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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.
Review
Immunomodulatory and therapeutic activity of curcumin
Raghvendra M. Srivastava
a
, Sarvjeet Singh
b
, Shiv K. Dubey
c
, Krishna Misra
d
, Ashok Khar
e,
a
Department of Otolaryngology, Hillman Cancer Centre, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
b
Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
c
Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
d
Division of Bioinformatics, Indian Institute of Information Technology, Allahabad, India
e
CMBRC, Apollo Hospitals Educational and Research Foundation, Apollo Health City, Jubilee Hills, Hyderabad 500033, India
abstractarticle info
Article history:
Received 1 July 2010
Accepted 22 August 2010
Available online 8 September 2010
Keywords:
Curcumin
Anti-inammatory
Anti-cancerous
Immune and metabolic diseases
Inammation 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
inammation 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 identied a plethora
of biological targets and intricate mechanisms of action that characterize curcumin as a potent drugfor
numerous ailments. During inammation the functional inuence 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.
© 2010 Elsevier B.V. All rights reserved.
Contents
1. Introduction .............................................................. 331
2. Immunomodulatory action of curcumin on T lymphocytes ........................................ 332
3. Immunoinhibitory action of curcumin on dendritic cells (DCs) ...................................... 333
4. Immunomodulatory effect of curcumin on natural killer (NK) cells .................................... 334
5. Immunomodulatory effect of curcumin on monocytes and macrophages (Mϕ)............................... 334
6. Immunomodulatory effect of Curcumin on B cells ............................................ 335
7. Immunomodulatory effect of curcumin on neutrophils and eosinophils and mast cells and its anti-oxidant properties ............ 336
8. Curcumin in health and disease ..................................................... 336
8.1. Role of curcumin in the neoplastic diseases ............................................ 336
8.2. Curcumin in cardiovascular disease ................................................ 337
8.3. Curcumin in neurodegenerative disease.............................................. 338
8.4. Immunomodulatory action of curcumin in the prevention of inammatory diseases ......................... 338
9. Concluding remarks and future perspectives ............................................... 339
References ................................................................. 339
1. 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
benets since centuries but the rst 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
International Immunopharmacology 11 (2011) 331341
Abbreviations: Ag, antigen; Ab, antibody; NO, nitric oxide; LPS, lipopolysaccharide;
ConA, concanavalin A; AP-1, activator protein 1; NF-κB, nuclear factor-kappaB; NF-AT,
nuclear factor of activated T cells; PMA, phorbol 12-myristate 13-acetate; PHA,
phytohaemagglutinin; ROS, reactive oxygen species; ROIs, reactive oxygen intermedi-
ates; COX-2, cyclooxygenase-2; APC, antigen presenting cells; DCs, dendritic cells; IDO,
indoleamine 2,3-dioxygenase.
Corresponding author.
E-mail address: ashok.khar@aherf.net (A. Khar).
1567-5769/$ see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.intimp.2010.08.014
Contents lists available at ScienceDirect
International Immunopharmacology
journal homepage: www.elsevier.com/locate/intimp
inammatory diseases, neoplastic disease, cardiovascular and neuro-
degenerative disease, diabetes, cystic brosis 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 [27] (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 uctuations in the cellular redox milieu [10,11]. These
transcription factors in turn control cell cycle, differentiation, stress
response and other physiological processes [1215]. The intricate
mechanismof 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. Over-
whelming reports have supported the anti-inammatory action of
curcumin and its potential role in the therapy of numerous immune cell
relateddiseases. Although curcumin doesnot have a drug prole 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 governingagency [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. Dueto 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 signicant concentration inside
the cells for anyphysiological effects. To address theselimitations 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.
2. 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 with the suppressive effects of curcumin on
AP-1 transcription factor activation; however no effect of curcumin
was seen on AP-1 under normal conditions [18]. In contrast to the
study of Sikora et al., an independent study showed that curcumin
(50 μM) could induce cell death in the normal quiescent and
proliferating human lymphocytes through caspase-3 activation but
Fig. 1. Curcuminoids present in turmeric.
Table 1
The potential of curcumin was shown in the various diseases involving multiple mechanisms in the respective cell types.
Diseases Cell types Mechanisms of action References
Alzheimer disease Monocytic THP-1 cell line,
peripheral blood monocytes
Anti-inammtory: by blocking the amyloid peptide induced expression of TNF-α, IL-1β,
MCP-1, IL-8, MIP-1βand CCR5
[59,61]
Multiple sclerosis Th-17 producing T cells, TLR4
and TLR 9 expressing T cells.
Anti-inammatory: blocking of EAE incidences by blocking IL-6; IL-21 signaling, and the
differentiation of Th-17 producing T cells, modulation of the function of TLR-4 and TLR-9 on T
cells, blocking of IL-12 signaling
[3133]
Allergy Eosinophils, bronchoalveolar
inammatory cells, mast cells
Anti-inammatory: decreased the frequency of eosinophils and the inammatory cells by the
regulation iNOS, inhibition of the IgE and Ag-induced degranulation of mast cells.
[7577]
Arthritis Neutrophils, T cells Anti-inammatory: suppressed ROIs generation, Blocks crystal induced neutrophil activation,
suppressed arthritis Ag-induced T cell proliferation
[34,70,71]
Inammatory bowel disease Intestinal mucosal biopsies of
patients.
Suppressed pp38, suppressed pro-inammatory IL-1βand enhanced IL-10 level [151,152]
Psoriasis Keratinocytes Blocks TNF-αmediated activation of cells [153]
Inammatory cardiovascular
disorders
Myocardial tissue, endothelial
cell line
Blocks neutrophils activation. Attenuate the plasma level of IL-10, IL-8 and TNF-α. Blocks TNF-α
induced pro-inammatory responses in cell line
[78,153]
Wound healing Inlitrating Mϕs, keratinocytes,
broblasts
Anti-androgen receptor signaling activity, decreased local TNF-αlevel [58]
Inammatory type II
diabetes
Inltrating Mϕs, adipose tissue,
hepatic tissue
Reduced Mϕs frequency in the adipose tissue, reduced expression of TNF-α, MCP-1 and reduced
NF-κB activity in the hepatic tissue
[7]
332 R.M. Srivastava et al. / International Immunopharmacology 11 (2011) 331341
without DNA degradation. This study also highlighted that curcumin
affects the viability of proliferating T cells much severely than
quiescent T cells [19,20]. Furthermore Deters et al. demonstrated
that curcumin (2.810 μM) can signicantly abrogate the prolifera-
tion of peripheral blood mononuclear cells (PBMC) induced by OKT3
mAb (a human TCR/CD3 complex Ab) [21]. The concentration range of
curcumin used by Deters et al. was similar to the concentrations that
was shown to signicantly affect human T cell proliferation induced
by various distinct stimuli viz. phorbol 12-myristate 13-acetate
(PMA), CD28, phytohaemagglutinin (PHA) [22]. Although direct
suppressive effects of curcumin on superantigen induced proliferation
of T cells were demonstrated in several studies as described before,
few studies also demonstrated that T cells fail to get appropriate
amount of co-stimulatory signals from curcumin-treated Ag present-
ing cells (APCs), as curcumin (2030 μM) aborted the upregulation of
CD86 and CD83 in response to the APC maturation stimuli. This
inhibitory effect of curcumin on T cells was independent of the HLA-
DR levels on the respective APCs as the HLA-DR level was not
downregulated by the curcumin. Curcumin, however, could also
reduce the DCs' dependent allogenic CD4
+
T cell proliferation in a
mixed lymphocyte reaction assay at 1:16 ratio of DCs to T cells. In this
study a probable affect of curcumin on the cytoskeleal elements of DCs
was argued in this context, which may be attributed to its inhibitory
anti-proliferative effects [23]. Another study demonstrated a signif-
icant increase in ConA-stimulated proliferation of splenic cells at
6.25 μM curcumin and a signicant decrease in proliferation at
12.5 μM and a complete blockage of proliferation with 25 μM
curcumin, which conrmed the distinct function of curcumin at
variable concentrations. Also, curcumin irreversibly inhibited the
induction of lymphoproliferation by other mitogens and alloantigens.
As the in-vivo effects of curcumin are highly dependent on the
bioavailable concentration of curcumin, it is indeed a daunting agenda
to correlate the in-vitro activities of curcumin and in-vivo responses in
the pathological conditions, especially in the localized pathological
conditions like non-metastatic tumors of different origins [24].As
highlighted in the review so far, a variety of results indicated the in-
vitro T cell immunosuppressive properties of curcumin in terms of T
cell death, as well as blocking the proliferation capacity of T cells.
Nevertheless curcumin has been in use since centuries and its
consumption has not been associated with any immunocompromised
disorders; seriously arguing the signicance of its immunosuppres-
sive properties on T cells that have been reported under in-vitro
conditions. We had demonstrated that T cells that were harvested
from the curcumin-injected (40 mg/kg/day; i.p) animals showed
enhanced lymphoproliferation and a similar proliferative effect of
curcumin was also observed when T cells were stimulated with ConA
and PHA in conjunction with curcumin. Our study also provided
evidence of specic lymphoproliferative effect of curcumin in-vivo,by
using cyclosporine A, a potent immunosuppressant drug. Interesting-
ly, the enhanced Antigen (Ag)-specic T cell proliferation was also
observed in curcumin-injected rats that had received a highly
immunogenic AK-5 histiocytoma cells as a source of tumor Ag [25].
The evidence for the enhanced frequency of CD4
+
T cells was
furthermore reported in another spontaneously generated tumor
model of adenoma in C57BL/6J-Min/+ (Min/+) mouse that were fed
with 0.1% dietary curcumin. In a statistically controlled lymphocyte
inltration setup, this study reported an enhanced number of CD8
+
,
CD4
+
and CD3
+
T cells in the curcumin fed animals. In this model the
spontaneous polyp formation in the mucosa was signicantly reduced
by the curcumin administration and the anti-tumor mechanism was
correlated with the enhanced cytokine level due to the increased
number of activated CD4
+
T cells, although no direct evidence for
such a conclusion was described in this study. Also, this study showed
enhanced level of B cells in the intestinal mucosa, but no role or
increase in the number of monocytes was found in this spontaneous
tumor model system [26]. In another elegant tumor model, in which
tumor growth could disintegrate the thymus morphology, curcumin
(50 mg/kg body weight) restored the thymic integrity including CD3
+
T cell frequency and served as immunoprotective compound during
carcinogenesis. This effect of curcumin was attributed mechanistically
to the anti-oxidant properties of curcumin because this tumor
induced oxidative stress in thymic T cells [27]. As an extension of
this work the same group demonstrated that curcumin could prevent
the tumor induced apoptosis of thymocytes as well as restoration of
the frequency of CD4
+
T/CD8
+
T cells in the same tumor model
system with the same dose of curcumin. Mechanistically it was also
shown that curcumin modulated Jak-3/Stat-5 activity to restore the
immune cell frequency and activity [28,29]. Curcumin decreased IL-
12-induced STAT4 phosphorylation but enhanced the (interferon)
IFN-β-induced STAT4 phosphorylation; curcumin decreased IL-12
induced IFN-γproduction and IL-12 Rβ1 and β2 expression, whereas
it enhanced IL-10 production and IFN receptor (IFNAR) subunits 1 and
2 expression. Curcumin also increased IFN-α-induced IL-10 and
IFNAR1 expression. Pretreatment with curcumin decreased IFN-α-
induced IFNAR2 expression and failed to modify the level of IFN-α-
induced phospho-STAT4 activation. These ndings favour the distinct
mode of action of curcumin when T cells get activated with different
stimuli and also conrmed the multifarious targets of curcumin in the
activated T cells [30]. It was recently acknowledged that IL-17
producing Th1 cells play an instrumental role in the established
model of experimental autoimmune encephalomyelitis (EAE), which
mimics multiple sclerosis. Oral curcumin (100 or 200 mg/kg body
weight) administration in the rats suppressed the frequency of
inammatory cells in the spinal cord along with lowering the
frequency of paralytic incidences, which was the disease marker in
this model. The decreased level of IL-17, transforming growth factor
beta (TGF-β), IL-6, IL-21, STAT3 expression and STAT3-phosphoryla-
tion was reported in curcumin-treated groups. Also, it was shown that
curcumin blocks the differentiation of Th-17 cells by blocking STAT-3
transcription in T cells. Moreover curcumin inhibited neural Ag-
MBP6886 peptide specic lymphocytes responses and IL-17 mRNA
expression. These recent evidences furthermore proved the signif-
icance of curcumin in the IL-17 mediated disorders [31].Brightand
colleague reported that T cells expressing Toll-like receptors-4 and 9
(TLR4 and TLR9) play an instrumental role in the pathogenesis of EAE
model. Curcumin treatment led to the decrease in the expression of
PLPp139151 and MOGp3555 Ag-induced TLR4 and TLR9 on the
CD4
+
T cells and CD8
+
T cells, which also ameliorated this disease. It
was found that TLR 4 and TLR9 acted as co-stimulatory receptors to
enhance the proliferation and cytokine production in response to the
specicagonists[32]. Previously Bright's group had also reported
that curcumin can inhibit IL-12 production in spleen cells, Mϕand
microglia an d curcumin can inhibit EA E by blocking IL-12 signa ling in
T lymphocytes [33]. Curcumin also inhibited the proliferation of
mouse splenic T cells that were stimulated with ConA and in a model
of type II collagen (CII)-induced arthritis (CIA) in which T cell
proliferation was induced by bovine type II collagen Ag. Moreover,
curcumin reduced anti-CII IgG2a Ab in the serum of CIA mouse [34].
3. 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 rst 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 immune cells as
described elsewhere in this review and the discrepancy between the
uses of different concentration of curcumin reects the variable dose
sensitivities of different immune cells and cell lines to curcumin.
333R.M. Srivastava et al. / International Immunopharmacology 11 (2011) 331341
However, it remains to be investigated if curcumin dose sensitivity of
immature and mature DCs results in distinct biological outcomes. Kim
et al. also showed that curcumin could suppress the lipopolysaccaride
(LPS) mediated surface overexpression of CD86, CD80 and MHCII
expression in murine DCs during maturation but at the same time
curcumin treatment increased the FITC-dextran particle uptake
signicantly. These observations provided the evidence to modulate
DC mediated specic immune response in the autoimmune disorders
for regulating the function of T cells [35]. Park and colleagues reported
that the pretreatment with curcumin (125 μM) could also suppress
the LPS (200 ng/ml) induced indoleamine 2,3-dioxygenase (IDO)
production in bone marrow derived-DCs (BMDCs). However, curcu-
min enhanced the COX-2 expression by three fold and prostaglandin
E2 production by two fold in the LPS treated DCs. The enhanced
prostaglandin E2 level by curcumin was attributed to the suppression
of LPS-induced IDO production in this study. The curcumin or
prostaglandin E2 treated DCs showed reduced proliferation of OVA-
specicCD8
+
T cells that was induced by LPS [36].Although
intravenous LPS (3 μg) injection reduces the splenic blood ow by
31% and reduces the access of Ag to the mouse spleen [37], a high dose
of LPS (1.5 mg/kg body weight, i.p.) induced heavy IDO in splenic DCs
and pre-injection of curcumin (50 mg/kg body weight, i.p.) inhibited
the LPS-induced IDO production in the splenic DCs [36]. In contrast to
the effect of curcumin on BMDCs showing enhanced COX-2
expression, another study showed the dose dependent (216 μM)
inhibiton of the production of LPS (0.2 ng/ml) induced COX-2 in the
BV2 microglial cells. This contrasting results on the COX-2 level in the
BV2 microglial cells and BMDCs may be due to a very high difference
in the LPS concentration (0.2 vs 200 ng/ml) or LPS serotype that were
used in these studies. Moreover, a distinct cellular response to LPS
could not be ruled out in different cell types that may greatly differ in
the density of LPS receptor or co-receptors [38]. IFN-γregulates
multiple elements of DCs response and since it is being used for
monocyte derived-DCs (MoDCs) conditioning in cancer therapy, it can
drive DCs for potent Th1 polarizing activities. Although IFN-γ(5 to
500 IU/ml) treatment was shown to upregulate CD86, CD38, CCR7 on
MoDCs in 48 h [39], no signicant increase in CD86 and CD80 level
was found at 24 h after 200 IU/ml of IFN-γtreatment in murine
BMDCs. However, IFN-γ(100 IU/ml) upregulated IDO production in
BMDCs and curcumin (125 μM) inhibited the functions as well as
level of IDO in IFN-γstimulated murine BMDCs. Thus curcumin
reversed the IDO-mediated reduced T cell proliferation function. This
study also showed that curcumin can modulate IFN-γinduced IDO
expression by affecting Janus kinase 1 (JAK) and protein kinase C δ
(PKC) signaling [40]. In a similar direction, additional data showed
that curcumin-treated DCs led to the development of anergic CD4
+
T
cells and curcumin-treated DCs could also induce regulatory T cells
(Tregs) development. More interestingly, curcumin-treated DCs also
promoted the production of IL-10 and αAlDHAa1 (αretinal
dehydrogensae). These retinoids function as the regulators of mucosal
immune responses. Curcumin induced Treg cells inhibited Ag-specic
T cell activation in-vitro and could inhibit colitis caused by Ag-specic
pathogenic T cells in-vivo. These ndings supported the important
role of curcumin in the modulation of DCs' function to achieve
tolerogenic responses [41]. Curcumin (1 μM) itself could suppress the
LPS-induced IL-12/23p40 production in-vitro, whereas IL-10 (2.5 ng/
ml) and curcumin (0.1 μM) at their suboptimal concentrations acted
synergistically to suppress the LPS-induced IL-12/23p40 production
from DCs. However, no appreciable therapeutic effect of the dietery
curcumin was noticed in the IL10-decient mice having Th1 mediated
colitis. Also, no signicant improvement in the colitis was observed as
curcumin failed to modify the pathogenic T cells in IL-10 decient
mouse. These results comprehensively conrmed the dependence of
curcumin on IL-10 for its immunoinhibitory actions. Nevertheless it
provided the evidence that a very little bioavailable concentration of
curcumin might effectively modify the overall immune response in
combination with IL-10. Curcumin and IL-10 also acted synergistically
to inhibit the NF-κB activity in intestinal epithelial cells and thus could
provide the additional benets without inuencing the function of
immune cells. These results also provoke the possibility of a
combinatorial approach to investigate the immunohibitory action of
curcumin with other immunohibitory molecules viz. TGF-β, prosta-
glandins etc. [42]. Such investigations will be valuable to specify the
action of curcumin in various pathogenic conditions in future.
4. 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 ve weeks showed no effect on the
NK cell activity in rats but enhanced the antibody (Ab) responses in
rats [43]. In another study, Yadav et al. showed that curcumin
treatment can augment NK cell cytotoxicity in-vitro that can further
be enhanced by IFN-γtreatment [44]. The generation of IL-2 induced
non-specic cytotoxic LAK cells (similar to cytotoxic NK cells) in the
presence of curcumin (at 1020 μM/l) was evaluated by Gau et al. and
the cytotoxic activity of LAK cells was determined against NK sensitive
YAC-1 lymphoma cells. The results showed little effect on the
generation of LAK cell-mediated cytotoxicity, whereas higher dose
(30 μM/l) of curcumin inhibited the cytotoxic LAK cell generation [24].
Few serious concerns for the use of curcumin in the melanoma
treatment were however raised, which were based on the facts that
NK cells from healthy donors treated with curcumin (10 or 20 μM/l)
and IL-12 (10 or 50 ng/ml) secreted less amount of IFN-γ. Moreover,
curcumin-treated NK cells also showed reduced granzyme B to kill
K562 and A375 melanoma cell lines and curcumin slightly reduced
production of IFN-γby NK cells in the presence of A375 melanoma
and K562 target cell lines. Although this study found the direct effect
of curcumin on tumor cells it could not provide appreciable reasons
for the use of curcumin as the modiers of NK mediated immune
responsesin favour of its use in anti-tumor therapies [45]. Similarly,
our previous study had shown that curcumin injections for prolonged
duration had no effect on the NK cell activity in-vivo, during the
progression of ascites tumor [25]. However, we observed larger solid
tumor with curcumin in the transplanted subcutaneous AK-5 tumor
that interestingly underwent rapid spontaneous regression. Also, an
enhanced activation of NK cells was observed after curcumin
treatment that correlated with the response of curcumin on the
tumor in-vivo [46]. Such an effect clearly describes the effect of
curcumin as NK cells modier, however its in-vivo effects may be
highly dependent on the specic pathology of the diseases. Recently,
tumor derived exosomes attracted much attention as they can
effectively modulate the anti-tumor immune responses. Zhang et al.
showed that curcumin enhanced the proteasomal degradation of
tumor derived exosomal proteins that inhibit IL2-induced NK cell
activity against breast carcinoma, partially restoring the NK cell
activity against tumor. Such an action of curcumin displayed that
curcumin can also target the immune escape strategies that are
critical for the immune responses [47].
5. Immunomodulatory effect of curcumin on monocytes and
macrophages (Mϕ)
Monocyte recruitment at the inammatory site plays a vital role in
the inammatory response. Curcumin inhibited the tumor necrosis
factor α(TNF-α) induced adhesion of monocytes on human
endothelial cells. The TNF-αinduced upregulation of Inter-Cellular
Adhesion Molecule 1 (ICAM-1), vascular cell adhesion molecule-1
334 R.M. Srivastava et al. / International Immunopharmacology 11 (2011) 331341
(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 was
attributed to the inhibitory effect on NF-κB activation. These results
showed the promising activities of curcumin in the local inammatory
responses like arthritis as well as in metastasis [48]. PMA or LPS-
induced production of inammatory cytokines viz. TNF-α, IL-8,
macrophage inammatory protein 1 alpha (MIP-1α), monocyte
chemoattractant protein (MCP-1) and IL-1βin monocytes and
alveolar Mϕs was signicantly inhibited by curcumin in a dose
dependent manner [49]. Lim et al. also showed that curcumin blocked
the enhanced expression and secretion of PMA induced inammatory
cytokine MCP-1 in U937 monocytic cell line [50]. Although curcumin
completely blocked LPS mediated NO production in RAW264.7 cell
line, it enhanced the phagocytosis of uorescent beads and the surface
expression of CD14. The enhancement of pahgocytic activity and the
surface expression of CD14 followed a similar pattern, however no
direct role of curcumin mediated enhanced CD14 surface expression
was described for the phagocytic capcity [51].Previously,an
independent study had also shown a signicant increase in Mϕ
phagocytic activity in curcumin-treated animals. These actions of
curcumin on Mϕs also described the enhanced scavenging capacity
under non-inammatory conditions [52]. Prolonged alcohol treat-
ment led to oxidative stress and the mononuclear cells obtained from
alcoholic animals showed lesser capacity for collagen surface
attachment; however alcohol in conjunction with curcumin showed
normal adhesion potential of mononuclear cells. This study showed
the reduction in the toxic effect of alcohol by curcumin in the
prolonged duration [53]. Pretreatment with curcumin inhibited the
LPS-induced TLR-2 mRNA and NF-κB level in RAW264.7 cells [54].
Treatment with bisdemethoxycurcumin inhibited the LPS-induced
NO production in RAW264.7 cells, which was abrogated by blocking
the activity or the expression level of heme oxygenase-1. It was also
shown that anti-inammatory effects mediated by bisdemethoxy-
curcumin signaling to heme oxygenase-1 involve **Ca
2+
/calmodulin-
CaMKII-ERK1/2-Nrf2 cascade in RAW264.7 Mϕcells [55]. Sumanont et
al. have furthermore reported that curcumin manganese complex
(CpCpx) and diacetylcurcumin manganese complex (AcylCpCpx)
have greater NO radical scavenging activity than their parent
compounds, curcumin and acetylcurcumin, respectively [56].
In diabetic condition, a massive increase in the inammatory
cytokines has been reported. To evaluate the anti-inammatory effect
of curcumin under high glucose mediated inammatory responses,
Jain et al. studied the effect of curcumin and placebo supplementation
on plasma level of TNF-α, IL-6, MCP-1, glucose and oxidative stress in
streptozotocin-treated diabetic rats [57]. Curcumin treatment signif-
icantly reduced the high glucose mediated upregulation of inam-
matory cytokines along with increasing the lipid peroxidation.
However curcumin had no effect on the reduced insulin level under
diabetic conditions. In this study, the anti-inammatory action of
curcumin on the high glucose induced IL-8, TNF-α, IL-6, MCP-1 was
also shown by using human promonocytic U937 cell line.
Androgen receptor is a nuclear receptor that translocates to the
nucleus following ligand binding and modulates the function of
various genes. In the healing skin androgen receptor were detected in
inlitrating Mϕs, keratinocytes and in dermal broblasts that
indicated its possible function in the healing process. Androgen
receptor activity in the presence of 5α-dihydrotestosterone induced
TNF-αpromoter activity in Mϕs. The curcumin derivative ASC-J9
disrupts the androgen receptor and its co-regulator interaction
resulting in the increased androgen receptor degradation and the
decreased androgen receptor transactivation. The topical application
of ASC-J9 cream in mouse resulted in quick wound healing and also
decreased local TNF-αexpression. This study concluded that the
curcumin derivative ASC-J9, which acts by inhibiting androgen
receptor activity, could be utilized in wound healing as an anti-
inammatory agent [58]. Alzheimer's disease is a complex disorder
mainly characterized by deposition of large amount of amyloid-β(Aβ)
peptide and subsequent massive inammatory response. Heavy
inlitration of monocytes and Mϕhas been observed in the affected
tissue with Aβdeposition. Giri et al. demonstrated that both Aβ
140
and brilar Aβ
142
peptide are abundantly present in the plasma of
patients along with the increase in the level of cytokines TNF-αand
IL-1βand chemokines MCP-1, IL-8 and MIP-1β. Activation of
transcription factors AP-1 and EGR-1 regulates the level of cytokines
and chemokines in THP-1 monocytic cells and in peripheral blood
monocytes [59]. Based on the ability of curcumin to block inamma-
tion as well as to modulate the activities of β-secretase and
acetylcholinesterase, in-vitro and in-vivo studies with curcumin led
to suppressed Aβdeposition and aggregation in experimental animals
[60]. In the evaluation study on the role of curcumin in Alzheimer
disorder Giri et al. furthermore showed that curcumin could block the
Aβ
140
-induced expression of TNF-α, IL-1β, MCP-1, IL-8, MIP-1βand
CCR5. Also, it was reported that curcumin could inhibit Aβ-induced
Egr-1 DNA-binding activity. These results provided the mechanism of
the anti-inammatory action of curcumin in this disease [61].
6. 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. Interestingly, however, curcumin inhibited the
TLR ligand and anti-IgM induced phosphorylation of ERK, Iκ-B and
p38 kinase along with inhibiting NF-κB activation. These observations
indicated the anti-inammatory effects of curcumin in the B cell
response [62]. Another study described that the mitogen-LPS-induced
proliferation of B cells can be dose dependently inhibited by curcumin
(120 μM); additionally the LPS-induced secretion of IgG1 and IgG2a
was inhibited by curcumin. However, the curcumin mediated
inhibition of IgG1 secretion was more pronounced than the inhibition
of IgG2a secretion [63]. An independent study also described that
curcumin (10 μM) can also inhibits the production of IgE from rat
splenocytes [64]. Epstein barr virus (EBV) can immortalize human B
lymphocytes in-vitro and immortalization is promoted by the
oxidative stress induced by potent immunosuppressive drug cyclo-
sporine A and with hydrogen peroxide. Curcumin (20 μM) aborted the
EBV induced B cell immortalization process. This effect of curcumin
may be exploited to prevent post-transplant lymphoproliferative
disorders in patient receiving cyclosporine A, which otherwise may
promote EBV induced B cell immortalization [65]. Later on, it was
found that the curcumin modulates this immortalization process by
enhanced apoptosis in the virus infected B cells [66]. In animals with
spontaneous polyps in the intestinal mucosa, curcumin treatment
resulted in 40% increase in B cell numbers in the intestinal mucosa,
suggesting the therapeutic responses to curcumin [26].
B cell receptor (BCR) signaling regulates the induction of apoptosis
in chronic lymphocytic lymphoma. The central mediator of BCR-
signaling is the spleen tyrosine kinases, that govern the function and
survival of B cells, and a high level of phosphorylated spleen tyrosine
kinase was found in lymphoma cells in comparison to healthy B cells
[67]. Curcumin differentially modulated the cytotoxicity of primary
chronic lymphocytic lymphoma in comparison to healthy B cells [67].
Rats that received 1, 20 or 40 mg/kg curcumin for 5 weeks showed
signicantly enhanced IgG only at 40 mg/kg levels whereas animals
receiving lower dietary concentrations (1 or 20 mg/kg) of curcumin
had same IgG level as that of control with no dietary curcumin. These
observations suggest that a threshold level of bioavailable curcumin is
335R.M. Srivastava et al. / International Immunopharmacology 11 (2011) 331341
also needed to modulate the IgG mediated responses [43]. A recent
study showed that curcumin (6 to 50 μM) could suppress the
expression of division dependent upregulation of activation-induced
cytosine deaminase, which plays pivotal role in the Ig class switch
recombination and somatic hyper-mutation and participates in
tumorigenesis. Also the decrease in the recovery of IgG+class-
switched B cells within the divided population was observed. These
observations suggest the potential of curcumin in the treatment of B
cell autoimmune disease [68].
7. 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 specic manner and may thus dampen the neutrophil
mediated inammatory response [69]. Chemotactic peptide N-
formyl-methionyl-leucyl-phenylalanine (FMLP) and zymosan acti-
vated 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 attenuated
by the curcumin treatment. Calcium ionophore A23187 could nullify
the curcumin effect by interfering with the effect of curcumin in
neutrophils [69]. Neutrophils play signicant role in the damage of
joint tissue in the rheumatoid arthritis. A recent study demonstrated
the reduced level of oxygen radical generation by neutrohphils upon
treatment with curcumin both in-vitro and in-vivo. Adjuvant induced
arthritis enhanced the neutrophil frequency in the blood that remain
unaltered by curcumin. The stimulation of neutrophils by PMA led to
increased level of PKC isozymes, αand βII, which was abrogated by
curcumin treatment without interfering with neutrophils vital
functions [70]. Similarly, the crystal induced neutrophil activation
that served as a model of induced arthritis or rheumatoid arthritis
condition was inhibited by curcumin [71]. Oral administration of
curcumin (4060 mg/kg body weight) increased survival of mice by
70% in response to heavy dose of LPS (40 mg/kg body weight).
Moreover curcumin suppressed the LPS mediated neutrophil inltra-
tion in liver that was the primary cause of liver damage. However, the
reduction of inltration was limited to the liver only, because whereas
hepatic venules had same frequency of neutrophils as that of without
curcumin. The reduction of LPS-induced inltration of neutrophils
was also correlated with the reduced levels of ICAM-1 and VCAM-1 in
the liver tissue that inuence neutrophil adhesion [72]. Without
affecting the viability, curcumin (100 μM) signicantly reduced the IL-
8 induced chemotactic activity of neutrophils in dose dependent
manner and curcumin modulated this chemotaxis by dampening the
IL-8 induced Ca
++
ion mobilization. Surface CXCR1 and CXCR2 were
internalized upon IL-8 treatment and curcumin treatment enhanced
the intracellular level of CXCR1 and CXCR2 in conjunction with IL-8,
which indicated that the effect of curcumin on the reduced migration
of neutrophils might be attributed to the reduced IL-8 receptors.
However, curcumin itself downregulated surface IL-8 receptor CXCR1
and CXCR2 and also blocked the recycling of these receptors on
neutrophils. The Rab GTPase family (Ras superfamily of monomeric G
proteins) plays pivotal role in the cellular transport mechanism.
Interestingly, both CXCR1 and CXCR2 showed enhanced binding with
Rab11 upon curcumin treatment, which could potentially block the
recovery of IL-8 to cell surface. This study revealed the intricate
mechanism that curcumin triggers to achieve anti-inammatory
responses meadiated by neutrophils [73]. LPS induced lung damage
and reduction in lung and bronchoalveolar lavage uid protein
content, which was accompanied by enhanced numbers of neutro-
phils and elevated myeloperoxidase activity in cell-free lavage.
Elevation in the cytokine-induced neutrophil chemoattractant-I
protein level was seen in response to LPS in the lung tissue, which
was signicantly reduced by the pretreatment with curcumin. This
shows an important protective response of curcumin by dampening
neutrophil function in lung injury [74].
In a murine model of asthama, which was induced by OVA-Ag and
which had airway hyper-responsiveness to allergens, curcumin (i.p,
10 or 20 mg/kg body weight) decreased the frequency of eosinophils
and the inammatory cells, inhibited iNOS (inducible nitric oxide
synthase) expression in lungs and also suppressed the level of IL-4
and IL-5 in bronchoalveolar lavage uid [75]. An interesting study
involving the action of curcumin on mast cells indicated that
curcumin reversibly inhibits the degranulation of mast cells along
with inhibiting secretion of IL-4 and TNF-α. The evaluation of the anti-
allergic affect of curcumin was performed by utilizing passive
cutaneous anaphylaxis in the mouse ear model. Oral administration
of curcumin (50 mg/kg) suppressed the mast cell dependent IgE and
Ag-induced local passive cuataneous anaphylaxis [76,77]. Effect of
curcumin during myocardial ischemia/reperfusion injury with cardi-
oplegia was also investigated [78]. The postoperative increase in the
IL-8, IL-10, TNF-αlevels in the plasma was decreased by curcumin.
Also curcumin inhibited the activation of neutrophils in myocardium
that was estimated by the myloperoxidase activity assay [78].
8. 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 inammatory and non-inammatory disorders. In this section,
we discuss most recent ndings related to its direct application in
health and disease.
8.1. Role of curcumin in the neoplastic diseases
Curcumin has received maximum attention owing to its anti-
tumor properties. Several hundred reports in the last two decades
have shown its ability to selectively kill transformed cells across
almost all types of tumors. Curcumin can exert its anti-tumor effects
at two levels, (i) at the level of tumorigenesis or (ii) in selectively
inducing apoptosis in tumor cells. Huang et al. have discussed the
anti-carcinogenic effects of curcumin in duodenal and colon cancer in
mice. In this study, dietary curcumin could signicantly reduce tumor
load during both pre initiation and post initiation of chemical induced
carcinogenesis [79]. Similarly, curcumin application inhibited the
induction of epidermal DNA synthesis and the tumor promotion in
skin following 12-0-tetradecanoyl phorbol-13-acetate (TPA) treat-
ment [80] as well as benzopyrene induced DNA adducts and skin
tumors and DMBA induced skin tumors [79]. Rao et al. have shown
that curcumin (200 ppm) in the diet could signicantly suppress
azoxymethane-induced colonic aberrant crypt foci formation, which
are early preneoplastic lesions, and colon tumor incidence and tumor
multiplicity [81]. These effects of curcumin in inhibiting tumorigen-
esis involve inhibition of arachidonic acid metabolism; decrease in
TPA induced ornithine decarboxylase activity and inhibition of DNA
synthesis. It was thought that metabolites of arachidonic acid such as
HPETEs, HETEs, leukotrienes and prostaglandins play an important
role in TPA induced inammation and tumor promotion [82,83].
Similarly ornithine decarboxylase (ODC) is a rate limiting enzyme in
polyamine synthesis [81] and its overexpression has been linked with
cell transformation and carcinogenesis in skin, breast and colon. Thus,
it is logical to speculate that inhibiting arachidonic acid metabolism
and/or ODC activity shall result in an inhibition of tumorigenesis. In
addition, curcumin has also been shown to cleave β-catenin, which
impairs Wnt signaling and cellcell adhesion pathways, which are
critical in the development and promotion of many types of tumors
including colorectal cancer [84]. Curcumin also induced downregula-
tion of cyclin D1 expression and CDK-4 activity in breast and
squamous cell carcinoma cell lines [85]. The suppression of cyclin
336 R.M. Srivastava et al. / International Immunopharmacology 11 (2011) 331341
D1 by curcumin led to inhibition of CDK-4 mediated phosphorylation
of retinoblastoma, which is a crucial step for the cell to pass through
the G1 phase of cell cycle and become transformed [86].
In addition to its inhibitory effects on neoplastic transformation,
curcumin has been shown to induce apoptosis in tumor cells by
various mechanisms, which include impairment of the ubiquitin
proteasome pathway, upregulation of proto-oncoprotein Bax, activa-
tion of caspases and induction of Fas receptor aggregation in a Fas
ligand dependent manner and the generation of free radicals [8790].
One of the several possible mechanisms of apoptosis induction by
curcumin involves the inhibition of proteasome complex. In mouse
neuro 2a cells, exposure to curcumin revealed a dose dependent
decrease in the proteasome activity and an increase in the
ubiquitinated proteins. Curcumin also decreased the turnover of the
destabilized enhanced green uorescent protein suggesting an
inhibition of the cellular proteasome machinery [90]. Another mode
of apoptosis induction by curcumin involves the upregulation of p53
in tumor cells. In human basal cell carcinoma, apoptosis induction by
curcumin resulted in induction of p53 and its downstream targets,
p21 waf1/cip1 and GADD45, which are known to regulate apoptosis
under stress conditions [91]. Work in our laboratory has shown that
curcumin induced apoptosis involves the production of reactive
oxygen intermediates (ROIs) and involves activation of caspase-3
[87]. A large number of reports conrm that curcumin induced typical
apoptotic mode of cell death in a wide variety of tumors complete
with mitochondrial depolarization and caspase-3 activation. Howev-
er, some studies suggest that apoptosis induced by curcumin is
independent of caspase-3 [92,93]. Curcumin has also been reported to
induce an apoptosis like pathway, which is independent of not only
caspases but mitochondria as well [93]. These effects of curcumin in
Jurkat T cells were accompanied by DNA fragmentation into high but
not low molecular weight fragments and the frequency of opening of
the mitochondrial permeability transition pores in curcumin-treated
cells was decreased compared to the control untreated cells. However,
one of the most commonly shown effects of curcumin on tumors is its
ability to induce the opening of mitochondrial permeability transition
pore, which in turn induces the collapse of the mitochondrial
membrane potential, respiration impairment ultimately leading to
cell death [94,95]. This observed difference in curcumin's action with
respect to the opening of permeability transition pore could be
attributed to the large difference in its concentrations that were used
during these studies.
8.2. Curcumin in cardiovascular disease
The therapeutic effects of curcumin in the development and
progression of cardiovascular disease have been studied to some
depth in the last decade. Owing to its ability to regulate oxidant stress,
curcumin has been shown to be effective against cardiac hypertrophy,
cardiomyocyte apoptosis following myocardial infarction and ische-
mia/reperfusion injury [9698]. Cardiac hypertrophy is the remodel-
ing of the left ventricle following pressure or volume overload that
results in ventricular wall thickening and an increase in overall
cardiac dimensions. It begins as a compensatory process that becomes
maladaptive over time and leads to heart failure [99,100]. Develop-
ment of hypertrophy involves activation of the calcium and redox
sensitive transcription factor NF-AT that brings about the metabolic
and biochemical changes within the cardiomyocyte [101]. Transcrip-
tional activation associated with hypertrophy has been recently
shown to be regulated by acetylation and deacetylation events at
histone lysine tails [102]. Acetylation and deacetylation of histones is
carried out by enzymes called histone acetyl transferases (HATs) and
histone deacetylases (HDACs), respectively. Various HDACs have been
implicated in the pathogenesis of cardiac hypertrophy. For example,
loss of class 2 HDAC results in development of hypertrophy while loss
of class-1 HDAC confers resistance to hypertrophic growth [102,103].
Morimoto et al. studied the effects of curcumin on HAT and
progression of hypertrophy and subsequent decompensated heart
failure. They have shown that exposure of isolated neonatal rat
cardiomyocytes (NRCMs) to 5 or 10 μM curcumin completely
suppressed the induction of hypertrophic response following phen-
ylephrine treatment, a known inducer of cardiac hypertrophy [97].In
an in-vivo setting also, administration of curcumin prevented the
development of hypertension induced heart failure in salt sensitive
Dahl rat model of hypertension [97]. These data strongly suggest that
curcumin possesses anti-hypertrophic properties both in-vitro and in-
vivo. It has been proposed that curcumin may inhibit hypertrophic
remodeling by two mechanisms (i) by inhibition of histone
acetylation through inhibition of HATs and (ii) by disrupting p300/
GATA4 transcriptional complex through a completely independent
mechanism. Curcumin has also been shown to inhibit p300 mediated
acetylation of p53, both in-vitro as well as in-vivo [104]. Similarly,
inhibition of NF-κB by curcumin could also be involved in the anti-
hypertrophic effects of curcumin since NF-κB signaling is involved in
cardiomyocyte hypertrophy [105].
Oxidative stress is a major outcome determinant in myocardial
infarction and ischemia/reperfusion and curcumin's anti-oxidant
property has been shown to prevent isoproterenol induced myocar-
dial necrosis in rats [106]. In models of experimentally induced
myocardial infarctions such as isoproterenol treatment, decrease in
lysosomal stability leading to increase in lysosomal autolytic enzymes
has been reported [107,108]. Curcumin has been shown to stabilize
membranes and thereby suppress the infarct induced increase in
myocardial lysosomal enzymes [109,110]. Besides, the generation of
free radicals following ischemia/reperfusion can also be controlled by
curcumin due to its strong anti-oxidant properties.
The cardiotoxicity associated with doxorubicin, a potent drug for
treatment of a broad array of cancers, is a major concern for cancer
patients [111]. Animal studies have shown that doxorubicin treatment
induces free radical generation and p53 activation, decreases glutathi-
one and increases serum peroxidase and catalase [96,112]. Curcumin
treatment signicantly attenuated thecardiotoxic effects of doxorubicin
[113].Thebenecial effect of curcumin in blockade of doxorubicin
cardiotoxicity can be linked to modulation of intracellular redox status
by curcumin. In a study by Feng et al., curcumin completely abrogated
the induction of glucose induced hypertrophy in cardiomyocytes [114].
Glucose induced cardiomyocyte hypertrophy is mediated by p300
upregulation and subsequent activation of p300 dependent transcrip-
tion factors. Since, curcumin can inhibit p300, exposure to curcumin
prevented the induction of p300 mediated hypertrophic response in
cardiomyocytes [114]. In human patients curcumin could markedly
reduce the generation of glucose induced reactive oxygen species (ROS)
in red blood cells. Myocardial tissue from diabetic rats exhibited higher
levels of eNOS and iNOS mRNA and curcumin treatment considerably
inhibited the upregulation in both eNOS and iNOS transcript levels
[115]. Collectively, these studies have established the usefulness of
curcumin in the treatment of various cardiovascular ailments. However,
caution need to be exercised while reproducing curcumin's anti-tumor
effects in the cardiovascular system due to the extremely different
metabolic and biochemical nature of the two cell types. The molecular
pathways targeted by curcumin in tumor cells may not be targeted at all
in the cardiomyocytes or may be modulated in a markedly different
manner so as to drastically change the physiological outcome. One of
most important difference between the two cell types is the metabolic
signature; tumor cells have a higher dependence on glycolysis while
cardiomyocytes mainly depend on lipid oxidation for their metabolic
needs. Similarly, the proteome and the transcriptome within cardio-
myocytes are regulated quite differently than in a transformed cell type.
This calls for a careful examination and analysis of curcumin dosage
along with mechanistic details of its physiological effects within
different cell types before establishing curcumin in any independent
or combinatorial drug regimen.
337R.M. Srivastava et al. / International Immunopharmacology 11 (2011) 331341
8.3. Curcumin in neurodegenerative disease
Brain is perhaps the most susceptible organ to oxidative damage
due to the highly oxidative intracellular environment of the neurons
and glial cells [116]. Oxidative stress has been shown to increase both
with normal brain ageing as well as with brain injury [117,118]. ROS
generation in the brain can enhance the production of nitric oxide by
activating neuronal nNOS and iNOS. Nitric oxide is a known mediator
of glutamatergic transmission and has been shown to be involved in
ageing and age related neurodegenerative disorders [117]. Accumu-
lation of redox active metals such as iron, copper and zinc, due to high
levels of ascorbic acid in the brain that facilitates redox metal
reactions, aggravates the oxidative load in the brain [119].An
elevation in the free radicals and oxidative stress in turn induces
the activation of NF-κB and other inammatory molecules such as IL-
1βand TNF-α[120,121]. The neuroprotective effects of curcumin
have been described in a variety of stress models. In an oxidative
damage induced neurodegeneration model, Guangwei et al. have
shown the ability of curcumin to attenuate acrylonitrile induced
oxidative damage in the brain [122]. In this study, curcumin dose of
100 mg/kg of body weight prevented lipid peroxidation and gluta-
thione depletion in response to acrylonitrile exposure. In another
study, curcumin could increase the cholinergic activity of neurons and
free radical scavenging in streptozotocin induced dementia in rats
[123]. The ability of curcumin to increase cholinergic activity in the
brain is mediated by an increase in the acetylcholinesterase enzyme. It
has been previously reported that curcumin attenuated diabetic
encephalopathy by a similar free radical scavenging effect and
increase in acetylcholinesterase activity [124].
Acute traumatic brain injury results in a widespread secondary
brain damagefollowing the primary mechanical damage. One of the
most critical mediators of the rather chronic secondary brain injury is
the oxygen derived free radical species. Kontos and Povlishock have
shown upregulation of the superoxide radical (O2
) in the brain
microvasculature immediately following acute injury [125,126]. The
superoxide radical can be generated from various enzymatic reactions
such as arachidonic acid cascade, oxidation of amine neurotransmit-
ters, mitochondrial leakage and xanthine oxidase activity [127]. The
ability of curcumin to sacavenge oxygen derived free radicals has been
implicated in its potential as a neuroprotective agent. Dietary
curcumin supplementation has been shown to maintain energy
homeostasis after brain trauma [128]. Cerebral edema, a cause of
increased intracranial pressure and poor clinical outcome after acute
brain injury, was signicantly controlled by pretreatment (75
150 mg/kg body weight) as well as post treatment (300 mg/kg body
weight) with curcumin [129]. The protective effects of curcumin were
associated with inhibition of IL-1βexpression and inhibition of
aquaporin-4 induction. Wakade et al. have shown that curcumin can
attenuate vascular inammation following subarachnoid hemorrhage
while another study by Zhao et al. has described neuroprotection
conferred by curcumin after cerebral ischemia [130,131]. These
ndings support the notion that intervention with curcumin
treatment at any point during the brain injury can change the clinical
outcome.
Effects of curcumin on the pathophysiology of Alzheimer's disease
have been studied somewhat extensively and several groups have
shown its ability to inhibit Aβ-plaque formation [132,133]. In a mouse
model of Alzheimer's disease, low doses of curcumin (160 ppm)
decreased the plaque burden and reduced the soluble as well as
insoluble forms of Aβby about 50% [134]. Yang et al. have described
the ability of curcumin to inhibit the formation of Aβ-oligomers. They
have also shown that curcumin can bind to the amyloid plaques and
signicantly reduce in-vivo plaque formation [135]. They have earlier
shown the efcacy of curcumin in reducing CNS lipid peroxidation
and iNOS [136], which in turn can lower the oxidative stress. One of
the possible mechanisms suggested in curcumin's ability to inhibit
plaque formation is the high afnity with which it binds redox
reactive metals such as copper and iron and therefore may act as a
potent anti-oxidant by chelating redox reactive metals [137]. Amyloid
plaque burden has been associated with depolarizing of the neuronal
membrane and enhanced glutamate-mediated excitotoxicity
[138,139] that results in impaired electrical ring of the neurons.
Curcumin administration has been shown to prevent misring of
neurons following Aβburden in embryonic hippocampal neurons
[140]. In nitrosourea induced neurotoxicity, curcumin administration
prevented increase in the activity of glucose metabolic pathway
enzymes including hexokinase, LDH and SDH [141]. Similarly, in
mercury induced neurotoxicity, pretreatment with curcumin abro-
gated the increase in metallothinine mRNA and suppressed the toxic
and oxidative stress load following mercury exposure in rats [142].
Cumulatively, these studies suggest that curcumin can help in
maintaining the oxidative intraneuronal environment and thereby
protect brain from a variety of oxidative, toxic and mechanical
injuries.
8.4. Immunomodulatory action of curcumin in the prevention of
inammatory diseases
Curcumin administration has been shown to be associated with a
positive outcome in a large number of chronic inammatory diseases
due to its ability to inhibit NF-κB activation and subsequent inamma-
tory pathways. Starting with its use in biliary disease in 1937,curcumin
has now been shown to ameliorate almost all kinds of liver toxicity and
disease. Curcumin can inhibit the increase in serum ALT and AST
enzymes following iron induced liver toxicity [143]. The biochemical
and histopathological changes induced by ethanol toxicity were
abrogated by curcumin administration [144]. Curcumin could also
protect against thiodoacetamide induced hepatitis and cirrhosis in rats.
It also protected against carbon tetrachloride induced livertoxicity and
reversed carbon tetrachloride induced cirrhosis [145]. The underlying
mechanismfor the effects of curcumin on liver involves its ability to act
as an oxidant and inhibit NFκB activation thereby inhibiting the
inammatory signaling cascade. Curcumin could protect against
dinitrobenzene sulfonic acid induced model of murine colitis by
suppressing p38 kinase and IL-1βactivation [146]. In a similar murine
model of inammatory bowel disease, intragastric administration of
curcumin inhibted the increase in intestinal neutrophil inltration and
serine protease activity, suggesting its promising therapeutic potential
in the treatment of inammatory bowel disease [147]. Rheumatoid
arthritis is another chronic pro-inammatory disease that has been
shown to be targeted by curcumin. Several studies have reported the
physiologically benecial effects of curcumin in the management of
rheumatoid arthritis [148,149]. These studies have shown the ability of
curcumin to inhibit the increase in serum acidic glycoproteins and
matrix metalloproteinase expression that is generally associated with
the progression of disease in rheumatoid arthritis patients. Decreased
apoptosis of synovial broblasts is one of causes for joint inammation
and stiffness in rheumatoid arthritis patients and Park et al. have shown
that curcumin could induce apoptosis in synovial broblast by
upregulation of proapoptotic genes including bax and a simultaneous
downregulation of anti-apoptotic genes including bcl-2 and XIAP [150].
Chronic inammatory bowel disease is a life threatening disease
that affects children and adults. Elevated level of pp38 kinase was
seen in the intestinal mucosa of ulcerative colitis and Crohn's disease
biopsies, which was inhibited by curcumin (520 μM) ex-vivo.
Curcumin suppressed the production of pro-inammatory cytokine
IL-1βand enhanced the production of IL-10 in the ex-vivo cultured
mucosal biopsies. However, it had modest yet consistent effect on the
reduction of IL-1βlevel [151]. Due to its strong inhibitory effects on
cyclooxygenases1 and cyclooxygeanse-2, lipoxygenase, TNF-α, IFN-γ,
iNOS and NF-κB, curcumin (360 mg/dose; 3 or 4 times/day for three
months) showed promising response in patients and could reduce
338 R.M. Srivastava et al. / International Immunopharmacology 11 (2011) 331341
clinical relapse in patients with quiescent inammatory bowel disease
[152].TNF-αplays instrumental role in the pathogenesis of inamma-
tory skin disorder psoriasis and since curcumin is a strong anti-
inammatory agent, its action in the HaCa T keratinocytes was
investiagted. Curcumin (20 μM) aborted the TNF-αinduced expression
of IL-1β, IL-6, IL-8 and TNF-αin keratinocytes. Curcumin also blocked
the activation of NF-κBp65, pJNK, pp38 kinase activation and down-
regulated Cyclin E level. Without modulating the TNF receptor I and II
expression, TNF-αinduced activation of NF-κB in human umbilical vein
endothelial cells was blocked by curcumin. Also, curcumin inhibited the
pJNK level, pP38 kinase level and STAT-3 activation along with lowering
the intracellular ROS level. The expression of ICAM-1, MCP-1, and IL-
8 was attenuated by curcumin at both mRNA and protein level. These
studies indicate the protective effect of curcumin in the treatment of
various pro-inammatory diseases [153].
9. Concluding remarks and future perspectives
Immunomodulatory properties of curcumin are mostly immuno-
suppressive, but in some cases immunostimulative effects have been
reported. Although studies with inammatory 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-inammatory and immunoactivating properties, studying the
mechanism of the action of curcumin is an intriguing challenge.
Dening the basis of the appropriate concentration in the host for the
effective therapeutic response, synthesis of curcumin analogues with
improved properties and the effect of curcumin on the cross-talk
among activated lymphocytes are some of the direct questions that
remain to be answered.
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341R.M. Srivastava et al. / International Immunopharmacology 11 (2011) 331341
... Mechanistically, its anti-inflammatory effects are prominent through the inhibition of the proinflammatory molecules: toll-like receptor (TLR-4), phosphatidylinositol-3 kinase (PI3K), and nuclear factor-kappa B (NF-kB). Turmeric also has the potential to repress the production of an array of pro-inflammatory cytokines such as IL-6, tumor necrosis factor-alpha (TNF-a), and interleukin 1 beta (IL-1b) (174,175). ...
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Background Being “positive” has been one of the most frustrating words anyone could hear since the end of 2019. This word had been overused globally due to the high infectious nature of SARS-CoV-2. All citizens are at risk of being infected with SARS-CoV-2, but a red warning sign has been directed towards cancer and immune-compromised patients in particular. These groups of patients are not only more prone to catch the virus but also more predisposed to its deadly consequences, something that urged the research community to seek other effective and safe solutions that could be used as a protective measurement for cancer and autoimmune patients during the pandemic. Aim The authors aimed to turn the spotlight on specific herbal remedies that showed potential anticancer activity, immuno-modulatory roles, and promising anti-SARS-CoV-2 actions. Methodology To attain the purpose of the review, the research was conducted at the States National Library of Medicine (PubMed). To search databases, the descriptors used were as follows: “COVID-19”/”SARS-CoV-2”, “Herbal Drugs”, “Autoimmune diseases”, “Rheumatoid Arthritis”, “Asthma”, “Multiple Sclerosis”, “Systemic Lupus Erythematosus” “Nutraceuticals”, “Matcha”, “EGCG”, “Quercetin”, “Cancer”, and key molecular pathways. Results This manuscript reviewed most of the herbal drugs that showed a triple action concerning anticancer, immunomodulation, and anti-SARS-CoV-2 activities. Special attention was directed towards “matcha” as a novel potential protective and therapeutic agent for cancer and immunocompromised patients during the SARS-CoV-2 pandemic. Conclusion This review sheds light on the pivotal role of “matcha” as a tri-acting herbal tea having a potent antitumorigenic effect, immunomodulatory role, and proven anti-SARS-CoV-2 activity, thus providing a powerful shield for high-risk patients such as cancer and autoimmune patients during the pandemic.
... Commercially, curcumin is one of the main active components in turmeric, which accounted for 77% of active components besides two other related compounds, demethoxycurcumin and bisdemethoxycurcumin (Figure 1) (27). Curcumin is a kind of natural polyphenol that possess a wide spectrum of biological and pharmacological activities, including anti-inflammatory (28)(29)(30), antioxidant (31)(32)(33), anti-tumor (34,35), anti-cancer (36,37), antiangiogenic (38), anti-aging (39), anti-microbial (24), and wound healing (40) activities, which confirmed by in vitro and in vivo studies. Chemically, curcumin is a bis-α,β-unsaturated βdiketone with two benzene rings that have phenolic hydroxyl and the methoxy, respectively (Figure 1). ...
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Intrauterine growth restriction (IUGR) refers to the slow growth and development of a mammalian embryo/fetus or fetal organs during pregnancy, which is popular in swine production and causes considerable economic losses. Nutritional strategies have been reported to improve the health status and growth performance of IUGR piglets, among which dietary curcumin supplementation is an efficient alternative. Curcumin is a natural lipophilic polyphenol derived from the rhizome of Curcuma longa with many biological activities. It has been demonstrated that curcumin promotes intestinal development and alleviates intestinal oxidative damage. However, due to its low bioavailability caused by poor solubility, chemical instability, and rapid degradation, the application of curcumin in animal production is rare. In this manuscript, the structural-activity relationship to enhance the bioavailability, and the nutritional effects of curcumin on intestinal health from the aspect of protecting piglets from IUGR associated intestinal oxidative damage were summarized to provide new insight into the application of curcumin in animal production.
... Various wet lab experimental tests with reference to some particular disease or target-protein/pathways have been performed to give the plausible mechanism of action of curcumin at the cellular site of action and its upregulating and down-regulating effect on various molecular species involved in the system. For example in case of cancer and immunomodulation both of which are governed by an array of modulators, curcumin has been reported to play an ubiquitous role, acting on multiple targets by modulating the key cell signaling mediators like AP-1, Cox-2, NFκB, EGFR, MMP9 and PKC which in turn control a systemic molecular machinery [44][45][46]. It shows chemopreventive potential of curcumin on various types of cancers like 40,41,33,42,43]. ...
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Curcumin molecule, the yellow pigment of the spice turmeric, has multiple targets in human body, probably the largest so far reported for any other lead compound, suggesting its remarkably fascinating character. Despite it's widely reported therapeutic applications no definite drug profile has so far emerged, due to its low bioavailability and non-specific target binding. The role of structurally related curcuminoids occurring in minor amounts in nature along with curcumin, in enhancing its activity also needs explanation. Their individual contribution to overall therapeutic activity which may be through synergistic action needs a logical interpretation. Present review deals with major structural and functional aspects of this fascinating and diversely active curcumin molecule along with drawing a comparative outlook for activities of structurally related curcuminoids. A comparative computational case study with all curcuminoids along with an established molecular target (COX2) of curcumin is also presented to establish the theoretical explanation of differential behaviour of curcuminoids. This review is likely to highlight the major problems and probable solutions associated with therapeutic application of curcumin molecule. Nonetheless, the review captures the upcoming potential disease specific research areas for curcuminoids and provides a perspective of future curcumin research.
... Throughout its multi-millennial medicinal use, turmeric proved therapeutic due to numerous activities against various diseases (Aggarwal et al., 2007). Longitudinal studies have shown curcumin, the main chemical constituent, and its analogs to have anti-inflammatory (Mukhopadhyay et al., 1982), anticancer (Brouet & Ohshima, 1995;Goel et al., 2008), immunomodulatory (Srivastava et al., 2011) and antioxidant properties (Ahsan et al., 1999), in addition to its antibacterial, antifungal, and antiviral activities (Zorofchian Moghadamtousi et al., 2014). ...
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The use of natural resources for the prevention and treatment of diseases considered fatal to humanity has evolved. Several medicinal plants have nutritional and pharmacological potential in the prevention and treatment of viral infections, among them, turmeric, which is recognized for its biological properties associated with curcuminoids, mainly represented by curcumin, and found mostly in rhizomes. The purpose of this review was to compile the pharmacological activities of curcumin and its analogs, aiming at stimulating their use as a therapeutic strategy to treat infections caused by RNA genome viruses. We revisited its historical application as an anti-inflammatory, antioxidant, and antiviral agent that combined with low toxicity, motivated research against viruses affecting the population for decades. Most findings concentrate particularly on arboviruses, HIV, and the recent SARS-CoV-2. As one of the main conclusions, associating curcuminoids with nanomaterials increases solubility, bioavailability, and antiviral effects, characterized by blocking the entry of the virus into the cell or by inhibiting key enzymes in viral replication and transcription.
... Also, curcumin can suppress the transcription factor NF-jB and lowers the expression of several proinflammatory cytokines and chemokines [58]. In addition, curcumin can modify intracellular redox status, which affects a variety of cellular pathways by influencing transcription of the activating factor including AP-1, STAT, NF-AT, p53, kinases, and cytokine release [59]. Therefore, curcumin affects both the innate and adaptive immune response and regulates immune cells like B and T cells, and macrophages. ...
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... Pounded, tincture, powder [122][123][124] Glycine max ...
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COVID-19 is catastrophic widespread in world history. There are many efforts and investments to develop the medicines as far the immune or treat this disease. However, drug and medication are paying to pivot the consideration; it seems from the results of different studies that have been done on plant-originated medicines. These medicines could also be potent candidates for the formulation and development of drugs that inhibit the activity of this virus and control the disease. In this study was discussed the antiviral capability of medicinal isolated natural products and phytochemicals from herbs and plant take part to prohibit the activity of many strains of coronaviruses (CoVs) that cause the diseases in the human. It shows that antiviral plant compounds or molecules is being used for the development of medicines against the CoVs which are responsible for the COVID-19 disease.
... 16 However, its poor solubility and rapid biotransformation to inactive metabolites limit the utility of formulated curcumin; therefore, products that provide >100-fold better absorption than unformulated curcumin are considered highly bioavailable. 17 Immunomodulatory properties of curcumin have been reported recently, 18 and benefits of curcumin in chronic phase of asthma have been investigated due to the complexity and involvement of many factors in the disease. Curcumin, having many beneficial properties, can be used as a potential therapeutic drug for the treatment of asthma. ...
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Bronchial epithelial cells and fibroblasts play an essential role in airway remodelling, due to their protective and secretory functions. There are many studies proving that infection caused by human rhinovirus may contribute to the process of airway remodelling. The beneficial properties of curcumin, the basic ingredient of turmeric, have been proved in many studies. Therefore, the aim of this study was the evaluation of curcumin immunomodulatory properties in development of airway remodelling. Fibroblasts (WI-38 and HFL1) and epithelial cells (NHBE) were incubated with curcumin. Additionally, remodelling conditions were induced with rhinovirus (HRV). Airway remodelling genes were determined by qPCR and immunoblotting. Moreover, NF-κB, c-Myc and STAT3 were silenced to analyse the pathways involved in airway remodelling. Curcumin reduced the expression of the genes analysed, especially MMP-9, TGF-β and collagen I. Moreover, curcumin inhibited the HRV-induced expression of MMP-9, TGF-β, collagen I and LTC4S (p < 0.05). NF-κB, c-Myc and STAT3 changed their course of expression. Concluding, our study shows that curcumin significantly downregulated gene expression related to the remodelling process, which is dependent on NF-κB and, partially, on c-Myc and STAT3. The results suggest that the remodelling process may be limited and possibly prevented, however this issue requires further research.
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A simple and versatile strategy for controlled production of monodisperse ethyl cellulose (EC) microcapsules by a single-stage emulsification method has been developed. Monodisperse oil-in-water emulsions, obtained by a microfluidic device, are used as templates for preparing EC microcapsules. Oil-soluble ethyl acetate (EA) is miscible with water, so the interfacial mass transfer between EA and water occurs sufficiently, which leads to water molecules pass through the phase interface and diffuse into emulsion interior. Water molecules aggregate at the interface, and some merge into a large water drop in the central position of the emulsion. After evaporation of EA solvent, monodisperse EC microcapsules create large numbers of pits on the surface with a hollow structure. Curcumin is used as a model drug and embedded in the hollow structure. EC microcapsules have good, sustained drug release efficacy in a simulated intestinal environment, and the release process of EC microcapsules containing 6.14% drug-loaded capacity is fully consistent with the vitro drug release model. Such simple techniques for making EC microcapsules may open a window to the controlled preparation of other multifunctional microcapsules. Besides, it offers theoretical guidance for the study of EC microcapsules as drug carriers and expanding clinical application of curcumin.
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Toll-like receptors (TLRs) are a family of mammalian homologues of Drosophila Toll and play important roles in host defense. Two of the TLRs, TLR2 and TLR4, mediate the responsiveness to LPS. Here the gene expression of TLR2 and TLR4 was analyzed in mouse macrophages. Mouse splenic macrophages responded to an intraperitoneal injection or in vitro treatment of LPS by increased gene expression of TLR2, but not TLR4. Treatment of a mouse macrophage cell line with LPS, synthetic lipid A, IL-2, IL-15, IL-1beta, IFN-gamma, or TNF-alpha significantly increased TLR2 mRNA expression, whereas TLR4 mRNA expression remained constant. TLR2 mRNA increase in response to synthetic lipid A was severely impaired in splenic macrophages isolated from TLR4-mutated C3H/HeJ mice, suggesting that TLR4 plays an essential role in the process. Specific inhibitors of mitogen-activated protein/extracellular signal-regulated kinase kinase and p38 kinase did not significantly inhibit TLR2 mRNA up-regulation by LPS. In contrast, LPS-mediated TLR2 mRNA induction was abrogated by pretreatment with a high concentration of curcumin, suggesting that NF-kappaB activation may be essential for the process. Taken together, our results indicate that TLR2, in contrast to TLR4, can be induced in macrophages in response to bacterial infections and may accelerate the innate immunity against pathogens.