarily exerts its therapeutic effects by inhibiting the degradation of IκBα and subsequent inactivation of NF-κB, thus initiating a cascade of downstream inflammatory and immunogenic events. Curcumin’s inhibition of NF-κB activation, in turn, leads directly to the inhibition of expression of a number of proinflammatory cytokines (e.g., TNF, IL-1, IL-2, IL-6, IL-8, and IL-12) and downregulation of the mRNA expression of several proinflammatory enzymes (e.g., COX, LOX, MMPs, and NOS). In addition, curcumin’s immunogenic response is further enhanced by its ability to inhibit TLRs, Finally, curcumin exerts proimmune activity in several autoimmune disorders including Alzheimer’s disease, multiple sclerosis, cardiovascular disease, diabetes, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis, renal ischemia, psoriasis, and scleroderma. Overall, these findings suggest that curcumin warrants further consideration as a potential immunoregulatory treatment in various immune disorders.
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ACKNOWLEDGMENTS
We would like to thank Walter Pagel for carefully proofreading the manuscript and providing valuable comments. Dr. Aggarwal is a Ransom Horne, Jr., Professor of Cancer Research. This work was supported by a grant from the Clayton Foundation for Research (to B. B. A.), National Institutes of Health PO1 grant CA91844 on lung chemoprevention (to B. B. A.), National Institutes of Health P50 Head and Neck SPORE grant P50CA97007 (to B. B. A); and a core grant (CA16672).
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Jagetia, G.C., Aggarwal, B.B. “Spicing Up” of the Immune System by Curcumin. J Clin Immunol 27, 19–35 (2007). https://doi.org/10.1007/s10875-006-9066-7
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DOI: https://doi.org/10.1007/s10875-006-9066-7