“Spicing Up” of the Immune System by Curcumin

Abstract

Curcumin (diferuloylmethane) is an orange-yellow component of turmeric (Curcuma longa), a spice often found in curry powder. Traditionally known for its an antiinflammatory effects, curcumin has been shown in the last two decades to be a potent immunomodulatory agent that can modulate the activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells. Curcumin can also downregulate the expression of various proinflammatory cytokines including TNF, IL-1, IL-2, IL-6, IL-8, IL-12, and chemokines, most likely through inactivation of the transcription factor NF-kappaB. Interestingly, however, curcumin at low doses can also enhance antibody responses. This suggests that curcumin's reported beneficial effects in arthritis, allergy, asthma, atherosclerosis, heart disease, Alzheimer's disease, diabetes, and cancer might be due in part to its ability to modulate the immune system. Together, these findings warrant further consideration of curcumin as a therapy for immune disorders.

Full text

Journal of Clinical Immunology, Vol. 27, No. 1, January 2007 (
C

2007)
DOI: 10.1007/s10875-006-9066-7
“Spicing Up” of the Immune System by Curcumin
GANESH CHANDRA JAGETIA
1
and BHARAT B. AGGARWAL
1,2
Received December 6, 2006; accepted December 11, 2006
Published online: 9 January 2007
Curcumin (diferuloylmethane) is an orange-yellow component
of turmeric (Curcuma longa), a spice often found in curry pow-
der. Traditionally known for its an antiinflammatory effects,
curcumin has been shown in the last two decades to be a potent
immunomodulatory agent that can modulate the activation of T
cells, B cells, macrophages, neutrophils, natural killer cells, and
dendritic cells. Curcumin can also downregulate the expression
of variousproinflammatorycytokines including TNF, IL-1, IL-2,
IL-6, IL-8, IL-12, and chemokines, most likely through inacti-
vation of the transcription factor NF-κB. Interestingly, however,
curcumin at low doses can also enhance antibodyresponses.This
suggests that curcumin’s reported beneficial effects in arthritis,
allergy, asthma, atherosclerosis, heart disease, Alzheimer’s dis-
ease, diabetes, and cancer might be due in part to its ability
to modulate the immune system. Together, these findings war-
rant further consideration of curcumin as a therapy for immune
disorders.
KEY WORDS: Curcumin; tumor necrosis factor; nuclear factor-κB;
interleukins; chemokines; immunomodulation.
INTRODUCTION
Turmeric (called Haldi in Hindi language) and named by
British as curry spice, is the dried rhizome powder of Cur-
cuma longa, a perennial herb of the Zingiberaceae (gin-
ger) family, which is 3–5 ft tall bearing oblong, pointed,
short-stemmed leaves and funnel-shaped yellow flowers.
The rhizome of turmeric is a valuable cash crop, which is
widely cultivated in Asia, India, China, and other tropical
countries (1). Turmeric, is commonly used as a spice
in curries, food additive and also, as a dietary pigment.
1
Cytokine Research Laboratory, Department of Experimental Therapeu-
tics, The University of Texas M. D. Anderson Cancer Center, Houston,
Texas.
2
To whom correspondence should be addressed at Department of Ex-
perimental Therapeutics, Unit 143, The University of Texas M. D.
Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas
77030; e-mail: aggarwal@mdanderson.org.
It has been used to treat various illnesses in the Indian
subcontinent from the ancient times. Turmeric finds its use
in one form or the other in the textile and pharmaceutical
industries (2). It is used in Hindu religious ceremonies and
Hindus also apply a mixture of turmeric and sandalwood
powder on their foreheads. Turmeric has been used as a
nontoxic drug in Ayurveda for centuries to treat a wide
variety of disorders including rheumatism, bodyache,
skin diseases, intestinal worms, diarrhea, intermittent,
fevers, hepatic disorders, biliousness, urinary discharges,
dyspepsia, inflammations, constipation, leukoderma,
amenorrhea, and colic (3). Turmeric has been considered
as an emmenagogue, diuretic, and carminative when taken
orally, whereas topical application is commonly used to
treat bruises, pains, sprains, boils, swellings, sinusitis, and
various skin disorders (4). Turmeric is used to treat angina
pectoris, stomachache, postpartum abdominal pain, and
gallstones in the Chinese system of medicine (5). It seems
to promote the qi flow, “stimulates menstrual discharge,”
and relieves menstrual pain (6). The poultices prepared
from turmeric are topically applied to relieve pain and
inflammation (7). A mixture of turmeric powder and
slaked lime is applied topically as a household remedy
to cure injury-related sprains and swelling. Turmeric
is also an effective household remedy for sore throat,
cough, and common cold, where it is taken orally with tea
or hot milk.
The major chemical principles of turmeric are curcum-
inoids, which impart characteristic yellow color to it. The
curcuminoids can be separated from turmeric by ethanol
extraction and it usually contains 0.3–5.4% curcumin (one
of the major curcuminoids) depending on the season of its
harvest (7). Vogel and Pellatier (8) first reported molecular
formula of curcumin as C
21
H
20
O
6
, which was later iden-
tified as diferuloylmethane (8). The IUPAC name of cur-
cumin is (1,7-bis (4-hydroxy-3-methoxy-phenyl) hepta-1,
6-diene-3, 5-dione) and its chemical structure (9)isde-
picted in Fig. 1. Curcumin is an orange-yellow, crystalline
powder and does not dissolve in water; however, it readily
goes into solution in ethanol and dimethylsulfoxide.
19
0271-9142/07/0100-0019/0
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2007 Springer Science+Business Media, LLC

20 JAGETIA AND AGGARWAL
H
3
CO
HO
OO
OH
OCH
3
Structure of curcumin (diferuloylmethane)
Fig. 1. Chemical structure of curcumin.
Curcumin as such does not possess any nutritive value
however; ithas beenin constantuse byhumans asturmeric
powder since Vedic times or even earlier and could be con-
sidered as pharmacologically safe. Human consumption
of curcumin as a dietary spice ranges up to 100 mg/day
(10) and recent phase I clinical trials indicate that hu-
mans can tolerate a dose of curcumin as high as 12 g/day,
without any toxic side effects (11). The latest report has
indicated safe dose of curcumin up to 12 g/day in humans
(12).
The degradation kinetics of curcumin have been worked
out under various pH conditions (13). Ninety percent of
curcumin gets decomposed within 30 min in 0.1 M phos-
phate buffer and serum-free medium (pH 7.2 at 37
◦
C). The
decomposition of curcumin is pH-dependent (pH 3–10)
and the rate of decomposition is higher under neutral-
basic conditions. Curcumin is comparatively more stable
in cell culture media containing 10% fetal calf serum and
in human blood. Less than 20% of curcumin gets de-
graded after 1 h and approximately 50% decomposes af-
ter 8 h. The trans-6-(4

-hydroxy-3

-methoxyphenyl)-2,4-
dioxo-5-hexenal has been reported as a major degradation
product of curcumin, whereas vanillin, ferulic acid, and
feruloyl methane were found to be the minor degradation
products. Among all the major degradation products re-
ported, the quantity of vanillin increases with time (13).
Levels as low as 0.017 ng/mL of curcumin can be detected
in aqueous solution in vitro by flurometric methods us-
ing mixed micelle of sodium dodecyl benzene sulfonate
(SDBS) and cetyltrimethylammonium bromide (CTAB)
surfactants (14).
Curcumin reportedly possesses several pharmacologi-
cal properties including antiinflammatory, antimicrobial,
antiviral, antifungal, antioxidant, chemosensitizing, ra-
diosensitizing, and wound healing activities (2, 15–33).
Curcumin can suppress tumor initiation, promotion, and
metastasis in experimental models (34–44). It can also
act as an antiproliferative agent by interrupting the cell
cycle, disrupting mitotic spindle structures, and inducing
apoptosis and micronucleation (45–48). Apparently, cur-
cumin is a pluripotent pharmacological agent that utilizes
multiple molecular pathways to leave its imprint on bi-
ological systems (47). This review is mainly focused on
curcumin’s immunomodulatory activities.
EFFECT OF CURCUMIN ON IMMUNE CELLS
Curcumin has been found to modulate the growth and
cellular response of various cell types of the immune
system (Fig. 2). How this agent affects T cells, B cells,
macrophages, neutrophils, NK cells, and dendritic cells is
discussed in the following text.
Effect of Curcumin on T Cells
Numerous lines of evidence suggest that curcumin can
modulate both the proliferation and the activation of T
cells. Curcumin inhibited the proliferation induced by
concanavalin A (Con A), phytohemagglutinin (PHA), and
phorbol-12-myristate-13-acetate (PMA) of lymphocytes
derived from fresh human spleen ((49); Table I). During
these studies, curcumin also suppressed IL-2 synthesis;
and IL-2 induced proliferation of lymphocytes. This cor-
related with suppression of NF-κB activation. Thus, these
results suggest that curcumin exhibits immunosuppressive
effects mediated through regulation of IL-2. In another
study, the same group reported that curcumin inhibits the
proliferation induced by PMA and anti-CD28 antibody
or that induced by PHA of T lymphocytes isolated from
healthy donors (50). In comparison, cyclosporine A was
found to suppress PHA-induced T-cell proliferation but
not that induced by PMA and anti-CD28 antibody. Thus,
curcumin can overcome the resistance of PMA and CD28
pathway to cyclosporine A. These results suggest that
curcumin exhibits immunosuppressive properties that are
superior than cyclosporine A. Yadav and his group also re-
ported that curcumin can suppress the PHA-induced pro-
liferation of human peripheral blood mononuclear cells
(PBMCs) and inhibit IL-2 expression and NF-κB(51). In
still another report, curcumin inhibited the activation of
human V γδT cells induced by phosphoantigens (52).
A study by Sikora et al., reported that curcumin treat-
ment completely abolished the proliferation of Con A
stimulated rat thymocytes and it also suppressed the
dexamethasone-induced apoptosis in stimulated as well
as nonstimulated rat thymocytes. This inhibition of apop-
tosis is accompanied by partial or complete oppression
of AP-1 activity in nonstimulated or Con-A-stimulated
thymocytes, respectively. A similar effect was also ob-
servable in rat thymocytes treated with dexamethasone;
however, curcumin per se did not have any adverse effect
on AP-1 activity (53). The immunomodulatory role of
Journal of Clinical Immunology, Vol. 27, No. 1, 2007

IMMUNE SYSTEM BY CURCUMIN 21
Curcumin
T Lymphocytes
(CD 8)
Macrophages
Natural killer cells
T Lymphocytes
(CD 4)
B
Lymphocytes
Dendritic cell
Regulation of various immune cells by curcumin (diferuloylmethane)
s
Other
immune cells
Fig. 2. Action of curcumin on different types of immune cells.
curcumin has been studied in HTLV-1-infected T-cells and
primary ATL cells, where curcumin treatment preferen-
tially inhibited the growth of HTLV-1-infected T-cells and
primary ATL cells, but spared the normal PMBCs. This
antiproliferative effect of curcumin on HTLV-1-infected
T-cells and primary ATL cells was directly correlated to
its ability to induce cell cycle arrest by downregulating
the expression of cyclin D1, Cdk1, and Cdc25C and in-
duce apoptosis by reducing the expression of XIAP and
survivin. In addition, it also suppressed the constitutive
AP-1 DNA-binding and transcriptional activity in these
cells (54, 55).
Another study on mouse lymphocytes has reported that
a low-dose curcumin increased the proliferation of splenic
lymphocytes, whereas high-dose curcumin depressed it
indicating its ability to differentially regulate the prolif-
eration of splenic lymphocytes (56). In yet another study,
curcumin treatment increased the proliferation of intesti-
nal mucosal CD3
+
T cells due to change in CD4
+
T sub-
sets in C57BL/6J-Min/
+
(Min/
+
) mice bearing a germline
mutation in Apc tumor suppressor gene (57). These studies
further demonstrate the ability of curcumin to modulate
immune functions in T cells.
The studies by Gerstch et al. on PMA-stimulated
PBMCs have revealed that the low concentrations of
curcumin significantly downregulated the expression of
PMA-induced granulocyte macrophage colony stimulat-
ing factor (GM-CSF) mRNAs, whereas high concentra-
tions upregulated interferon gamma (IFN-γ )mRNAs.
These effects of curcumin were linked with the suppres-
sion of PMA-induced activation of NF-κB and downreg-
ulation of PMA-induced cyclin D1 mRNA expression in
PMBCs (58). The experiments on rat splenic lymphocytes
showed that curcumin treatment enhances the immune re-
sponse of the lymphocytes by increasing IgG production
(59).
The studies of ion transport enzyme activity in stim-
ulated T cells revealed a marked regulatory activity of
turmeric and its active principles, turmerin or curcumin.
Treatment of Con A-stimulated and control human blood
mononuclear T cells with different concentrations of
turmeric, curcumin, and turmerin reduced ATPase levels
on 3 and 5 days after treatment than the control. On the
contrary, a three and twofold elevation in Ca
2+
ATP as e
and Na/K
+
ATPase activities were observed on day 7,
respectively (60). This could be one of the mechanisms of
immunomodulation by curcumin in T cells.
Curcumin not only plays an important role in the im-
munomodulation of normal but also transformed T cells,
where it adversely affects the cell proliferation of these
cells by suppression of IL-2 gene expression and by in-
hibiting the activation of NF-κB(58). These results indi-
cate that the antiproliferative activity of curcumin against
T cells may be relevant for T-cell leukemia.
Effect of Curcumin on B Cells
In addition to affecting T cells, curcumin can also in-
fluence the proliferation of B cells and B lymphocyte-
mediated immune function. Curcumin has been reported
Journal of Clinical Immunology, Vol. 27, No. 1, 2007

22 JAGETIA AND AGGARWAL
Table I. Modulation of Immune Cells by Curcumin
T lymphocytes
Inhibits the proliferation of human spleen T cells induced by PHA, PMA, and CON-A (49).
Inhibits the proliferation of human T cells induced by PMA and anti-CD28 (50).
Inhibits the proliferation of human T cells induced by PHA (51).
Inhibits the proliferation of human PBMC induced by PHA (51).
Inhibits the activation of human VγδT cells induced by phosphoantigens (52).
Inhibits IL-2 expression in various T cells (50).
Inhibits proliferation of Con-A stimulated rat thymocytes and dexamethasone-induced apoptosis in stimulated as well as
unstimulated rat thymocytes (53).
Inhibits the proliferation of HTLV-1 infected T cells and ATL cells but not normal PMBCs, induces apoptosis in infected
cells, and downregulates the expression of cyclin D1, Cdk1, and Cdc25C (54, 55).
Increases cell proliferation of splenic lymphocytes and CD4
+
T cells (56, 57).
Decreases ATPase early (3 & 5 days), whereas increases by 7 days in Con-A stimulated T cells (60).
B cells
Inhibits Epstein bar virus-induced B-cell proliferation and immortaliztion (61).
Increases B-cell proliferation in intestinal mucosa of mice (57).
Macrophages
Increases phagocytosis of macrophages and differentially regulates splenocyte proliferation (56).
Reduces the ROS generation ability of macrophages and secretion of lysosomal enzymes (63, 64).
Differentially activates macrophages by downregulating Th1 and NO production (65).
NK Cells
Low dose enhances proliferation of YAC-1 cells but not of splenocytes or EL4 cells (66).
Decreases proliferation of splenic lymphocytes, cytotoxic T lymphocytes (CTLs), lymphokine-activated killer (LAK) cells,
and macrophages (67).
Increases NK-cell cytotoxicity (51).
Effect on dendritic cells
Suppresses expression of CD80, CD86, and MHC class II antigens in GM-CSF/IL-4 stimulated DCs without affecting MHC
class I antigens (73).
Inhibits LPS-induced IL-12, IL-1β, IL-6, and TNF-α and the phosphorylation of MAPK and NF-κB nuclear translocation
(73).
PMN
Increases total white blood cell count, circulating antibody titer, plaque-forming cells, α-esterase-positive cells, and
phagocytic activity of macrophages (75).
Induces reaginic antibody in β-lactoglobulin-challenged brown Norway rats (76).
Inhibit 5-hydroxyeicosatetraenoic acid in human neutrophils (77).
to block Epstein-bar virus (EBV) induced immortaliza-
tion of human B cells. This effect of curcumin ap-
pears to be mediated through downregulation of oxidative
stress induced by cyclosporine and hydrogen peroxide.
Thus, posttransplant lymphoproliferativedisorder (PLTD)
associated with the use of cyclosporine during organ trans-
plantation, can be reversed by curcumin (61). Churchill
et al., have reported that curcumin treatment stimulates
proliferation of B cells in the mucosa of intestine of
C57BL/6J-Min/
+
(Min/
+
) mice indicating its immunos-
timulatory activity (57).
Apart from affecting normal B-cells, curcumin has been
found to differentially reduce the proliferation of imma-
ture B-cell lymphoma (BKS-2) cells, but not of normal
cells, by inducing apoptosis and this is associated with
downregulation of egr-1, c-myc, bcl-XL, and the tumor
suppressor gene p53, and almost complete inhibition of
NF-κB activity (62). These studies indicate that curcumin
differentially regulates the immune function in normal as
well as tumor cells, which could confer advantage in a
therapeutic setting.
Effect of Curcumin on Macrophages
Many studies have shown curcumin’s ability to mod-
ulate the activation of macrophages. For example, cur-
cumin seems to regulate the immune function of mice in a
dose-dependent fashion as curcumin treatment enhanced
the phagocytosis of peritoneal macrophages and differ-
entially regulates the proliferation of splenocytes (56).
Apart from cell proliferation, a daily diet of curcumin
(30 mg/kg body weight/day) for 2 weeks in rats report-
edly attenuated the ability of macrophages to generate
ROS, (63) and secrete lysosomal enzymes collagenase,
elastase, and hyaluronidase (64). The ability of curcumin
to downregulate Th1 and NO production has been directly
correlated to its ability to differentially activate the host
macrophages (65).
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IMMUNE SYSTEM BY CURCUMIN 23
Effect of Curcumin on Natural Killer Cells
Curcumin can also apparently modulate the activation
of natural killer (NK) cells. Studies by South and his
colleagues, in rats showed that curcumin at a dose of 1
and 20 mg/kg body weight could not enhance the IgG lev-
els in the NK cells, whereas a higher dose (40 mg/kg) did
elevate IgG levels significantly. More importantly, none of
the three doses of curcumin significantly enhanced either
delayed-type hypersensitivity or NK cell activity (66).
The extended studies by these authors on YAC-1 and EL4
tumor cells and normal splenocytes in vitro showed that
curcumin treatment exerted differential effects on cell vi-
ability and proliferation. Treatment with low-dose cur-
cumin (1.25 µg/mL) enhanced the proliferation of YAC-1
cells but not that of either splenocytes or EL4 cells (66).
A similar differential effect has been reported on NK cells
by curcumin and it was linked to its ability to upregulate
Th1 and NO production (65). In yet another study, cur-
cumin treatment retarded the proliferation of splenic lym-
phocytes, cytotoxic T lymphocytes (CTLs), lymphokine-
activated killer (LAK) cells, and macrophages (67). In one
of the investigations, curcumin has been found to augment
NK-cell cytotoxicity (51). All these studies indicate that
curcumin acts like a good immunomodulatory agent.
In addition to its immunomodulation of normal NK
cells, curcumin could also increase cell death of refrac-
tory natural killer/T-cell lymphoma (NKTL) cell lines
(i.e., NKL, NK-92, and HANK1), which are resistant to
other therapies. This was directly linked to the suppres-
sion of the NF-κB activation including the constitutively
expressed NF-κB and also blockage of Bcl-xL, cyclin D1,
XIAP, and c-FLIP expression and the subsequent cleav-
age and activation of caspase-8 and poly (ADP-ribose)
polymerase (68). These observations indicate its potential
as an antiproliferative agent that could play an important
and decisive role in cancer chemotherapy.
Effect of Curcumin on Dendritic Cells
Dendritic cells are professional antigen-presenting cells
that play a key role as immune sentinels in the initiation of
T-cell responses to microbial pathogens, tumors, and in-
flammation (69, 70). Peripheral DCs are generally imma-
ture both phenotypically and functionally (71). They nev-
ertheless have clinical potential as cellular adjuvants in the
treatment of chronic infectious diseases and tumors (72).
There is only one report to date on immune modulation
of murine DCs using curcumin by Kim et al., who found
that curcumin significantly depressed the expression of
CD80, CD86, and MHC class II antigens in GM-CSF/IL-4
stimulated DCs without affecting MHC class I antigens.
They also found that curcumin efficiently blocked the
LPS-induced expression of IL-12 and inflammatory cy-
tokines including IL-1β, IL-6, and TNF-α. Curcumin
treatment enhanced the Ag capturing ability of DCs via
mannose receptor-mediated endocytosis. However, their
Th1 and normal cell-mediated immune response was very
poor. Further studies showed that treatment of DCs with
curcumin before LPS stimulation completely suppressed
the LPS-induced phosphorylation of MAPK and NF-κB
nuclear translocation (73). The direct suppression of these
activities by curcumin in DCs may leadto the attenuated T-
cell-mediated immune responses by interfering with han-
dling and presentation of antigens by DCs.
Effect of Curcumin on Other Immune Cells
Apart from affecting T cells, B cells, macrophages, and
NK cells, curcumin has also been reported to affect other
immune cells such as neutrophils, etc. In one of the stud-
ies, curcumin inhibited the FMLP (a chemotactic peptide)
and zymosan-activated plasma (ZAP)-induced aggrega-
tion of monkey neutrophils. However, such an action was
absent in serum-treated zymosan (STZ) and arachidonic
acid (AA) treated neutrophils. Curcumin also blocked the
production of O
2
−
radicals, and myeloperoxidase, in AA-,
STZ-, and fmlp-stimulated cells, except lysozymes, which
were mildly affected (74). The studies on Balb/c mice
spleen immunized with sheep red blood cells have shown
several immunostimulatory actions of curcumin includ-
ing increase in total white blood cell count, circulating
antibody titer, and plaque-forming cells (75). In addition,
curcumin also raised bone marrow cellularity, α-esterase-
positive cells, and phagocytic activity of macrophages
(75).
Moreover, curcumin has been found to induce reaginic
antibody in β-lactoglobulin-challenged brown Norway
rats maintained on diets comprising 10% coconut oil
(CO), high oleic safflower oil, safflower oil (SO), or fish
oil. Curcumin also reduced the secretion of rat chymase
II (RChyII) in rats fed with SO and 0.5% curcumin, indi-
cating variable effect on the synthesis of immunoglob-
ulin E and the degranulation of intestinal mast cells
(76). Curcumin treatment has been reported to inhibit
5-hydroxyeicosatetraenoic acid in human neutrophils in
one of the studies (77).
In yet another study, curcumin caused cell death by
apoptosis in both normal and transformed human (HL
60) and rodent cells despite the lack of oligonucleosomal
DNA fragmentation (DNA “ladder”). However, curcumin
blocked HL-60 in sub-G1 and increased caspase-3 activity
(78). These results indicate that curcumin exerts its im-
munomodulatory action on other immune cells described
earlier.
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24 JAGETIA AND AGGARWAL
EFFECT OF CURCUMIN ON IMMUNE CYTOKINES
Effect of Curcumin on Expression and Action of
TNF/TRAIL and Their Receptors
Cytokines are autocrine, paracrine, and acrine cell sig-
naling molecules that play a crucial role in acquired
as well as innate immunity. TNF-α is one of the most
versatile pleiotropic cytokine that induces growth stimu-
lation as well as inhibition by self-regulatory mechanisms
of its own and plays a crucial role as an immunostimulant
and mediator of host resistance to many infectious agents.
Curcumin exerts its profound effects on various cytokines
of the TNF superfamily. Curcumin can modulate the ex-
pression of both TNF and TNF-induced signaling and can
also inhibit LPS-induced expression of TNF-α (79–81).
It has also been reported to inhibit LPS or PMA-induced
TNF-α in dendtritic cells, macrophages, monocytes, alve-
olar macrophages, and endothelial and bone marrow
cells (73, 82, 83). An almost identical observation has
been made in rats, where curcumin treatment attenuated
TNF-α in sodium taurocholate-induced acute pancreatitis
(84).
In another study, curcumin treatment blocked the ex-
pression of TNF-α mRNA in the rat model of hemor-
rhage and resuscitation (85). Studies by Siddiqui et al.,on
septic rats revealed that curcumin treatment both before
and after the onset of sepsis could reduce tissue injury,
mortality, and decrease TNF-α expression (86). The anal-
ysis of molecular pathways revealed that curcumin re-
stores PPAR-γ expression in the liver of septic rats within
20 h. Similar results were obtained in endotoxin-treated
cultured RAW 264.7 cells, where curcumin suppressed
endotoxin-indued TNF-α expression and markedly ele-
vated PPAR-γ expression (86).
Experiments on HT29 intestinal epithelial cells (IECs)
stimulated with TNF-α and IL-1β, showed that curcumin
can block the binding of Shiga-like toxins (Stx) to IECs by
inhibiting Gb3 synthase (GalT6) mRNA expression (83).
In another set of experiments, three major active principles
namely, 1,7-bis (4-hydroxyphenyl)-1,4,6-heptatrien-3-
one, procurcumenol, and epiprocurcumenol isolated from
the crude methanol extract of the rhizomes of Curcuma
zedoaria were reported to suppress the production of
TNF-α in LPS-stimulated macrophages (87). These stud-
ies suggest that antiinflammatory activity of curcumin
could well be correlated to its ability to inhibit inflam-
matory cytokines at protein as well as mRNA levels.
TNF-related apoptosis-inducing ligand (TRAIL) is an-
other member of TNF superfamily that has been found to
be markedly influenced by curcumin treatment in various
investigations. Experiments conducted on the androgen-
sensitive human prostate cancer cell line LNCaP have
shown that curcumin increases cell death-promoting ac-
tivity of TRAIL by inducing DNA fragmentation even
though neither agent alone is significantly cytotoxic to
LNCaP cells at low concentrations (10 µM curcumin and
20 ng/mL TRAIL). Further analysis of molecular mech-
anisms showed that combination treatment resulted in
cleavage of procaspase-3, procaspase-8, and procaspase-
9; truncation of Bid, and release of cytochrome c from the
mitochondria (88
, 89) and could be responsible for the
observed increase in cytotoxicity.
Another study has reported the effect of curcumin on
death receptor DR5 (DR5/TRAIL-R2) in Caki, HCT 116,
HT 29, HepG2, and Hep 3B cells. This study clearly
demonstrated that curcumin and TRAIL treatment syn-
ergistically increased the death of TRAIL-resistant Caki
cells in a curcumin concentration-dependent manner,
which could be directly correlated to the upregulated ex-
pression of DR5 and proapoptotic gene, C/EBP homol-
ogous protein (CHOP), at both the mRNA and protein
levels in HCT 116, HT29, and HepG2 cell lines after cur-
cumin treatment. This upregulation of DR5 and CHOP
and cytotoxic effect of curcumin were due to its ability
to generate ROS (90, 91). The combination studies on
curcumin and TRAIL point that curcumin enhances the
effect of TRAIL and could make TRAIL-resistant cells
amenable to TRAIL therapy.
Effect of Curcumin on Interleukins
Interleukins are a group of cytokines that are secreted
by leukocytes and act as communication channels be-
tween them. Curcumin can also alter the expression and
activity of a variety of interleukins, especially IL-1, IL-2,
IL-6, IL-8, IL-10, and IL-12 and thus can influence func-
tions of different cells in a variety of ways (Table II). For
example, treatment of PMBCs with curcumin inhibited
LPS-induced IL-1β, IL-6, and TNF-α. Similarly, in rab-
bit experiments, curcumin reduced LPS-induced fever by
attenuating the expression of IL-1β, IL-6, and TNF-α in
the serum (81). This action of curcumin was mediated by
suppression of NF-κB activation and downstream events
that blocked these cytokines (81). Curcumin reportedly
reduced PMA- or LPS-stimulated production of IL-1 and
IL-8 in human peripheral blood monocytes and alveo-
lar macrophages in a concentration- and time-dependent
manner (79). A similar effect was observed for IL-2 pro-
duction in PHA-stimulated human PMBCs (51).
In endothelial cell-based experiments, curcumin sig-
nificantly retarded the transcriptional upregulation of
IL-1α and TNF-α-induced HO-1 (an inducible form
of hemeoxygenase that is upregulated in oxidant and
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IMMUNE SYSTEM BY CURCUMIN 25
Table II. Modulation of Various Cytokines by Curcumin
TNF-α
Inhibits LPS-induced expression of TNF-α andIL-1(80, 81).
Decreases sepsis-induced TNF-α and restores PPAR-γ expression (86).
Inhibits endotoxin-induced TNF-α in RAW 264.7 cells (86).
Suppression of TNF- α mRNA in hemorrhage and resuscitation rat model (85).
TRAIL
Increases activity of TRAIL in LNCaP cells by cleavage of procaspase-3, procaspase-8, and procaspase-9; truncation of Bid, and release of
cytochrome c from the mitochondria (88, 89).
Increases expression of DR5 and proapoptotic gene, C/EBP homologous protein (CHOP), at both the mRNA and protein levels in HCT 116,
HT29, and HepG2 cells (90, 91).
Interleukins
Inhibits LPS-induced IL-1β, IL-6, and TNF-α in PMBCs and rabbit serum and also inhibits NF-κB activation (81).
Decreases PMA- or LPS-stimulated IL-1 and IL-8 in human peripheral blood monocytes and alveolar macrophages (79, 82).
Inhibits PHA-stimulated IL-2 production in human PMBCs (51).
Decreases the transcriptional upregulation of IL-1α and TNF-α-induced HO-1 mRNA in endothelial cells (92).
Reduces IL-8 production in human pancreatic cells (94, 95).
Inhibits expression of IL-6 in WI-38 VA13 cells, dendritic cells, and sodium taurocholate-induced pancreatitis rats (73, 84, 95).
Inhibits IL-2 synthesis in Con A-, PHA-, and PMA-stimulated human splenocytes by blocking NF-κB activation (49).
Inhibits IL-1β-stimulated IL-8 gene expression in human bone marrow stromal cells (97).
Inhibits mRNA transcripts of IL-1α, IL-ß, IL-2, and IL-6 in hemorrhage/resuscitation rat model by suppressing the activation of NF-κBand
AP-1 (85).
Inhibits IL-12 p40 promoter activation in RAW264.7 monocytic cells transfected with p40 promoter/reporter constructs by blocking the
activation of NF-κB(98).
Decreases IL-12 production and Th1 cytokine profile in CD4
+
T cells stimulated with either LPS or heat-killed Listeria monocytogenes (99).
Toll-like receptors
Inhibits LPS-induced mRNA expression of TLR2 and blocks NF-κB activation in C3H/HeN mouse splenic macrophages (103).
Chemokines
Inhibits constitutive production of IL-8 and increases the expression of IL-8 receptors CXCR1 and CXCR2 in pancreatic cells (93).
Inhibits IL-1β-stimulated and neurotensin receptor-induced expression of IL-8 in human colorectal cancer cells (94).
Decreases expression of IL-6 in WI-38 VA13 and dendritic cells and also in sodium taurocholate-induced acute pancreatitis in rats (73, 84, 95).
Inhibits IL-8 secretion by blocking nuclear translocation of NF-κB in BCG-stimulated human monocytes (104).
Inhibits LPS-induced expression of MCP-1 and IP-10 mRNA in mouse bone marrow stromal cells (105).
Reduces P-LPS-induced expression of MCP-1 gene and activation of AP-1 and NF-κB in human gingival fibroblasts (108).
Inhibits the proliferation of lymphocytes and their ability to secrete IL-2, IL-5, GM-CSF, and IL-4 (109).
Adhesion molecules
Inhibits transcription of ICAM-1, VCAM-1, and E-selectin in human umbilical vein endothelial cells (110).
inflammatory settings) mRNA (92). Curcumin can also
reportedly block the activity of interleukin-1 (IL-1)
receptor-associated kinase (IRAK) thiols in murine EL4
thymoma cells. It also abrogates the recruitment of IRAKs
to the IL-1RI followed by the phosphorylation of IRAK
and IL-1RI-associated proteins (93). In other studies,
the production of IL-8 was abolished by curcumin in a
dose and time-dependent fashion (93, 94). In experiments
with SV40-transformed embryonic (WI-38 VA13) cells,
dendritic cells and sodium taurocholate-induced pancre-
atitic rats, curcumin was able to arrest the expression
of IL-6 (73, 84, 95). The studies conducted on IEC-6,
HT-29, and Caco-2 cells showed that curcumin treatment
represses the IL-1β-mediated ICAM-1 and IL-8 gene ex-
pression (96) and this action of curcumin was a result of
suppression of NF-κB activation, RelA nuclear translo-
cation, IκBα degradation, IκB serine 32 phosphorylation,
and IκB kinase activity (96).
In still another study, curcumin depressed IL-2 synthe-
sis in Con A-, PHA-, and PMA-stimulated human spleno-
cytes in a concentration-dependent manner by blocking
NF-κB activation (49). Similarly, curcumin successfully
blocked the IL-1β-stimulated IL-8 gene expression in hu-
man bone marrow stromal cells (97). A study on a rat
model of hemorrhage and resuscitation reported that cur-
cumin treatment suppresses the production of multiple
mRNA transcripts of IL-1α,IL-β, IL-2, IL-6, and IL-10 at
2 and 24 h after hemorrhage/resuscitation and this action
is mediated through the inhibition of NF-κB activation
and AP-1 (85). In another study, curcumin was found to
exert a repressive effect on IL-12 p40 promoter activa-
tion in RAW264.7 monocytic cells transfected with p40
promoter/reporter constructs by blocking the activation
of NF-κB(98). Similarly, curcumin pretreatment signifi-
cantly suppressed IL-12 production and Th1 cytokine pro-
file (i.e., decreased IFN-γ and increased IL-4 production)
Journal of Clinical Immunology, Vol. 27, No. 1, 2007

26 JAGETIA AND AGGARWAL
in CD4
+
T cells stimulated with either LPS or heat-killed
Listeria monocytogenes and ability of macrophages to in-
duce IFN-γ (99). These studies show that one of the most
important mechanisms of immunoregulation by curcumin
is suppression of activation of NF-κB.
Effect of Curcumin on Toll-Like Receptors
Toll-like receptors (TLRs) are, type I transmembrane
proteins that are key regulators of innate and adaptive im-
mune responses in mammals that can recognize distinct
pathogen-associated molecular signatures (100). A few
studies have reported the influence of curcumin on TLRs.
In one such study with Ba/F3 cells, curcumin abated
LPS-induced IRF3 activation and LPS-induced TLR4
signaling by arresting both myeloid differentiation fac-
tor 88 (MyD88)- and the TIR domain containing adaptor
inducing IFN-β (TRIF)-dependent pathways. However,
curcumin could not abrogate the IRF3 activation in 293T
cells caused by increased expression of TRIF, indicating
that curcumin also targets the TLR4 receptor complex
in addition to IKKβ (101). In studies using peritoneal
mesothelial cells from C3H/HeN mice, curcumin has been
shown to suppress lipid A-induced NF-κB, MCP-1, and
MIP-2 mRNA, implying its role in TLR4 signaling (102).
In still another experiment, treatment of C3H/HeN mouse
splenic macrophages with curcumin was found to abro-
gate LPS-induced mRNA expression of TLR2 and block
NF-κB activation (103). Studies on TLRs indicate that
immunomodulatory activity of curcumin may also be due
to its ability to target TLRs.
Effect of Curcumin on Chemokines
Chemokines are small, chemotactic cytokines, which
direct leukocyte migration, activate inflammatory re-
sponses, and help regulate tumor growth. A number of
studies in various study systems have confirmed cur-
cumin’s potential to suppress various chemokines. In ex-
periments with human pancreatic carcinoma cell lines,
curcumin abated the constitutive production of IL-8
while raising the expression of IL-8 receptors CXCR1
and CXCR2 (93). Similarly, in human colorectal cancer
cells, curcumin blocked in a time- and dose-dependent
manner the IL-1β-stimulated and neurotensin receptor-
induced expression of IL-8 (94). In other studies, cur-
cumin blocked the expression of IL-6 in WI-38 VA13 and
dendritic cells and also in sodium taurocholate-induced
acute pancreatitis in rats (73, 84, 95, 96). The studies
by Mendez-Samperio et al.,onMycobacterium bovis
Calmette-Guerin (BCG)-stimulated human monocytes re-
ported that curcumin abated BCG-induced IL-8 secretion
by blocking nuclear translocation of NF-κB(104).
Curcumin reportedly arrests the expression of the
chemokines MCP-1 (105) and interferon-inducible
protein-10 kDa (IP-10) in mouse bone marrow stromal
cells. This effect is apparently mediated by curcumin’s
ability to prevent TNF, IL-1, and LPS-induced expres-
sion of MCP-1 and IP-10 mRNA, and it is completely
reversible within 24 h after removing curcumin from the
cell culture medium. The inhibition of AP-1 and NF-κB
activation are responsible for this activity of curcumin
(106, 107).
Studies on human gingival fibroblasts have shown that
curcumin impedes the chemotactic activity of monocytes
isolated from the culture supernatant of Porphyromonas
gingivalis LPS (P-LPS)-treated cells (108). This effect
of curcumin seems to be mediated by blocking the P-
LPS-induced expression of MCP-1 gene and AP-1 and
NF-κB activation in human gingival fibroblasts (108).
Experiments by Kobayashi et al. have shown that cur-
cumin arrests in a concentration-dependent manner the
proliferation of lymphocytes from common house dust
mite (Dermatophagoides jhrinea) atopic asthmatics and
also their ability to secrete IL-2, IL-5, GM-CSF, and IL-4
(109). The immunomodulatory activity of curcumin may
also be due to its ability to alter chemokine expression as
indicated earlier.
Effect of Curcumin on Adhesion molecules
Experiments on human umbilical vein endothelial cells
demonstrated that curcumin blocks the steady-state tran-
scription of ICAM-1, VCAM-1, and E-selectin both tem-
porally and reversibly (110).
EFFECT OF CURCUMIN ON INFLAMMATORY ENZYMES
Curcumin can markedly influence the activities of en-
zymes that are hallmark of inflammation and subsequently
various disease states in humans (Table III). Curcumin
can differentially block inflammatory enzymes involved
in inflammation and extracellular matrix degradation at
both the mRNA and protein levels (111–127). In several
murine studies, curcumin has been shown to abate TPA-
induced epidermal inflammation, and inhibit epidermal
lipooxygenase and cyclooxygenase (COX) activities in
dose-dependent fashion by downregulating TPA-induced
NF-κB activation (111–113). Another study has also re-
ported suppression of TPA-induced COX-2, prostaglandin
E
2
(PGE
2
), and MMP-9 expression. This was in direct cor-
relation with the inhibition of ERK1/2 phosphorylation
and NF-κB activation (114). A similar effect has been re-
ported in Colo 205 colon carcinoma cells, where curcumin
Journal of Clinical Immunology, Vol. 27, No. 1, 2007

IMMUNE SYSTEM BY CURCUMIN 27
Table III. Modulation of Inflammatory Enzymes and Other Inflammatory Mediators by Curcumin
Cyclooxygenase
Inhibits TPA-induced COX-2, prostaglandin E
2
(PGE
2
), and MMP-9 expression, ERK1/2 phosphorylation, and NF-κB activation in mouse
(114).
Inhibits COX-2, PGE
2
, matrix metalloproteinase (MMP)-2, COX-1, and MMP-9 levels, without affecting MMP-7 levels in Colo 205 colon
carcinoma cells (115).
Inhibits the expression of COX-2 mRNA but had no effect on COX-1 mRNAs (116, 117, 126).
Inhibits LPS-induced COX-2 and PGE
2
in human leucocytes in a dose-dependent manner (118).
Inhibits IL-1β or IFN-α-induced PGE
2
and COX-2 at the protein and the mRNA levels (119, 120).
Inhibits expression of COX-2 and inflammatory cytokines while increasing PGE
2
levels in TNBS-induced colitis in rats (121).
Inhibits cigarette smoke or smokeless tobacco-induced NF-κB activation and COX-2 expression in human lung epithelial cells (122, 123).
Inhibits MAPK and JNK activity in HaCaT cells (124).
Inhibits TNF-α, and fecapentaene-12-induced COX-2 by blocking NF-κB activation and IKK activity in human colon epithelial cells (125).
Inhibits LPS-induced COX-2 expression, PGE
2
formation, and the catalytic activities of 5-LOX in RAW-264.7 cells (127).
Nitric oxide
Inhibits LPS- and IFNγ -induced NO production at low doses but not at higher doses (128).
Inhibits production of LPS-induced iNOS mRNA in cultured BALB/c mouse peritoneal macrophages ex vivo and mouse liver in vivo (129).
Inhibits NO production in activated macrophages (130).
Inhibits LPS-induced NO production in mouse macrophages (51).
Transcription factor NF-κB
Inhibits TNF-α,PMA,orH
2
O
2
-induced NF-κB activation by blocking the phosphorylation of IκKα (131).
Inhibits tobacco smoke-induced NF-κB activation and the phosphorylation and degradation of IκBα in myeloblastic and mantle cell lymphoma
cells (132).
Downregulates IL1 or TNF-α or LPS-induced NF-κB activation (51, 99, 133, 134).
Inhibits TRAIL-induced apoptosis by blocking IκBα phosphorylation and degradation and NF-κB activation in LNCaP cancer cells (88, 89).
Inhibits UVB-induced NF-κB activation in NCTC 2544 keratinocytes (135).
Inhibits degradation of IκBα, NF-κB DNA-binding activity and NF-κB-dependent expression of IL-6 in WI-38 VA13 cells (95).
Inhibits NF-κB and Ap-1 activation induced by hemorrhage/resuscitation injury in rats (85).
Inhibits TPA-induced NF-κB activation and degradation of IκBα in cultured HL-60 cells (136).
Inhibits cytokine-induced NF-κB DNA binding activity, RelA nuclear translocation, IκBα degradation, IκB serine 32 phosphorylation, and IKK
activity in EC-6, HT-29, and Caco-2 cells (96).
Inhibits TNBS-induced intestinal inflammation by simultaneously blocking NF-κB activation, degradation of cytoplasmic IκBα protein, and
cytokine mRNA expression (137).
Inhibits LPS-mediated TLR2 mRNA induction by inhibiting NF-κB activation (102, 103
).
Inhibits BCG-induced IL-8 production in human monocytes and gingival fibroblasts by blocking NF-κB activation (108).
Inhibits constitutive activation of NF-κB in HTLV-1 infected T-cell lines and primary ATL cells, by inhibiting phosphorylation of IκBα and
Tax-induced NF-κB transcriptional activity (55).
reduced COX-2, PGE
2
, matrix metalloproteinase (MMP)-
2, COX-1, and MMP-9 levels, but had no effect on MMP-
7levels(115). Other studies have reported that curcumin
blocked the expression of COX-2 mRNA (116, 117)but
had no effect on COX-1 mRNAs (116). Plummer et al.
observed that curcumin suppressed the protein levels of
LPS-induced COX-2 and PGE
2
in human leucocytes in
a dose-dependent manner (118). A similar effect was re-
ported in A549 human lung epithelial cells, where cur-
cumin inhibited IL-1β or IFN-α-induced prostaglandin
E2 and cyclooxygenase-2 at both the protein and the
mRNA levels (119, 120). In rats with TNBS-induced col-
itis, curcumin blocked the expression of COX-2 and in-
flammatory cytokines while increasing PGE
2
levels (121).
Various studies on human lung epithelial cells exposed
to cigarette smoke have shown that curcumin inhibited
NNK-induced activation of NF-κB and COX-2expression
(122, 123). Similarly, in HaCaT cells, curcumin abol-
ished UVB-induced COX-2 expression by suppressing
p38 MAPK and JNK activity (124).
In human colon epithelial cells, curcumin arrested the
TNF-α, and fecapentaene-12-induced COX-2 by blocking
NF-κB activation and IKK activity (125). A similar effect
has been observed in HT-29 colon cancer cells, where cur-
cumin arrested the mRNA and protein expression of COX-
2 but not of COX-1 (126). Studies on LPS-stimulated
RAW-264.7 cells indicate that curcumin reduces COX-2
expression, PGE
2
formation, and the catalytic activities
of 5-LOX (127).
The studies on mouse peritoneal exudates have revealed
that low-dose curcumin reduces LPS- and IFNγ -induced
NO production, whereas higher doses do not (128). In
another investigation, curcumin reduced the production
of iNOS mRNA in cultured BALB/c mouse peritoneal
macrophages ex vivo in a concentration-dependent man-
ner and also iNOS mRNA expression in the livers of mice
receiving two oral doses of 0.5 mL of a 10-µM curcumin
(92 ng/g of body weight) and LPS (129). Similarly, in
studies using activated macrophages, low-dose curcumin
inhibited NO production at24 h(IC
50
of 6 µM) and10 µM
Journal of Clinical Immunology, Vol. 27, No. 1, 2007

28 JAGETIA AND AGGARWAL
curcumin also reduced NOS activity than noncurcumin-
treated activated macrophages (130). In another study,
curcumin has been reported to reduce LPS-induced NO
production in mouse macrophages (51). These studies
affirm that curcumin acts as a strong antiinflammatory
agent.
EFFECT ON CURCUMIN ON TRANSCRIPTION
FACTOR NF-κB
The nuclear factor NF-κB is a ubiquitous transcrip-
tion factor important for its pleiotropic effects, inducible
expression patterns, unique regulatory mechanisms, and
involvement in a large number of signaling and gene ex-
pression pathways (Table III). The activation of NF-κBis
crucial to innate and adaptive immunity and it plays an
important role in inflammation, autoimmune diseases, and
cancer. As shown in a seminal study performed in our lab-
oratory, curcumin abrogates NF-κB activation induced by
TNF-α,PMA,orH
2
O
2
, by blocking the phosphorylation
of IKKα (131). Moreover, our studies on tobacco smoke-
induced NF-κB activation in myeloblastic and mantle cell
lymphoma cells revealed that curcumin blocks NF-κB ac-
tivation by inhibiting the phosphorylation and degradation
of IκBα (132). Curcumin also reportedly abrogates LPS-
induced MAPK activation and the translocation of NF-κB
p65 in DCs (73). In several other experiments, curcumin
has been reported to downregulate IL1 or TNF-α or LPS-
induced NF-κB activation (51, 99, 133, 134). A study with
A549 cells has reported that the ability of curcumin to ar-
rest NF-κB binding activity is reversible within 30 min
after IFN-α administration (134). In studies on LNCaP
cancer cells, curcumin mediated TRAIL-induced apop-
tosis by blocking IκBα phosphorylation and degradation
and subsequently abrogated NF-κB activation (88, 89).
The studies with NCTC 2544 keratinocytes have shown
that curcumin can inhibit UVB-induced TNF-α, IL-6, and
IL-8 by impeding NF-κB activation (135).
The studies with WI-38 VA13 cells have revealed that
curcumin can also inhibit the degradation of IκBα up-
stream and subsequent NF-κB DNA-binding activity and
NF-κB-dependent expression of IL-6 downstream (95).
Curcumin treatment also repressed NF-κB and Ap-1 acti-
vation induced by hemorrhage/resuscitation injury in rats
(85). Similar to this, curcumin has also been found to
arrest the TPA-induced NF-κB activation by attenuating
the degradation of IκBα and the subsequent translocation
of the p65 subunit in cultured HL-60 cells. Alternatively,
curcumin also repressed the TPA-induced activation of
NF-κ
B through direct interruption of the binding of NF-
κB to its consensus DNA sequences (136). The exper-
iments on EC-6, HT-29, and Caco-2 cells revealed that
curcumin blocks cytokine-induced NF-κB DNA binding
activity, RelA nuclear translocation, IκBα degradation,
IκB serine 32 phosphorylation, and IKK activity (96).
Furthermore, as already mentioned earlier, curcumin
can prevent and treat wasting and histopathologic symp-
toms associated with TNBS-induced intestinal inflam-
mation by simultaneously blocking NF-κB activation,
degradation of cytoplasmic IκBα protein, and cytokine
mRNA expression (137). The experiments on mouse
splenic macrophages have shown that high-dose curcumin
can abrogate LPS-mediated TLR2 mRNA induction by
inhibiting NF-κB activation (102, 103). The studies by
Watanabe et al. have shown that curcumin can also arrest
BCG-induced IL-8 production in human monocytes and
gingival fibroblasts by inhibiting NF-κB activation (108).
Finally, curcumin abolished constitutive activation of NF-
κB in HTLV-1 infected T-cell lines and primary ATL cells,
by inhibiting phosphorylation of IκBα and Tax-induced
NF-κB transcriptional activity (55). The various studies
outlined earlier indicate that suppression of NF-κB ac-
tivity may be one of the most important properties of
curcumin that could be responsible for its various immune
functions.
EFFECT OF CURCUMIN ON IMMUNE DISEASES
Because of its ability to modulate immune cells and
immune cell cytokines, curcumin has been shown to af-
fect several autoimmune diseases (Fig. 3). Inflammation
is a critical feature of most autoimmune diseases. Thus,
the role of curcumin in the therapy of such disorders is
expected.
Alzheimer’s Disease
Several reports suggest that curcumin has potential
against Alzheimer’s disease (138–141), a disease char-
acterized by the amyloid-induced inflammation in the
brain. The effect of curcumin in Alzheimer’s disease is
mediated through the downmodulation of cytokine (i.e.,
TNF-α and IL-1β) and chemokine (i.e., MIP-1b, MCP-
1, and IL-8) activity in peripheral blood monocytes and
reduces amyloid-β plaque formation (138–141).
Multiple Sclerosis
There are reports that curcumin may have potential
against multiple sclerosis, another autoimmune disease.
In animal model of this disease, curcumin was found to
inhibit IL-12-induced tyrosine phosphorylation of Janus
kinase 2, tyrosine kinase 2, and STAT3 and STAT4 tran-
scription factors (142).
Journal of Clinical Immunology, Vol. 27, No. 1, 2007

IMMUNE SYSTEM BY CURCUMIN 29
Alzheimer’s
disease
Curcumin
Cardiovascular
diseases
Multiple
sclerosis
Diabetes
Allergy
Arthritis Renal
ischemia
Inflammatory
bowel disease
Psoriasis
SclerodermaAsthma
Regulation of autoimmune diseases by curcumin (diferuloylmethane)
Fig. 3. Immune diseases that may be potentially treated with curcumin.
Cardiovascular Diseases
Curcumin has established antioxidant and antiinflam-
matory activities that offer promise in the treatment of
cardiovascular diseases. For example, it can inhibit lipid
peroxidation; reduce creatinine kinase and lactate dehy-
drogenase levels; and restore reduced glutathione, glu-
tathione peroxidase, and superoxide dismutase to normal
levels. Curcumin can also downregulate the expression of
myocardial TNF-α and MMP-2 and upregulate the ex-
pression of eNOS mRNA (143–147).
Diabetes
In diabetes, curcumin can suppress blood glucose lev-
els, increase the antioxidant status of pancreatic β-cells,
and enhance the activation of PPAR-γ (148–153).
Allergy
As shown in experiments in vivo (in guinea pigs) and
in vitro (rat basophilic leukemia cells), curcumin can help
clear constricted airways and increase antioxidant levels
(154, 155).
Asthma
That curcumin can relieve symptoms of asthma, has
been reported. These effects are linked with reduction of
the lymphocytic production of IL-2, IL-5, GM-CSF, and
IL-4 that is associated with bronchial asthma (110, 154).
Inflammatory Bowel Disease
As shown in vivo in humans and rats, curcumin can
ameliorate inflammatory bowel disease by reducing in-
flammatory cytokine levels, blunting NO and O
2
produc-
tion, and suppressing NF-κB activation in colon epithe-
lium (156, 157).
Rheumatoid Arthritis
In rheumatoid arthritis, curcumin exerts beneficial ef-
fects by inhibiting the expression of collagenase and
stromelysin and the proliferation of synoviocytes (158,
159).
Renal Ischemia
In renal ischemia, curcumin can exert beneficial effects
that include reducing creatine levels; upregulating Mn-
SOD levels; and inhibiting the expression of RANTES,
MCP-1, and allograft inflammatory factor (160, 161).
Psoriasis
Clinical evaluation of topical application of 1% cur-
cumin gel in psoriatic areas reduced the density of CD8
+
T cells when compared to untreated areas, where density
of CD8
+
T cells showed an elevation (162). This and
other studies suggest that curcumin treatment could be an
effective paradigm in the treatment of psoriasis as it could
also reduce the activity of phosphorylase kinase (163).
Scleroderma
Because scleroderma is a disease that involves exces-
sive collagen deposition and hyperproliferation of fibrob-
lasts, curcumin may be able to provide a therapeutic ben-
efit through its ability to suppress the proliferation of lung
fibroblasts in a process involving the inhibition of protein
kinase Cε (164).
Journal of Clinical Immunology, Vol. 27, No. 1, 2007

30 JAGETIA AND AGGARWAL
Acquired Immunodeficiency Disease (AIDS)
There are several reports indicating that curcumin may
have potential against AIDS. These effects of curcumin
are mediated through suppression of replication of hu-
man immunodeficiency virus (HIV) by inhibition of HIV
long terminal repeat (165, 166) and HIV protease (167),
inhibits HIV-1 integrase (168, 169), inhibits p300/CREB-
binding protein-specific acetyltransferase, and represses
the acetylation of histone/nonhistone proteins and his-
tone acetyltransferase-dependent chromatin transcription
(170). Thus, curcumin has a great potential also against
AIDS.
CONCLUSIONS
The curcumin, an orange-yellow polyphenol present
in curry spice, Curcuma longa has a long history of
therapeutic use in the Ayurvedic and Chinese systems
of medicine. The wisdom and scientific credentials of
this approach have been corroborated by numerous stud-
ies conducted over the past 30 years. Indeed, curcumin
has been found to possess antioxidant, antiinflammatory,
anticancer, and several other activities listed in this re-
view. Mechanistic studies have not only confirmed beyond
doubt that curcumin employs multiple pathways to leave
its imprint on biological systems, but also warrants its po-
tential use as a modern nontoxic chemotherapy for numer-
ous disorders. Curcumin primarily exerts its therapeutic
effects by inhibiting the degradation of IκBα and sub-
sequent inactivation of NF-κB, thus initiating a cascade
of downstream inflammatory and immunogenic events.
Curcumin’s inhibition of NF-κB activation, in turn, leads
directly to the inhibition of expression of a number of
proinflammatory cytokines (e.g., TNF, IL-1, IL-2, IL-6,
IL-8, and IL-12) and downregulation of the mRNA ex-
pression of several proinflammatory enzymes (e.g., COX,
LOX, MMPs, and NOS).In addition, curcumin’s immuno-
genic response is further enhanced by its ability to inhibit
TLRs, Finally, curcumin exerts proimmune activity in
several autoimmune disorders including Alzheimer’s dis-
ease, multiple sclerosis, cardiovascular disease, diabetes,
allergy, asthma, inflammatory bowel disease, rheumatoid
arthritis, renal ischemia, psoriasis, and scleroderma. Over-
all, these findings suggest that curcumin warrants further
consideration as a potential immunoregulatory treatment
in various immune disorders.
ACKNOWLEDGMENTS
We would like to thank Walter Pagel for carefully proof-
reading the manuscript and providing valuable comments.
Dr. Aggarwal is a Ransom Horne, Jr., Professor of Cancer
Research. This work was supported by a grant from the
Clayton Foundation for Research (to B. B. A.), National
Institutes of Health PO1 grant CA91844 on lung chemo-
prevention (to B. B. A.), National Institutes of Health P50
Head and Neck SPORE grant P50CA97007 (to B. B. A);
and a core grant (CA16672).
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