ReviewImmunomodulatory and therapeutic activity of curcumin
Introduction
Turmeric is a mixture of compounds related to curcumin known as curcuminoids consisting of curcumin [i.e.diferuloylmethane or 1,7-bis (4-hydroxy-3-methoxy-phenyl) hepta-1, 6-diene-3, 5-dione)] as the major component, demethoxycurcumin, bisdemethoxycurcumin and cyclocurcumin [1] (Fig. 1). Curcumin has been in use for its medicinal benefits since centuries but the first documented case of its use as a drug emerged only in 1937 when it was utilized to treat biliary disease. Since then its therapeutic potential has been explored in inflammatory diseases, neoplastic disease, cardiovascular and neurodegenerative disease, diabetes, cystic fibrosis and other disorders. Due to a vast number of biological targets and virtually no side effects, curcumin has achieved the potential therapeutic interest to cure immune related, metabolic diseases and cancer [2], [3], [4], [5], [6], [7] (Table 1). Majority of the studies suggested that the biological effects of curcumin are mainly derived from its ability to either bind directly to various proteins such as cyclooxygenase-2 (COX-2), lipoxygenase, GSK3b and several other regulatory enzymes or by its ability to modulate intracellular redox state [1], [8], [9]. Modulation of cellular redox homeostasis exerts an indirect but more global effect on a number of cellular processes, since several critical transcription factors such as activator protein 1 (AP1), nuclear factor-kappaB (NF-κB), nuclear factor of activated T cells (NF-AT), p53 etc. are sensitive to even minor fluctuations in the cellular redox milieu [10], [11]. These transcription factors in turn control cell cycle, differentiation, stress response and other physiological processes [12], [13], [14], [15]. The intricate mechanism of action of curcumin involves various biological targets viz transcription factors: NF-AT, AP-1, signal transducers and activator of transcription (STAT), p53 and kinases: mitogen-activated protein kinases, cytokines release, and the receptors found on different immune cell type. These actions of curcumin greatly affect the innate and adaptive arms of immunity, especially in the pathological conditions. Curcumin effectively modulates the function of T cells, B cells, dendritic cells (DCs), monocytes, macrophages (mφ) and neutrophils. Overwhelming reports have supported the anti-inflammatory action of curcumin and its potential role in the therapy of numerous immune cell related diseases. Although curcumin does not have a drug profile yet, the safety and non-toxic effect of oral curcumin (12 g/day) which is much higher than its regular in-take as food supplement have been established by the drug governing agency [16]. Recently, the pre-clinical and clinical studies that were conducted at different places have been reviewed [17]. However, there are certain limitations concerning the use of curcumin as a drug. Due to its insolublility in water, curcumin has very poor bioavailability, its cellular uptake is slow and it gets metabolized very fast once inside the cell. Therefore it requires repetitive oral doses in order to achieve significant concentration inside the cells for any physiological effects. To address these limitations a large number of curcumin analogues have been prepared that have shown improved uptake, metabolism and activity.
In this review we discuss the effect and applications of curcumin across a spectrum of pathological conditions involving immune cells, metabolic targets and diseases.
Section snippets
Immunomodulatory action of curcumin on T lymphocytes
Sikora et al. demonstrated that the mitogen concanavalin A (ConA) stimulated and the spontaneous proliferation of rat thymocytes could be inhibited by curcumin (50 μM) and similar anti-proliferative effects of curcumin on ConA-stimulated Jurkat T cell line were also reported. In contrast, the similar dose of curcumin could protect rat thymocytes and Jurkat T cells from dexamethasone and ultra-violet irradiation induced apoptosis, respectively. These bimodal effects of curcumin were correlated
Immunoinhibitory action of curcumin on dendritic cells (DCs)
Being at the centre of various immunological responses, DCs control various pathogenic conditions and recently several groups have investigated the action of curcumin on DCs' function. In a detailed study Kim et al. reported for the first time that curcumin, at a dose of up to 25 μM, inhibits DC maturation and the related immunostimulatory function. They also showed that more than 50 μM concentration was toxic for DCs. Surprisingly however various studies have used 50 μM concentration in different
Immunomodulatory effect of curcumin on natural killer (NK) cells
NK cells directly participate in the killing of tumor cells after the recognition of stress inducible ligands and killing involves the induction of cell death by perforin and granzyme B. Various investigators have directly measured the NK cell activity against tumor cells both, in-vitro and in-vivo. In the initial studies, curcumin feeding (1, 20 or 40 mg/kg) up to five weeks showed no effect on the NK cell activity in rats but enhanced the antibody (Ab) responses in rats [43]. In another study,
Immunomodulatory effect of curcumin on monocytes and macrophages (Mϕ)
Monocyte recruitment at the inflammatory site plays a vital role in the inflammatory response. Curcumin inhibited the tumor necrosis factor α (TNF-α) induced adhesion of monocytes on human endothelial cells. The TNF-α induced upregulation of Inter-Cellular Adhesion Molecule 1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelial cell leukocyte adhesion molecule-1 (ELAM-1) on monocytes was completely inhibited by curcumin. The curcumin mediated blocking of these adhesion molecules
Immunomodulatory effect of Curcumin on B cells
Decoté-Ricardo et al. evaluated the effects of curcumin on murine spelnic B cells. LPS-induced IgM secretion as well as CpG and TLR4-induced proliferation of B cells was inhibited following curcumin treatment. However curcumin failed to exert anti-proliferative effect when the B cell prolifearion was induced by the T-independent type 2 stimuli anti-delta-dextran or by the anti-IgM Ab. Moreover curcumin (10 μM) had no effect on the calcium mobilization induced by anti-IgM (10 μg/ml) Ab.
Immunomodulatory effect of curcumin on neutrophils and eosinophils and mast cells and its anti-oxidant properties
Several independent studies have provided the evidence that curcumin can act on various aspects of neutrophil function, in a stimulus specific manner and may thus dampen the neutrophil mediated inflammatory response [69]. Chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) and zymosan activated plasma induced aggregation of the monkey neutrophils could be inhibited by the curcumin (1 mM). FMLP peptide, zymosan and arachidonic acid induced production of oxygen radical was
Curcumin in health and disease
Due to the fact that curcumin has been shown to be associated with a number of physiological processes and that it has a wide variety of cellular targets, its therapeutic role has been studied in several inflammatory and non-inflammatory disorders. In this section, we discuss most recent findings related to its direct application in health and disease.
Concluding remarks and future perspectives
Immunomodulatory properties of curcumin are mostly immunosuppressive, but in some cases immunostimulative effects have been reported. Although studies with inflammatory disease might direct the investigators towards the exploration of only immunosuppressive properties of curcumin, caution shall be exercised regarding the immunostimulative effect of curcumin. Due to the potent neoplastic, anti-inflammatory and immunoactivating properties, studying the mechanism of the action of curcumin is an
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