Review
Immunomodulatory and therapeutic activity of curcumin

https://doi.org/10.1016/j.intimp.2010.08.014Get rights and content

Abstract

Inflammation is a disease of vigorous uncontrolled activated immune responses. Overwhelming reports have suggested that the modulation of immune responses by curcumin plays a dominant role in the treatment of inflammation and metabolic diseases. Observations from both in-vitro and in-vivo studies have provided strong evidence towards the therapeutic potential of curcumin. These studies have also identified a plethora of biological targets and intricate mechanisms of action that characterize curcumin as a potent ‘drug’ for numerous ailments. During inflammation the functional influence of lymphocytes and the related cross-talk can be modulated by curcumin to achieve the desired immune status against diseases. This review describes the regulation of immune responses by curcumin and effectiveness of curcumin in treatment of diseases of diverse nature.

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

References (153)

  • L. Xie et al.

    Amelioration of experimental autoimmune encephalomyelitis by curcumin treatment through inhibition of IL-17 production

    Int Immunopharmacol

    (2009)
  • D.O. Moon et al.

    Curcumin attenuates inflammatory response in IL-1beta-induced human synovial fibroblasts and collagen-induced arthritis in mouse model

    Int Immunopharmacol

    (2010)
  • I.D. Jung et al.

    COX-2 and PGE2 signaling is essential for the regulation of IDO expression by curcumin in murine bone marrow-derived dendritic cells

    Int Immunopharmacol

    (2010)
  • G. Kang et al.

    Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression by inhibiting activator protein 1 and nuclear factor kappab bindings in BV2 microglial cells

    J Pharmacol Sci

    (2004)
  • Y.I. Jeong et al.

    Curcumin suppresses the induction of indoleamine 2, 3-dioxygenase by blocking the Janus-activated kinase-protein kinase Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells

    J Biol Chem

    (2009)
  • S. Bhaumik et al.

    Differential modulation of nitric oxide production by curcumin in host macrophages and NK cells

    FEBS Lett

    (2000)
  • H.G. Zhang et al.

    Curcumin reverses breast tumor exosomes mediated immune suppression of NK cell tumor cytotoxicity

    Biochim Biophys Acta

    (2007)
  • A. Kumar et al.

    Curcumin (Diferuloylmethane) inhibition of tumor necrosis factor (TNF)-mediated adhesion of monocytes to endothelial cells by suppression of cell surface expression of adhesion molecules and of nuclear factor-kappaB activation

    Biochem Pharmacol

    (1998)
  • Y. Abe et al.

    Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages

    Pharmacol Res

    (1999)
  • J.H. Lim et al.

    Curcumin inhibits phorbol myristate acetate (PMA)-induced MCP-1 expression by inhibiting ERK and NF-kappaB transcriptional activity

    Food Chem Toxicol

    (2010)
  • K. Bisht et al.

    Curcumin enhances non-inflammatory phagocytic activity of RAW264.7 cells

    Biochem Biophys Res Commun

    (2009)
  • A.N. Kim et al.

    Up-regulation of heme oxygenase-1 expression through CaMKII-ERK1/2-Nrf2 signaling mediates the anti-inflammatory effect of bisdemethoxycurcumin in LPS-stimulated macrophages

    Free Radic Biol Med

    (2010)
  • D. Decote-Ricardo et al.

    Modulation of in vitro murine B-lymphocyte response by curcumin

    Phytomedicine

    (2009)
  • D. Ranjan et al.

    Enhanced apoptosis mediates inhibition of EBV-transformed lymphoblastoid cell line proliferation by curcumin

    J Surg Res

    (1999)
  • V. Jancinova et al.

    Decreased activity of neutrophils in the presence of diferuloylmethane (curcumin) involves protein kinase C inhibition

    Eur J Pharmacol

    (2009)
  • D.O. Moon et al.

    Curcumin attenuates ovalbumin-induced airway inflammation by regulating nitric oxide

    Biochem Biophys Res Commun

    (2008)
  • J.H. Lee et al.

    Curcumin, a constituent of curry, suppresses IgE-mediated allergic response and mast cell activation at the level of Syk

    J Allergy Clin Immunol

    (2008)
  • C.H. Yeh et al.

    Inhibition of NFkappaB activation with curcumin attenuates plasma inflammatory cytokines surge and cardiomyocytic apoptosis following cardiac ischemia/reperfusion

    J Surg Res

    (2005)
  • A.L. Berger et al.

    Curcumin stimulates cystic fibrosis transmembrane conductance regulator Cl channel activity

    J Biol Chem

    (2005)
  • C.J. Sherr

    D-type cyclins

    Trends Biochem Sci

    (1995)
  • A. Khar et al.

    Antitumor activity of curcumin is mediated through the induction of apoptosis in AK-5 tumor cells

    FEBS Lett

    (1999)
  • J.A. Bush et al.

    Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53

    Exp Cell Res

    (2001)
  • S. Pal et al.

    Mechanisms of curcumin-induced apoptosis of Ehrlich's ascites carcinoma cells

    Biochem Biophys Res Commun

    (2001)
  • N.R. Jana et al.

    Inhibition of proteasomal function by curcumin induces apoptosis through mitochondrial pathway

    J Biol Chem

    (2004)
  • S.H. Jee et al.

    Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells

    J Invest Dermatol

    (1998)
  • K. Piwocka et al.

    A novel apoptosis-like pathway, independent of mitochondria and caspases, induced by curcumin in human lymphoblastoid T (Jurkat) cells

    Exp Cell Res

    (1999)
  • D. Morin et al.

    Curcumin induces the mitochondrial permeability transition pore mediated by membrane protein thiol oxidation

    FEBS Lett

    (2001)
  • W. Wongcharoen et al.

    The protective role of curcumin in cardiovascular diseases

    Int J Cardiol

    (2009)
  • S. Singh et al.

    Biological effects of curcumin and its role in cancer chemoprevention and therapy

    Anticancer Agents Med Chem

    (2006)
  • M.E. Egan et al.

    Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects

    Science

    (2004)
  • M. Mall et al.

    Correction of the CF defect by curcumin: hypes and disappointments

    Bioessays

    (2005)
  • M. Fiala et al.

    Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin

    Proc Natl Acad Sci USA

    (2007)
  • C.H. Hsu et al.

    Clinical studies with curcumin

    Adv Exp Med Biol

    (2007)
  • S. Miriyala et al.

    Cardioprotective effects of curcumin

    Adv Exp Med Biol

    (2007)
  • S.P. Weisberg et al.

    Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity

    Endocrinology

    (2008)
  • J. Hong et al.

    Modulation of arachidonic acid metabolism by curcumin and related beta-diketone derivatives: effects on cytosolic phospholipase A(2), cyclooxygenases and 5-lipoxygenase

    Carcinogenesis

    (2004)
  • V.J. Bykov et al.

    Mutant p53 rescue and modulation of p53 redox state

    Cell Cycle

    (2009)
  • K. Sabapathy et al.

    Regulation of ES cell differentiation by functional and conformational modulation of p53

    EMBO J

    (1997)
  • E. Shaulian et al.

    AP-1 in cell proliferation and survival

    Oncogene

    (2001)
  • E. Shaulian et al.

    AP-1 as a regulator of cell life and death

    Nat Cell Biol

    (2002)
  • Cited by (0)

    View full text