See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/321280987

Curcumin: A natural modulator of immune cells in systemic lupus

erythematosus

Article  in  Autoimmunity Reviews · November 2017

DOI: 10.1016/j.autrev.2017.11.016

CITATIONS READS

57 1,047

6 authors, including:

Amir Abbas Momtazi Saeed Mohammadian Haftcheshmeh

Mashhad University of Medical Sciences Neyshabur University of Medical Sciences
127 PUBLICATIONS   2,476 CITATIONS    24 PUBLICATIONS   1,146 CITATIONS   

SEE PROFILE SEE PROFILE

Seyed-Alireza Esmaeili Thomas Johnston

Mashhad University of Medical Sciences University of Missouri - Kansas City
60 PUBLICATIONS   1,573 CITATIONS    186 PUBLICATIONS   5,921 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Are chitosan natural polymers suitable as adjuvant/delivery system for anti-tuberculosis vaccines? View project

Curcumin View project

All content following this page was uploaded by Amir Abbas Momtazi on 02 February 2018.

The user has requested enhancement of the downloaded file.

AUTREV-02095; No of Pages 11
Autoimmunity Reviews xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Autoimmunity Reviews

journal homepage: www.elsevier.com/locate/autrev

Review

Curcumin: A natural modulator of immune cells in systemic

lupus erythematosus
Amir Abbas Momtazi-Borojeni a, Saeed Mohammadian Haftcheshmeh b, Seyed-Alireza Esmaeili b,
Thomas P. Johnston c,⁎⁎, Elham Abdollahi b, Amirhossein Sahebkar d,e,⁎
a
Nanotechnology Research Center, BuAli Research Institute, Student Research Committee, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences,
Mashhad, Iran
b
Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
c
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
d
Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
e
School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

a r t i c l e i n f o a b s t r a c t

Available online xxxx Curcumin is a polyphenol natural product isolated from turmeric, interacting with different cellular and molec-
ular targets and, consequently, showing a wide range of pharmacological effects. Recent preclinical and clinical
Keywords: trials have revealed immunomodulatory properties of curcumin that arise from its effects on immune cells and
Curcumin mediators involved in the immune response, such as various T-lymphocyte subsets and dendritic cells, as well
Dendritic cell as different inflammatory cytokines. Systemic lupus erythematosus (SLE) is an inflammatory, chronic
Regulatory T cell
autoimmune-mediated disease characterized by the presence of autoantibodies, deposition of immune com-
Systemic lupus erythematosus
plexes in various organs, recruitment of autoreactive and inflammatory T cells, and excessive levels of plasma
T helper 1
T helper 17 proinflammatory cytokines. The function and numbers of dendritic cells and T cell subsets, such as T helper 1
(Th1), Th17, and regulatory T cells have been found to be significantly altered in SLE. In the present report, we
reviewed the results of in vitro, experimental (pre-clinical), and clinical studies pertaining to the modulatory ef-
fects that curcumin produces on the function and numbers of dendritic cells and T cell subsets, as well as relevant
cytokines that participate in SLE.
© 2017 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.1. Curcumin and its immunomodulatory effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.2. Immunopathology of SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Overview of curcumin's effects on deficient immune cells in SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.1. Role of dendritic cells in the pathogenesis of SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.2. Modulatory effects of curcumin on dendritic cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.3. Role of Th1 cells in the pathogenesis of SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.4. Modulatory effects of curcumin on Th1 cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.5. Role of Th17 cells in the pathogenesis of SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.6. Modulatory effect of curcumin on Th17 cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.7. Role of Treg cells in the pathogenesis of SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.8. Modulatory effects of curcumin on Treg cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.9. Modulatory effects of curcumin on Th17/Treg balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.10. Curcumin bioavailability can influence its therapeutic effects on SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

⁎ Correspondence to: A. Sahebkar, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, P.O. Box 91779-48564, Iran.
⁎⁎ Correspondence to: T.P. Johnston, Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Rm. 4243 HSB, 2464 Charlotte St., Kansas City, MO
64108-2718, USA.
E-mail addresses: johnstont@umkc.edu (T.P. Johnston), sahebkara@mums.ac.ir, amir_saheb2000@yahoo.com (A. Sahebkar).

https://doi.org/10.1016/j.autrev.2017.11.016
1568-9972/© 2017 Elsevier B.V. All rights reserved.

Please cite this article as: Momtazi-Borojeni AA, et al, Curcumin: A natural modulator of immune cells in systemic lupus erythematosus,
Autoimmun Rev (2017), https://doi.org/10.1016/j.autrev.2017.11.016
2 A.A. Momtazi-Borojeni et al. / Autoimmunity Reviews xxx (2017) xxx–xxx
Disclosures by authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Systemic lupus erythematosus (SLE) is a debilitating autoimmune
disease. Fortunately, the outlook for patients now is much better than
it was 50 years ago. This is due to improved and more rapid diagnosis,
renal dialysis and kidney transplant, and just better patient care in gen-
eral. As an example of improved patient care, making sure that blood
pressure is controlled, as well as treating osteoporosis, have been cor-
nerstones in the treatment of SLE. Unfortunately, the progression to
end-stage renal disease with SLE has not changed with improved pa-
tient care. To date, the use of corticosteroids and immunosuppressive
drugs has been the foundation of drug treatment for SLE, although
hydroxychloroquine, antihypertensive drugs, and anti-osteoporosis
drugs also play an important role in the management of SLE. The med-
ical community has attained a temporary plateau with regard to the
treatment of SLE, because even though more steroid-sparing medica-
tions and less toxic doses of immunosuppressive drugs have improved
therapeutic efficacy and reduced side effects, the use of these agents
has essentially been fully optimized and promise little additional signif-
icant benefits. This has prompted the introduction of biologics (e.g.,
monoclonal antibodies) to alter the course of SLE, but, regrettably, the
results of clinical trials have been disappointing thus far. Therefore,
there exists an urgent need for alternative treatments, which may in-
clude medical procedures, lifestyle changes, and the use of exogenous
therapeutic compounds of both synthetic and natural origin. One such
natural compound that has shown promise in the treatment of several
diseases is curcumin. This review will explore the use of this natural
compound to ameliorate the symptoms of SLE.
1.1. Curcumin and its immunomodulatory effects
Curcumin is one of the most well-known natural products used
today. This natural compound is isolated from turmeric and is used ei-
ther alone, or as adjunct therapy with other conventional medications,
to treat various diseases. Curcumin is generally regarded as safe. In
fact, various human clinical trials have shown no dose-limited toxicity
when administered at doses up to 10 g/day [1,2]. Curcumin has also
been found to have a wide range pharmacological activities, including
anti- and pro-oxidant, anti-inflammatory, and antimicrobial properties,
as well as chemopreventive and chemotherapeutic activity [3–16]. Of
note, studies have also revealed interesting insight into the immuno-
modulatory potential of curcumin [17–24]. The immunomodulatory
property of curcumin arises from its interaction with various immune
mediators, including B and T lymphocytes, macrophage and dendritic
cells, cytokines, and various transcription factors. These transcription
factors include nuclear factor kappa B (NF-κB), activator protein-1
(AP-1), signal transducer and activator of transcription (STAT), and
also their downstream signaling pathways [25–31].
NF-κB exerts a key role in producing pro-inflammatory cytokines
such as interleukin (IL)-1, IL-2, and interferon-γ (IFNγ) in T-cells
[32–35]. The pleiotropic effects of curcumin are found to originate
from suppression of NF-κB activity by inhibiting I kappa B kinase-a
(IKK-a) phosphorylation and preventing nuclear translocation of the
NF-κB p65 subunit [36–38]. B lymphocyte stimulator (BLYS) is an im-
portant cytokine for B cell proliferation and autoantibody secretion in
autoimmune diseases [39]. It has been suggested that curcumin could
potentially serve as a novel therapeutic agent in the treatment of auto-
immune diseases, such as SLE and rheumatoid arthritis (RA), by
targeting BLYS. The inhibitory effect of curcumin on BLYS expression is
due to a reduction in NF-κB activity mediated by an inhibition in DNA
Please cite this article as: Momtazi-Borojeni AA, et al, Curcumin: A natural modulator of immune cells in systemic lupus erythematosus,
Autoimmun Rev (2017), https://doi.org/10.1016/j.autrev.2017.11.016
0
0
binding of NF-κB and the nuclear translocation of p65 [40]. Another
mechanism for the immunomodulatory effect of curcumin is related
to inhibition of mammalian target of rapamycin (mTOR) signaling by
suppression of cytokine production, for example, IL-2 [41].
1.2. Immunopathology of SLE
SLE is an chronic, inflammatory, autoimmune-mediated disease,
which primarily causes intolerance towards self-antigens [42,43]. SLE
is commonly characterized by the presence of autoantibodies, deposi-
tion of immune complexes in various organs [44,45], recruitment of
autoreactive and inflammatory T-cells, and excessive levels of plasma
proinflammatory cytokines [46–48]. Autoantibody production by
autoreactive B cells leads to the formation and deposition of
immunecomplexes in multiple organs and tissues, including the heart,
kidneys, brain, joints, skin, and the central nervous system [46,49]. Ap-
proximately 80–90% of cases of SLE occur in women [50], who suffer
from a mixture of mild skin or musculoskeletal and hematological
symptoms [44]. It is believed that heredity, viruses, ultraviolet light,
hormonal factors, and drugs may all contribute to some degree in the
development of SLE [45].
As it pertains to the immune-based causes of SLE, an imbalance in
various T-helper cell subsets (Th1/Th17), regulatory T cells (Tregs),
and dendritic cells (DCs) has been suggested to contribute to the path-
ogenesis of SLE [51]. An immoderate number and function of Th17 cells
[52–54] is known to be a preliminary trigger of autoimmune responses,
which is mediated through excessive secretion of proinflammatory cy-
tokines, including IL-17 and IL-23. This leads to inflammation and tissue
destruction in SLE patients [55,56]. The reduced number and compro-
mised function of Treg cells and the resistance of effector T-cells to the
suppressor effects of Tregs are additional mechanisms that have been
identified to be involved with the immunopathology of SLE [57–59].
The dysregulated release or functions of pro/anti-inflammatory cy-
tokines in SLE, which can stem from an imbalance among different im-
mune cell subsets, such as Th17/Treg cells, also have a role in the
pathogenesis of SLE [60]. Hence, restoring the imbalance in cytokines
and deficient immune cells has the potential to be a promising thera-
peutic target for ameliorating the symptoms of SLE.
Accumulating evidence has demonstrated the usefulness of
curcumin in alleviating the effects of several diseases, including SLE,
by affecting various types of immune cell [61–63]. In this review, we
focus on the positive effects of curcumin as an effective therapeutic
agent with which to modulate the function of DCs, Th1, Th17, and
Treg cells in SLE.
2. Overview of curcumin's effects on deficient immune cells in SLE
2.1. Role of dendritic cells in the pathogenesis of SLE
Immune cells play an important role in priming, initiating, develop-
ing, and in the functional phases of the immune response against for-
eign pathogens, cancer antigens, and autoantigens. DCs, as key
regulatory cells in the innate and adaptive immune response, direct
the primary immune response of naïve T-cells against protein antigens
[64,65]. DCs, which are widely distributed in most tissues and exist in
a so-called ‘immature’ state are unable to stimulate CD4+ or CD8+ T-
cell responses. Immature DCs (iDCs) express low levels of major histo-
compatibility complex (MHC) class І and class II on the cell surface,
but these cells are highly capable of capturing antigens and then pro-
cessing the ingested proteins into peptides, which are present in the
 A.A. Momtazi-Borojeni et al. / Autoimmunity Reviews xxx (2017) xxx–xxx
complexes with MHC molecules and recognized by T-cells [64–68]. Con-
current with the uptake of antigens, iDCs are activated through patho-
gen recognizing receptors (PRRs), resulting in an up-regulation of
HLA-DR, CD40 [that binds to CD154 (CD40L) expressed on activated
T-cells], and membrane-bound molecules (co-stimulatory molecules)
such as CD80, CD86, and CD83 (that bind to CD28 expressed on T-
cells). These co-stimulatory molecules provide a second signal for the
activation and differentiation of naïve T-cells. In addition, the interac-
tion between T-cells and DCs through CD40:CD40L results in the pro-
duction of several inflammatory cytokines and chemokines, such as
tumor necrosis factor alpha (TNF-α), IL-1, IL-12, type І IFN, IL-8, and
macrophage inflammatory protein-1α and β by DCs [64,69]. In addition,
the shift from iDCs to mature DCs (mDCs) leads to the expression of C-C
chemokine receptor type 7 (CCR7) and the loss of their adhesiveness to
epithelial cells, which results in migration into T-cell-rich regions of the
lymph nodes [70,71].
In contrast with mDCs, DCs are involved in ‘intolerance’ to self-
antigens, in which iDCs, in the absence of inflammation or infection, in-
corporate self-antigens and migrate to the lymph nodes. Once there,
these cells present autoantigens to the autoreactive T-cells without ex-
pression of any co-stimulatory molecules and secretion of cytokines.
The role of these iDCs, which are also referred to as ‘tolerogenic DCs’,
may be related to the stimulation of immune tolerance through several
mechanisms, such as anergy, deletion of clonal autoreactive T-cells, and
the generation of Tregs [72–74]. Importantly, these complex tolerance
mechanisms are dysfunctional in autoimmune disorders.
Regarding the essential roles of DCs in initiating immune responses
against both exogenous and endogenous antigens, DCs are also involved
in the initiation of hypersensitivity and autoimmunity [75]. Additional-
ly, as it pertains to the pathogenesis of autoimmune diseases in which
Th1, Th2, and Th17 contribute to the immune response, the role of
DCs are known to be significant. The breakdown of tolerance in both
autoreactive B- and T-cells in SLE, which supports the fact that SLE is
an immune complex–mediated disease, has been previously document-
ed [76,77]. Unabated activation of DCs under inflammatory conditions,
such as an excess of type-I IFN, is necessary for induction of the immune
response against nuclear antigens (chromatin and RNA-associated pro-
teins) in naïve autoreactive T-cells. The foregoing process is well-
accepted to represent a break in peripheral tolerance [78,79].
It has been suggested that SLE is associated with MHC haplotypes,
which means T-cell immune responses that are initiated by DCs are pri-
marily responsible for the pathogenesis of the disease [79]. It appears
that DCs, by providing stimulatory signals, as well as the secretion of
IL-12, promote activation, expansion, and differentiation of naïve self-
reactive T-cells that have previously escaped from central tolerance.
Thus, unchecked activation of DCs is a crucial process in the pathogene-
sis of SLE.
2.2. Modulatory effects of curcumin on dendritic cells
It has been reported that curcumin, by reducing the expression of
CD80, CD86, and MHC-II molecules, inhibits the maturation and func-
tion of murine bone marrow-derived DCs (BMDCs) in a dose-
dependent manner [80]. Curcumin treated-BMDCs were shown to
have impaired secretion of IL-12 and other inflammatory cytokines,
which results in an inhibition of Th1-mediated immune responses. In
addition to the inhibitory effects of curcumin on the BMDCs, curcumin
was also found to maintain DCs in an immature state [80]. An in vitro
study was conducted to evaluate the effects of both curcumin and
hydroethanolic extracts of turmeric (which contains 10–20% curcumin)
on human DCs. The findings were consistent with the above-mentioned
study, which included reduced expression of co-stimulatory molecules
such as CD80, CD86, and CD83, decreased production of IL-12, IL-6,
and TNF-α, and, lastly, prevention of T CD4+ proliferation [81,82]. In ad-
dition, both chemokine secretion and cell migration were prevented
when DCs had been treated with curcumin, which subsequently led to
Please cite this article as: Momtazi-Borojeni AA, et al, Curcumin: A natural modulator of immune cells in systemic lupus erythematosus,
Autoimmun Rev (2017), https://doi.org/10.1016/j.autrev.2017.11.016
3
a decrease in contact between DCs and T-cells located in lymph nodes
[81]. As an aside, curcumin-treated DCs are phenotypically similar to
iDCs, and T-cells primed with these DCs exhibit tolerogenic functions
[81].
Colitis is a chronic inflammatory disease in which there is a predom-
inance in the Th1 immune response. Curcumin has been shown to re-
tard the maturation of CD8 + DCs and subsequent Th1 response in
colitis by reducing the expression of MHC-II, co-stimulatory molecules
(CD80, CD86, CD40, CD205, CD54, CD252, and CD256) and inflammato-
ry cytokines (IL-1, IL-6, TNF-α, IL-12p40, and IL-12p70) [83,84]. These
iDCs were found to be unable to effectively stimulate T-cell responses
and, as a result, caused an increase in the number of Tregs in gut-
associated lymphoid tissue (GALT), which provides a ‘recovery effect’
in colitis [83]. Consistent with this result, it was also reported that injec-
tion of curcumin-treated DCs into BALB/c mice leads to the expansion of
CD4+ CD25+ FoxP3+ Treg cells [85]. In addition to immunomodulatory
effects of curcumin on the NF-κB and AP1 pathway [80,85–87],
curcumin can also modulate the Janus Kinase (JAK)/STAT pathway,
which suppresses the activation and maturation of DCs [84]. Finally, in
a mouse model of asthma, curcumin attenuated asthma symptoms by
activating the Wnt/β-catenin signaling pathway in DCs, which resulted
in the reduced expression of co-stimulatory molecules (CD86, CD40,
and CD11c) and decreased the activation and proliferation of CD4+ T-
cells [88]. Collectively, mounting experimental evidence would seem
to suggest that curcumin, as an anti-inflammatory agent, can modulate
DC-mediated immune responses and, therefore, represents a potential
therapeutic compound for the treatment of SLE.
2.3. Role of Th1 cells in the pathogenesis of SLE
Ever since the distinct subtypes of T helper cells were identified by
Coffman and Mosmann, it is well established that the Th1 subset, best
characterized by the production of IL-2, IFN-γ, and limphotoxin-α (LT-
α) (also called the ‘Th1 cytokine profile’), promotes a cell-mediated im-
mune response against intracellular pathogens by activation of macro-
phages [89,90]. It has been found that IL-12, IFN-γ, T-box transcription
factor T-bet, STAT1, and STAT4 are responsible for differentiation of
Th1 cells. Importantly, during primary activation of naïve CD4+ T-
cells, these cells develop into Th1 or other T-helper subsets such as
Th2 and Th17 cells [91,92].
In addition to the physiological roles associated with Th1, these cells
are also involved in delayed-type hypersensitivity reactions and the path-
ogenesis of several autoimmune diseases, such as RA, multiple sclerosis,
and type 1 diabetes mellitus [93]. It has been reported that renal damage
in SLE is associated with an increase in the Th1/Th2 ratio [94]. Disease ac-
tivity of lupus patients with diffuse proliferative glomerulonephritis is as-
sociated with the ‘Th1 cytokine profile’ mentioned above [95,96].
Some studies have indicated a crucial role of IFN-γ in the develop-
ment of autoimmune-based kidney disease [97,98]. In addition, an in-
creased level of IFN-γ has been reported in the serum of patients with
SLE [99–101]. It appears that the high levels of IFN-γ induce production
of IgG-subclasses that deposit in the kidney and promote local inflam-
mation, which leads to the development of SLE in human and mouse
models [95,97,102,103]. Furthermore, T-bet, as the master regulator
for differentiation of Th1 cells, is induced by IFN-γ in a positive
feedback-loop, and has been found to be up-regulated (both in mRNA
and protein levels) in the urinary sediment of patients with active
lupus [104]. In addition, there is a shift towards the Th1 pathway in ac-
tive lupus, suggesting an effective role of Th1 cells in the pathogenesis of
SLE. The aforementioned findings reveal that Th1 cells are a valuable
therapeutic target for the treatment of SLE patients.
2.4. Modulatory effects of curcumin on Th1 cells
Recent evidence suggests that curcumin can reduce pro-
inflammatory cytokines such as IFN-γ, TNF-α, IL-1, and IL-8 through
4 A.A. Momtazi-Borojeni et al. / Autoimmunity Reviews xxx (2017) xxx–xxx

its effects on NF-κB, STAT, and AP1 [105–107]. In animal models of that leads to autoimmune disease [127,128]. The IL-23/IL-17 axis is re-
autoimmune-mediated diabetes and neuritis, which have been identi- ported to have an exacerbating effect on the pathogenesis of SLE
fied to be facilitated by Th1 cells, curcumin reduced IFN-γ production [129]. Plasma levels of IL-23 and IL-17 were found to be increased in
by modulation of T-bet expression in T-cells. In addition, curcumin SLE patients and also associated with auto-inflammatory and immuno-
treatment was associated with a decrease in the proliferation of CD4+ pathological symptoms, and demonstrated a positive correlation with
T lymphocytes, as well as inhibition of NF-κB activation and T-bet ex- disease activity [123].
pression, which led to a reduction in differentiated Th1 cells [108,109]. In summary, IL-17, IL-21, and IL-23 play critically important roles in
Curcumin was also reported to inhibit the production of IL-12 by DCs the dysregulation of the immune response. Thus, these cytokines are
and macrophages, which gave rise to reduced production of IFN-γ potential therapeutic targets for the intentional modulation of Th17
and, consequently, suppression of naive CD4+ cell differentiation into cells in SLE patients [130].
Th1 cells [110,111].
In an acute graft-versus-host disease (GvHD) murine model charac-
2.6. Modulatory effect of curcumin on Th17 cells
terized by a predominance of Th1 and Th17 cells, treatment with
curcumin was shown to decrease the number of CD4+ IFN-γ+ T-cells,
Experimental autoimmune encephalomyelitis (EAE) is an
as well as reduce the production of IFN-γ [112]. Using a New Zealand
established model of autoimmune disease in which IL-23-induced
Black/White (NZB/W) mouse model of lupus nephritis, a recent study
Th17 cells are known to have an important effect on pathogenesis
showed that treatment with curcumin resulted in a decrease in the ex-
[131,132]. Curcumin was found to ameliorate EAE through modulation
pression of T-bet, which, in turn, resulted in suppression in the differen-
of Th17 cell differentiation and inhibition of IFN-γ, IL-17, and IL-23 cyto-
tiation of Th1 cells from naïve T-cells. Additionally, curcumin treatment
kines, which have been identified to be upregulated in the EAE mouse
in a mouse model of lupus nephritis was also demonstrated to reduce
model. Ex vivo and in vitro studies have also demonstrated that
the production of IgG2a and IgG3, which is closely dependent on Th1
curcumin can dose-dependently reduce the secretion of IFN-γ, IL-17,
cell response [113].
and IL-23 in cultured cells [133]. These findings are in accordance with
From the studies described above, it can be concluded that curcumin
another study that showed that curcumin diminished inflammation
is able to modulate Th1-mediated inflammatory responses by regulat-
and the pathological symptoms of acute EAE in the Lewis rat model by
ing critical transcription factors and cytokines and, thereby, ameliorate
inhibiting differentiation and the development of Th17 cells. This effect
some of the factors involved with the pathogenesis of SLE. This certainly
was suggested to be mediated by downregulation of effector cytokines
provides evidence that curcumin would appear to be a beneficial, non-
and transcription factors, which included IL-17, IL-6, IL-21, RORγt, and
toxic natural supplement for the treatment of SLE.
STAT3 [134]. In another study, it was found that curcumin modulated
the systemic response of Th17 cells through an effect on the IL-17/IL-
2.5. Role of Th17 cells in the pathogenesis of SLE
23 axis by reducing the expression of IL-17 and RORγt [135]. Further-
more, in vitro and in vivo studies in a murine model of acute GvHD, a
As the main branch of the immune system, T-cells have various ef-
process driven mainly by Th17- and Th1-mediated immune responses,
fects depending on the physiological state or environment for which
showed that curcumin could improve acute GvHD by reducing both
the response is required. T-cell subsets comprised of either tolerogenic,
the Th17 cell population and also inhibiting the production of IFN-γ
or inhibitory and inflammatory cells, are involved in the maintenance of
and IL-17 [112,136].
the immune response and, additionally, the pathophysiological re-
An additional experimental animal model that represents a Th cell-
sponse in autoimmune disease [114,115].
mediated autoimmune disease is one that involves autoimmune neuri-
Inflammatory T-cells are the main players that initiate and promote
tis (EAN). EAN is a demyelinating inflammatory disease of the peripher-
the inflammatory response against self-antigens, or to increase antigen
al nervous system. Th17 cells are suggested to have a considerable role
mimicry effects. Th17 is an important inflammatory T-cell derived from
in the pathogenesis and development of EAN [137,138]. In vivo and
naïve T-cells in an inflammatory microenvironment [116,117]. Th17
in vitro investigations have demonstrated that curcumin treatment
cells are a CD3+ CD4+ RORγt+ T-cell subset that are differentiated
was able to reduce inflammation and paraparesis in rats with EAN by
from naïve Th cells in response to the production of inflammatory cyto-
partially modulating the polarization of Th17 cells [109]. It was found
kines such as IL-6 and IL-23 [118]. Following their activation, mature
that curcumin reduced the expression of RORγt (the main transcription
and developed Th17 cells release inflammatory cytokines such as IL-
factor of Th17 cells), IL-17 (mainly produced by Th17 cells), and IL-6 (a
17A-F, IL-22, and IL-21 [119,120]. The function of Th17 cells stems
favorable cytokine for Th17 differentiation) [139].
from the secretion of inflammatory mediators that recruit innate im-
In conclusion, the above findings strongly suggest that curcumin can
mune cells from Neu to the site of inflammation, as well as activate
reduce Th17 cell responses by inhibiting cell proliferation and relevant
adaptive immune cells [121].
inflammatory cytokines and transcription factors, which include IL-17,
IL-17 is a family of cytokines comprising six cytokines, with IL-17A
IL-23, IL-6, IL-21, RORγt, and STAT3. Therefore, as mentioned above,
and IL-17F showing the greatest degree of homology. The dysregulated
curcumin may represent a potential treatment to improve the symp-
function of this cytokine is thought to play a primary role in several au-
toms and pathological processes associated with SLE.
toimmune diseases (e.g., SLE). However, IL-17E (IL-25) is engaged in the
Th2 immune response, while the role of IL-17B, C, and D have not yet
been determined [122,123]. Different studies have revealed that the cir- 2.7. Role of Treg cells in the pathogenesis of SLE
culating plasma levels of IL-17 in SLE patients is higher than in healthy
subjects [123,124]. IL-17 induces the secretion of pro-inflammatory Treg cells play an important role in the homeostasis of immune re-
chemokines that recruit neutrophils and circulating monocytes to the sponses. Treg cells are the main subset of T-cells that keep the body
site of inflammation. In addition, IL-17 in secondary lymphoid organs from developing autoimmune responses and help to produce central
assists with germinal center formation by inhibiting C-X-C chemokine and peripheral tolerance. Treg cells primarily modulate the immune re-
receptor type 5 (CXCR5) and CXCR4 signaling [125,126]. sponse through surface contact and cytokine production [140]. A Treg
Several studies have demonstrated that both mRNA and plasma cell is a CD3+, CD4+, CD25+, and Foxp3+ T-cell, which can decrease in-
levels of the cytokine IL-21 are higher in SLE patients and in a mouse flammation in patients with several autoimmune diseases [141]. There
model of SLE when compared to healthy subjects and controls, respec- are two subsets of Treg cells; the nTreg (natural Treg) subset that is de-
tively [127]. IL-21 also has a critical role in plasma cell differentiation veloped and reaches maturity in the thymus, and the iTreg (induced
and, therefore, results in autoantibody production and accumulation Treg) subset that is differentiated from CD4+ naïve T-cells in response

Please cite this article as: Momtazi-Borojeni AA, et al, Curcumin: A natural modulator of immune cells in systemic lupus erythematosus,
Autoimmun Rev (2017), https://doi.org/10.1016/j.autrev.2017.11.016
 A.A. Momtazi-Borojeni et al. / Autoimmunity Reviews xxx (2017) xxx–xxx
to TGF-β present in the peripheral immune system, or present in an
in vitro cell culture [142,143].
The nTreg subset act as a Treg cell with surface markers, expressing
CTLA4 on the membrane surface, along with the high-affinity T-cell re-
ceptor (TCR), which recognizes antigens and suppresses their targets by
‘contact inhibition’ (a more common process than cytokine production)
[144]. It has been shown that the transfer of nTreg to an animal model
can modulate both the innate and adaptive immune response, decrease
inflammation, and provide a functional ‘cure’ for autoimmune disease
by maintaining ‘tolerance’ [145].
iTreg cells act as critical inhibitory cells in the amelioration of periph-
eral inflammation. They also help to maintain peripheral tolerance and
preserve homeostasis of the immune and autoimmune response. The
inhibitory roles of iTreg cells are implicated in the production of secre-
tory cytokines, including IL-10, IL-35, and TGF-β [146]. IL-10 is a general
inhibitory cytokine that can induce the innate and adaptive immune re-
sponse. IL-10 can also modulate DC differentiation and reduce the co-
stimulatory markers on the DC surface [147]. In SLE patients, plasma
levels of IL-10 have been shown to be elevated, which exacerbates its
role in the pathogenesis of SLE [147,148].
TGF-β is considered an important regulatory cytokine, which is se-
creted from Treg cells, and, as alluded to above, it is TGF-β that helps
to maintain peripheral tolerance, reduce inflammation, and preserve
homeostasis of the immune response. Many studies have shown the
regulatory effect of TGF-β in modulating the immune response in auto-
immune disorders [149,150]. TGF-β induces CD4+ CD25+ T-cells and
upregulates CTLA4 expression [151]. TGF-β null mice have been
shown to exhibit an excessive inflammatory response due to no mea-
surable expression of TGF-β mRNA and protein [152]. Moreover, it has
been demonstrated that the administration of TGF-β can be beneficial
in some autoimmune diseases by reducing inflammation [153,154].
This is accomplished by TGF-β's effects on macrophages, B-cells, and
T-cells [153,154].
2.8. Modulatory effects of curcumin on Treg cells
Most previous studies, as well as new investigations for the treat-
ment of immune disorders with an excessive immune response, such
as SLE, have focused on increasing and shifting Treg cells and their asso-
ciated inhibitory cytokines. Different factors are responsible for the
changes, modulation, and increased numbers of Treg cells seen in SLE
patients. Curcumin, as a traditional and safe remedy to reduce inflam-
mation and increase the number of Treg cells, has been studied for its ef-
fects in SLE.
Curcumin was found to upregulate the expression of CD69 and, con-
sequently, suppress the activation and differentiation of CD4+ T-cells
[155]. CD69 is suggested to be a negative regulator in the development
of chronic inflammatory diseases [156,157] by suppressing the differen-
tiation of Treg cells into Th17 cells. This occurs by induction of TGF-β
biosynthesis [158] and by activation of JAK3-STAT5 signaling [159,
160]. An in vitro study showed that curcumin could indirectly induce
the late-phase generation of Treg cells through activation of TGF-β1 sig-
naling [155]. Additionally, an ex vivo study showed that both CD4+ and
CD8+ Treg cells were increased in a murine model of acute GvHD when
transplanted with curcumin-treated allogeneic splenocytes. This was
accompanied by a reduction of IL-17 and INF-γ production, which
exerted a direct effect on the development of the GvHD [112,136].
In vitro and in vivo studies have also shown that curcumin can shift
DC differentiation towards tolerogenic Treg cells by its inhibitory effects
on NF-κB [161]. An ex vivo study on C57BL/6 mice showed that in vivo
infusion of ‘allogeneic, curcumin-pretreated DC’ promoted and in-
creased the population of tolerogenic Treg cells and, therefore, reduced
alloproliferative capacity in mice [161]. Another study, which used a
mouse model of inflammatory bowel disease (IBD), demonstrated that
oral administration of curcumin could partially reduce inflammation
in the mucosa of the ileum by elevating the number of Treg cells [162].
Please cite this article as: Momtazi-Borojeni AA, et al, Curcumin: A natural modulator of immune cells in systemic lupus erythematosus,
Autoimmun Rev (2017), https://doi.org/10.1016/j.autrev.2017.11.016
5
Using an established lupus nephritis (LN) model in NZB/W female
mice, another investigation revealed that curcumin could significantly
increase the expression of Foxp3 (as the main promoter of the transcrip-
tion factor influencing Treg differentiation) in the curcumin-treated
group vs. controls [61]. The increase in the number of Treg cells can sup-
press the function of Th1 and Th2 cells. However, curcumin treatment
changes the Th1 to Th2 response in mice and, therefore, reduces the
contact of B-cells with Th2 cells. In turn, this results in a decrease in
the production of IgG and the formation of immune complexes [61]. In
summary, as it pertains to LN, curcumin can improve the renal manifes-
tations of LN in mice by suppressing the production of autoantibodies.
The suppression in autoantibody production is thought to occur by
modulation in the differentiation and function of Treg cells.
In conclusion, since Treg cells and their regulatory cytokines (espe-
cially TGF-β) are considered important mediators of self-tolerance,
then curcumin, by virtue of the fact that it can increase cytokine secre-
tion, as well as enhance the function and number of Treg cells, may
hold promise as a significant therapeutic natural compound with
which to modulate inflammation in autoimmune diseases like SLE.
Contrary to the findings described above, one study showed that
curcumin treatment decreased the function of Treg cells [163]. Results
of this study demonstrated that curcumin failed to exert a suppressor
function of mouse CD4+ CD25+ Treg cells on activation-induced prolif-
eration of CD4+ T-lymphocytes [163]. Curcumin was found to inhibit
the suppressor function of Treg cells and halt the expression of Foxp3
transcription factor [163], which controls the development and function
of Treg cells [164]. It was shown that curcumin inhibits the expression of
Foxp3 by suppressing IL-2 receptor-induced STAT5A phosphorylation
[163], which is essential to the consecutive expression of Foxp3 by
Treg cells [165]. In brief, curcumin inhibits IL-2 receptor expression
and, thereby, decreases the expression of Foxp3. Consequently, this re-
sults in the loss of suppressor function of Treg cells against T-
lymphocytes [163].
2.9. Modulatory effects of curcumin on Th17/Treg balance
A new paradigm in the pathogenesis of SLE is an imbalance between
Treg and Th17 cells. This new paradigm suggests that this imbalance
mediates an abnormal immune response by causing an alteration
from a state of ‘tolerance’ to ‘nonself-tolerance’ [167–171]. In SLE pa-
tients, it has been shown that CD4+ T-cells are highly susceptible to dif-
ferentiation into Th17 cells, whereas differentiation and functions of
Treg cells are markedly suppressed. Thus, by regulating the Th17/Treg
ratio, it might be possible to reduce the severity of symptoms associated
with SLE [170]. However, neither drugs, nor natural compounds that
can rectify the imbalance in the Th17/Treg subsets have been developed
to date, although curcumin, which elicits anti-inflammatory properties,
may hold promise [172–174]. It has been reported that curcumin (plas-
ma concentrations approx. 0.1 to 1 μg/ml) can modulate the imbalance
between the Th17/Treg ratio [172]. The ability of curcumin to modulate
the Th17/Treg ratio is thought to occur by decreasing the in vitro differ-
entiation of Th17 cells from CD4+ cells that have been isolated from SLE
patients using appropriate cell culture conditions, while significantly in-
creasing Treg differentiation. Moreover, it has been reported that TGF-
β1 and IL-17A expressed by Treg and Th17 cells, respectively, are dys-
regulated in patients with SLE [172]. Curcumin has also been shown to
modulate the function of both Treg and Th17 cells by increasing TGF-
β1, while decreasing IL-17A expression, of CD4+ T-cells cultured from
SLE patients without inducing these same effects in healthy volunteers
[175]. In conclusion, the findings described above can be summarized
as follows. Low doses of curcumin that result in plasma concentrations
of 0.1 to 1 μg/ml can regulate the Th17/Treg balance (particularly in
cell cultures of CD4+ T-cells obtained from patients with SLE over the
same concentration range) by reducing the percentage of Th17 cells
and the production of IL-17A, as well as increasing the percentage of
Treg cells and the production of TGF-β1. These effects elicited by
6 A.A. Momtazi-Borojeni et al. / Autoimmunity Reviews xxx (2017) xxx–xxx

Table 1
Cellular and molecular targets in curcumin-mediated modulation of deficient immune cells in SLE.

Type of study Type of modulated cell Biologic effect Molecular targets (changes) Ref.

- In vitro DCs - Inhibit maturation and function of BMDCs - CD80 (−) [80]
- In vivo - Keep DCs on the immature state - CD86 (−)
- MHC-П (−)
- IL-12 (−)
- In vitro DCs - Inhibit CD4+ T cell proliferation - CD80 (−) [81,82]
- In vivo - Inhibit DCs migration - CD86 (−)
- Reduce chemokine secretion - CD83 (−)
- IL-6 (−)
- IL-12 (−)
- TNF-α (−)
In vivo DCs - Keep DCs on the immature state - CD80 (−) [83,84]
- Reduce ability of DCs to induce T cell responses - CD86 (−)
- Increase number of Treg cells - CD40 (−)
- CD205 (−)
- CD54 (−)
- CD252 (−)
- CD256 (−)
- IL-1 (−)
- IL-6 (−)
- TNF-α (−)
- IL-12p40 (−)
- IL-12p70 (−)
Ex vivo DCs - Induce the expansion of the CD4+ CD25+ FoxP3+ Treg cells ND [85]
In vivo DCs Reduce activation and proliferation of CD4+ T cells - Wnt/β-catenin signaling (+) [88]
- CD86 (−)
- CD40 (−)
- - CD11c (−)
In vivo Th1 cells Reduce differentiation of Th1 cells - NF-κB (−) [108–111]
- T bet (−)
- INFγ (−)
- IL-12 (−)
In vivo CD4+ IFN-γ+ T cells Reduce number of CD4+ IFN-γ+ T cells INFγ (−) [112]
In vivo Th1 cells - Reduce differentiation of Th1 cells T bet (−) [113]
- Reduce levels of IgG2a and IgG3
In vivo Thr17 cell Reduce differentiation of Th17 cells - IFNγ (−) [133]
- IL17 (−)
- IL23 (−)
In vivo Th17 cells Reduce differentiation of Th17 cells - IL-17 (−)
- IL-6 (−)
- IL-21 (−)
- TGF-β (−) [134]
- RORγt (−)
- STAT3 (−)
- In vitro Th17 cells Reduce number of Th17 cells - IFNγ (−) [112]
- In vivo - IL-17 (−)
- In vitro Th17 cells Reduce differentiation of Th17 cells - IL-6 (−) [109]
- In vivo - IL-17 (−)
- RORγt (−)
- In vitro Treg cells Suppress differentiation of Treg cells into Th17 cells - CD69 (+) [154–158]
- In vivo - TGF-β (+)
- JAK3-STAT5 signaling (+)
In vitro Treg cell Induce the late-phase generation of Treg cells - TGF-β (+) [153]
Ex vivo - CD4+ Treg cells Increase population of CD4+ and CD8+ Treg cells - IL17 (−) [112]
- CD8+ Treg cells - INF-γ (−)
- In vitro - Treg cells Shift DC differentiation towards tolerogenic Treg cells - NF-κB (−) [159]
- In vivo - DCs
In vitro Treg cells Increase Treg differentiation - Foxp3 (+) [61]
In vitro CD4+ CD25+ Treg cells Decrease inhibitory function of Treg on T lymphocytes - Foxp3 (−) [161]
- IL-2 (−)

Abbreviations: bone marrow-derived DCs; BMDCs, dendritic cells; DCs, not defined; ND, regulatory T; Treg, systemic lupus erythematosus; SLE, T helper; Th. (−) and (+) signs show de-
creased and increased levels of targeted molecules, respectively.

curcumin occur in a dose-dependent manner and do so without affect-
ing the CD4+ T-cells of healthy volunteers.
2.10. Curcumin bioavailability can influence its therapeutic effects on SLE
In the body, the bioavailability of any compound is defined by its
pharmacokinetic profile comprising absorption, biodistribution, metab-
olism, and excretion. Preclinical and clinical studies have shown a low
intestinal absorption of curcumin, which leads to its low oral bioavail-
ability. Furthermore, pharmacokinetic studies in animal models
have also demonstrated that curcumin is immediately metabolized,
conjugated in the liver, and excreted in the feces. The low oral bioavail-
ability of curcumin arises from its low water solubility and extensive
first-pass intestinal and liver metabolism [176].
Upon oral administration, curcumin is subjected to metabolic O-
conjugation to curcumin glucuronide and curcumin sulfate in the
liver, renal, and intestinal mucosae. Moreover, with intravenous (i.v.)
or intraperitoneal (i.p) administration, curcumin is metabolically
biotransformed to tetrahydrocurcumin, hexahydrocurcumin, and
hexahydrocurcuminol [176–179]. Further glucuronidation reactions
subsequently occur on the reduced curcumin to yield curcumin
glucuronide, dihydrocurcumin glucuronide, and tetrahydrocurcumin

Please cite this article as: Momtazi-Borojeni AA, et al, Curcumin: A natural modulator of immune cells in systemic lupus erythematosus,
Autoimmun Rev (2017), https://doi.org/10.1016/j.autrev.2017.11.016
 A.A. Momtazi-Borojeni et al. / Autoimmunity Reviews xxx (2017) xxx–xxx 7

glucuronide [176,179]. Consequently, the conjugated and/or the re-
duced metabolites of curcumin are known to be biologically inactive,
or at least less effective, than the parent compound.
It has been found that the dose and water solubility of curcumin
can affect the clinical outcome and therapeutic effects observed in SLE
[180,181]. In one study, the therapeutic effects of curcumin in the allevi-
ation of SLE were evaluated using MRL/lpr mice as a lupus model [179].
In contrast to results contained in many reports that used curcumin to
treat various autoimmune diseases, such as multiple sclerosis, Type-1
diabetes mellitus, and RA [166], this study showed that MRL/lpr mice
treated with curcumin (30 mg/kg i.p.) for 12–20 weeks exhibited wors-
ening neurological symptoms. Moreover, in this same study, curcumin
aggravated the histological changes in the brain of MRL/lpr mice, such
as enlarged lateral and third ventricles, an increase in edematous cells,
elevated expression of brain aquaporin 4 (AQP4) [the main water chan-
nel of the brain], as well as reduced volume of the hippocampus (which
results in brain atrophy). In addition, treatment with curcumin at the
dose and duration mentioned above activated various inflammatory
pathways, which resulted in an increase in IgG deposition and reduced
C3 deposition (a key component of the alternative complement path-
way). This, in turn, further resulted in elevation of immune complexes
in the brain and the circulation of MRL/lpr mice [179]. These results
are in contrast to other studies, which suggest and support the fact
that curcumin can inhibit the complement cascade [181]. Consequently,
at the dose used in the study mentioned above [179], curcumin exacer-
bated various CNS symptoms in the lupus brain mouse model, which
suggests that curcumin has to be utilized with caution and carefully
monitored when used as an adjunct treatment for SLE.
Further studies have provided possible solutions to the issues raised
above. In fact, two separate studies showed that alteration of some of
the physicochemical properties of curcumin can enhance its therapeutic
effects [180,181]. Solubilization of curcumin in water by application of
heat or pressure leads to about a 35-fold increase in curcumin's water
solubility [181]. The solubilized curcumin was shown to significantly
ameliorate SLE in MRL-lpr/lpr mice by reducing lymphadenopathy
[181].
In conclusion, limited aqueous solubility and poor oral bioavailabili-
ty have hampered curcumin's therapeutic effects in SLE. Thus, further
research is urgently needed to increase the aqueous solubility and im-
prove the oral bioavailability of curcumin to maximize its therapeutic
potential in the treatment of SLE [180,181].
3. Concluding remarks
The present review concludes with the following remarks about the
modulatory effects of curcumin on defective immune cells in SLE
(Table 1, Figure 1). Curcumin has been found to inhibit the maturation
and function of DCs by reducing the expression of MHC-II and co-
stimulatory molecules, such as CD11c, CD40, CD54, CD80, CD83, CD86,
CD252, and CD256, as well as proinflammatory cytokines including IL-
1, IL-6, IL-12, IL-1, IL-6, IL-12p40, IL-12p70, and TNF-α. Therefore,
curcumin maintains DCs in an immature state and, consequently, sup-
presses DC-mediated stimulation of inflammatory T-cells that have a
key role in the severity of symptoms seen in SLE. Moreover, curcumin
prevents DC and T-cell contact in the lymph nodes by impeding chemo-
kine secretion and DC migration. In addition, curcumin has been found
to inhibit cell proliferation and differentiation, as well as ameliorate the
immune response, of Th1 cells. This effect has been shown to occur
through inhibition of IFN-γ production due to curcumin's effect of sup-
pressing NF-κB activation and T-bet expression; both, of which, are
over-expressed in SLE patients. Finally, curcumin can reduce Th17 cell
responses by inhibiting cell proliferation and the production of relevant
inflammatory cytokines and transcription factors, which include IL-17,
IL-23, IL-6, IL-21, TGF-β, RORγt, and STAT3. All of these inflammatory

Fig. 1. A schematic view of curcumin's effects on T-cells and dendritic cells in SLE. Curcumin inhibits maturation of immature dendritic cells into immunogenic dendritic cells that promote
an inflammatory response through activating naïve CD4+ T-cells. Curcumin also inhibits differentiation of naïve CD4+ T cells into Th17 and Th1 cells via inhibition of IL-6 and IL-12
production. Curcumin suppresses Th1 activity via reduction of IFN-γ production, which is mediated by the inhibition of T-bet expression. In addition, curcumin suppresses
differentiation and development of Th17 cells via downregulation of effector cytokines and transcription factors including IL-17, IL-21, IFN-γ, RORγt, and STAT3. In contrast, curcumin
activates tolerogenic dendritic cells and, thereby, activates regulatory T-cells that inhibit inflammatory responses through the secretion of IL-10, IL-35, and TGF-β, which subsequently
leads to suppression of Th1 and Th17 activation.

Please cite this article as: Momtazi-Borojeni AA, et al, Curcumin: A natural modulator of immune cells in systemic lupus erythematosus,
Autoimmun Rev (2017), https://doi.org/10.1016/j.autrev.2017.11.016
8 A.A. Momtazi-Borojeni et al. / Autoimmunity Reviews xxx (2017) xxx–xxx
cytokines and transcription factors are routinely determined to be ele-
vated in SLE patients. Conversely, curcumin can enhance the number
and function of Treg cells through upregulation of Foxp3 and CD69,
which, in turn, suppresses the differentiation of Treg cells into Th17
cells. Curcumin has also been found to shift the differentiation of DCs to-
wards tolerogenic Treg cells by upregulating Foxp3 and inhibiting NF-
κB. Taken together, these effects elicited by curcumin lead to a reduction
of Th1 function. In addition, it has been reported that curcumin can fa-
vorably modulate the imbalance in the Th17/Treg ratio observed in
SLE patients. Altogether, the current literature would strongly support
the use of curcumin as an adjunct therapy to more conventional medi-
cations in the treatment of SLE, albeit much more experimental re-
search, and especially randomized, two-way crossover, double-
blinded clinical trials, are required to unequivocally establish
curcumin's therapeutic role in the treatment of SLE.
Disclosures by authors
1. The authors' declare that there is no conflict of interest, including any
financial, personal, or other relationships with people or organiza-
tions within 3 years of beginning the submitted work that could in-
appropriately influence, or be perceived to influence, the work.
2. The authors' declare that this manuscript has not been published
elsewhere and is not presently under consideration for publication
by any other journal. This manuscript is approved by all authors. Fur-
thermore, if the manuscript is accepted for publication, it will not be
published elsewhere in the same form, in English or any other lan-
guage, including electronically without the written consent of the
copyright-holder.
3. The policies of the journal entitled Autoimmunity Reviews have been
reviewed prior to submission.
4. The research conducted for this review paper did not receive any
specific grant from funding agencies in the public, commercial, or
not-for-profit sectors.
References
[1] Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and
clinical studies. Anticancer Res 2003;23:363–98.
[2] Julie S, Jurenka M. Anti-inflammatory properties of curcumin, a major constituent
of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev
2009;14(2):141–53.
[3] Sahebkar A, Mohammadi A, Atabati A, Rahiman S, Tavallaie S, Iranshahi M, et al.
Curcuminoids modulate pro-oxidant-antioxidant balance, but not the immune re-
sponse to heat shock protein 27 and oxidized LDL in obese individuals. Phytother
Res 2013;27:1883–8.
[4] Sahebkar A. Dual effect of curcumin in preventing atherosclerosis: the potential
role of pro-oxidant-antioxidant mechanisms. Nat Prod Res 2015;29:491–2.
[5] Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-
inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, meta-
bolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol 2009;41:40–59.
[6] Mirzaei H, Naseri G, Rezaee R, Mohammadi M, Banikazemi Z, Mirzaei HR, Salehi H,
Peyvandi M, Pawelek JM, Sahebkar A. Curcumin: A new candidate for
melanomatherapy? Int J Cancer 2016 Oct 15;139(8):1683–95.
[7] Panahi Y, Alishiri GH, Parvin S, Sahebkar A. Mitigation of systemic oxidative stress
by curcuminoids in osteoarthritis: Results of a randomized controlled trial. J Diet
Suppl 2016;13(2):209–20.
[8] Panahi Y, Ghanei M, Bashiri S, Hajihashemi A, Sahebkar A. Short-term curcuminoid
supplementation for chronic pulmonary complications due to sulfur mustard in-
toxication: Positive results of a randomized double-blind placebo-controlled trial.
Drug Res (Stuttg) 2015 Nov;65(11):567–73.
[9] Bachmeier BE, Nerlich AG, Iancu CM, Cilli M, Schleicher E, Vené R, et al. The chemo-
preventive polyphenol curcumin prevents hematogenous breast cancer metastases
in immunodeficient mice. Cell Physiol Biochem 2007;19:137–52.
[10] Bhardwaj RS, Bhardwaj KS, Ranjeet D, Ganesh N. Curcuma longa leaves exhibits a
potential antioxidant, antibacterial and immunomodulating properties. Int J
Phytomed 2011;3:270–8.
[11] Sahebkar A. Curcuminoids for the management of hypertriglyceridaemia. Nat
RevCardiol 2014 Feb;11(2):123.
[12] Vanichkul K, Areechon N, Kongkathip N, Srisapoome P, Chuchird N. Immunological
and bactericidal effects of turmeric (Curcuma longa Linn.) extract in pacific white
shrimps (Litopenaeus vannamei Boone). Kasetsart J (Nat Sci) 2010;44:850–8.
[13] Rahmani S, Asgary S, Askari G, Keshvari M, Hatamipour M, Feizi A, Sahebkar A.
Treatment of non-alcoholic fatty liver disease with curcumin: A randomized place-
bo-controlled trial. Phytother Res 2016 Sep;30(9):1540–8.
Please cite this article as: Momtazi-Borojeni AA, et al, Curcumin: A natural modulator of immune cells in systemic lupus erythematosus,
Autoimmun Rev (2017), https://doi.org/10.1016/j.autrev.2017.11.016
[14] Momtazi AA, Derosa G, Maffioli P, Banach M, Sahebkar A. Role of microRNAs in the
therapeutic effects of curcumin in non-cancer diseases. Mol Diagn Ther 2016 Aug;
20(4):335–45. https://doi.org/10.1007/s40291-016-0202-7.
[15] Momtazi A, Sahebkar A. Difluorinated curcumin: a promising curcumin analogue
with improved anti-tumor activity and pharmacokinetic profile. Curr Pharm Des
2016;22:4386–97.
[16] Rezaee R, Momtazi AA, Monemi A, Sahebkar A. Curcumin: a potentially powerful
tool to reverse cisplatin-induced toxicity. Pharmacol Res 2017;117:218–27.
[17] Momtazi AA, Shahabipour F, Khatibi S, Johnston TP, Pirro M, Sahebkar A. Curcumin
as a MicroRNA regulator in cancer: a review. Rev Physiol Biochem Pharmacol 2016;
171:1–38.
[18] Jagetia GC, Aggarwal BB. “Spicing up” of the immune system by curcumin. J Clin
Immunol 2007;27:19–35.
[19] Hatcher H, Planalp R, Cho J, Torti F, Torti S. Curcumin: from ancient medicine to
current clinical trials. Cell Mol Life Sci 2008;65:1631–52.
[20] Gao X, Kuo J, Jiang H, Deeb D, Liu Y, Divine G, et al. Immunomodulatory activity of
curcumin: suppression of lymphocyte proliferation, development of cell-mediated
cytotoxicity, and cytokine production in vitro. Biochem Pharmacol 2004;68:51–61.
[21] Ahmed AM, El Fouhil AF, Mohamed RA, Atteya M, Abdel-Baky NA, AlRoalle AH,
et al. Curcumin ameliorates experimental autoimmune acute myocarditis in rats
as evidenced by a decrease in thioredoxin immunoreactivity. Folia Morphol
(Warsz) 2015;74(3):318–24. https://doi.org/10.5603/FM.2015.0048.
[22] Cundell DR, Wilkinson F. Curcumin: powerful immunomodulator from turmeric.
Curr Immunol Rev 2014;10:122–32.
[23] Varalakshmi C, Ali AM, Pardhasaradhi BVV, Srivastava RM, Singh S, Khar A. Immu-
nomodulatory effects of curcumin: in-vivo. Int Immunopharmacol 2008;8:
688–700.
[24] Seyedzadeh MH, Safari Z, Zare A, Gholizadeh Navashenaq J, Razavi SA, Kardar GA,
et al. Study of curcumin immunomodulatory effects on reactive astrocyte cell func-
tion. Int Immunopharmacol 2014;22:230–5.
[25] Soetikno V, Sari FR, Veeraveedu PT, Thandavarayan RA, Harima M, Sukumaran V,
et al. Curcumin ameliorates macrophage infiltration by inhibiting NF-κB activation
and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy.
Nutr Metab 2011;8:1.
[26] Shishodia S, Sethi G, Aggarwal BB. Curcumin: getting back to the roots. Ann N Y
Acad Sci 2005;1056:206–17.
[27] Shishodia S, Singh T, Chaturvedi MM. Modulation of transcription factors by
curcumin. The molecular targets and therapeutic uses of curcumin in health and
disease. Springer; 2007. p. 127–48.
[28] Ganjali S, Sahebkar A, Mahdipour E, Jamialahmadi K, Torabi S, Akhlaghi S, Ferns G,
Parizadeh SM, Ghayour-Mobarhan M. Investigation of the effects of curcumin on
serum cytokines in obese individuals: a randomized controlled trial. Sci World J
2014 Feb 11;2014:898361. https://doi.org/10.1155/2014/898361.
[29] Gonzales AM, Orlando RA. Curcumin and resveratrol inhibit nuclear factor-kappaB-
mediated cytokine expression in adipocytes. Nutr Metab 2008;5:1.
[30] Han S-S, Keum Y-S, Seo H-J, Surh Y-J. Curcumin suppresses activation of NF-κB and
AP-1 induced by phorbol ester in cultured human promyelocytic leukemia cells.
BMB Rep 2002;35:337–42.
[31] Jiang CX, Wu L, Wu J, ZM Yu, Li XK. Curcumin analog exhibited anti-inflammatory
activity through inhibiting ERK/JNK and NF-κB signaling pathway. Chin Tradit Herb
Drug 2016;47:2871–6.
[32] Park K-R, Lee J-H, Choi C, Liu K-H, Seog D-H, Kim Y-H, et al. Suppression of
interleukin-2 gene expression by isoeugenol is mediated through down-
regulation of NF-AT and NF-κB. Int Immunopharmacol 2007;7:1251–8.
[33] Fantini MC, Pallone F. Cytokines: from gut inflammation to colorectal cancer. Curr
Drug Targets 2008;9:375–80.
[34] Pahl HL. Activators and target genes of Rel/NF-κB transcription factors. Oncogene
1999;18:6853–66.
[35] Okunieff P, Xu J, Hu D, Liu W, Zhang L, Morrow G, et al. Curcumin protects against
radiation-induced acute and chronic cutaneous toxicity in mice and decreases
mRNA expression of inflammatory and fibrogenic cytokines. Int J Radiat Oncol
Biol Phys 2006;65:890–8.
[36] Huang S, Zhao L, Kim K, Lee DS, Hwang D. Inhibition of NOD2 signaling and target
gene expression by curcumin. Mol Pharmacol 2008;74:274–81.
[37] Jobin C, Bradham CA, Russo MP, Juma B, Narula AS, Brenner DA, et al. Curcumin
blocks cytokine-mediated NF-κB activation and proinflammatory gene expression
by inhibiting inhibitory factor I-κB kinase activity. J Immunol 1999;163:3474–83.
[38] Grandjean-Laquerriere A, Gangloff SC, Le Naour R, Trentesaux C, Hornebeck W,
Guenounou M. Relative contribution of NF-κB and AP-1 in the modulation by
curcumin and pyrrolidine dithiocarbamate of the UVB-induced cytokine expres-
sion by keratinocytes. Cytokine 2002;18:168–77.
[39] Krivosikova M, Dallos T, Maslinski W, Buc M. B cell activating factor, its role in au-
toimmunity, and targeting in autoimmune diseases. Bratisl Lek Listy 2008;110:
137–45.
[40] Huang G, Yang Y, Xu Z, Zhou P, Gong W, Li Y, et al. Downregulation of B lymphocyte
stimulator expression by curcumin in B lymphocyte via suppressing nuclear trans-
location of NF-κB. Eur J Pharmacol 2011;650:451–7.
[41] Deters M, Hütten H, Kaever V. Synergistic immunosuppressive effects of the mTOR
inhibitor sirolimus and the phytochemical curcumin. Phytomedicine 2013;20:
120–3.
[42] Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008;358:
929–39.
[43] Avrămescu C, Biciuşcă V, Dăianu T, Turculeanu A, Bălăşoiu M, Popescu S, et al. Cy-
tokine panel and histopathological aspects in the systemic lupus erythematosus.
Romanian J Morphol Embryol 2010;51:633–40.
[44] Krishnamurthy S, Mahadevan S. Systemic lupus erythematosus: recent concepts in
genomics, pathogenetic mechanisms, and therapies. ISRN Immunol 2011:868964.
[45] Dai Y, Li X-L, Wang L, Qiu Z-F, Li T-S. Change of plasma TH1/TH2 cytokines levels in
patients with hemorrhagic fever with renal syndrome. Zhongguo Yi Xue Ke Xue
Yuan Xue Bao Acta Acad Med Sinicae 2010;32:108–12.
[46] Tsokos GC. Systemic lupus erythematosus. N Engl J Med 2011;365:2110–21.
 A.A. Momtazi-Borojeni et al. / Autoimmunity Reviews xxx (2017) xxx–xxx
[47] Buckner JH. Mechanisms of impaired regulation by CD4+ CD25+ FOXP3+ regu-
latory T cells in human autoimmune diseases. Nat Rev Immunol 2010;10:849–59.
[48] Rastin M, Mahmoudi M, Hatef M, Sahebari M, Tabasi N, Haghmorad D, et al. T lym-
phocyte apoptosis in systemic lupus erythematosus patients. IJBMS 2013;16:
936–41.
[49] Zhang W, Reichlin M. A possible link between infection with Burkholderia bacteria
and systemic lupus erythematosus based on epitope mimicry. Clin Dev Immunol
2008:683489.
[50] Costenbader KH, Feskanich D, Stampfer MJ, Karlson EW. Reproductive and meno-
pausal factors and risk of systemic lupus erythematosus in women. Arthritis
Rheum 2007;56:1251–62.
[51] Talaat RM, Mohamed SF, Bassyouni IH, Raouf AA. Th1/Th2/Th17/Treg cytokine im-
balance in systemic lupus erythematosus (SLE) patients: correlation with disease
activity. Cytokine 2015;72:146–53.
[52] Chen XQ, YC Yu, Deng HH, Sun JZ, Dai Z, YW Wu, et al. Plasma IL-17A is increased in
new-onset SLE patients and associated with disease activity. J Clin Immunol 2010;
30:221–5.
[53] Crispín JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, et al. Expanded
double negative T cells in patients with systemic lupus erythematosus produce IL-
17 and infiltrate the kidneys. J Immunol 2008;181:8761–6.
[54] Doreau A, Belot A, Bastid J, Riche B, Trescol-Biemont M-C, Ranchin B, et al. Interleukin
17 acts in synergy with B cell–activating factor to influence B cell biology and the
pathophysiology of systemic lupus erythematosus. Nat Immunol 2009;10:778–85.
[55] Qu N, Xu M, Mizoguchi I, J-i Furusawa, Kaneko K, Watanabe K, et al. Pivotal roles of
T-helper 17-related cytokines, IL-17, IL-22, and IL-23, in inflammatory diseases.
Clin Dev Immunol 2013:968549.
[56] Pan H-F, Leng R-X, Feng C-C, Li X-P, Chen G-M, Li B-Z, et al. Expression profiles of
Th17 pathway related genes in human systemic lupus erythematosus. Mol Biol
Rep 2013;40:391–9.
[57] Lyssuk EY, Torgashina AV, Soloviev SK, Nassonov EL, Bykovskaia SN. Reduced num-
ber and function of CD4+ CD25 high FoxP3+ regulatory T cells in patients with
systemic lupus erythematosus. Adv Exp Med Biol 2007:113–9 (Springer).
[58] Valencia X, Yarboro C, Illei G, Lipsky PE. Deficient CD4+ CD25high T regulatory cell
function in patients with active systemic lupus erythematosus. J Immunol 2007;
178:2579–88.
[59] Gómez J, Prado C, López P, Suárez A, Gutiérrez C. Conserved anti-proliferative effect
and poor inhibition of TNFα secretion by regulatory CD4+ CD25+ T cells in pa-
tients with systemic lupus erythematosus. Clin Immunol 2009;132:385–92.
[60] Su D-L, Lu Z-M, Shen M-N, Li X, Sun L-Y. Roles of pro-and anti-inflammatory cyto-
kines in the pathogenesis of SLE. Biomed Res Int 2012:968549.
[61] Cong Y, Wang L, Konrad A, Schoeb T, Elson CO. Curcumin induces the tolerogenic
dendritic cell that promotes differentiation of intestine-protective regulatory T
cells. Eur J Immunol 2009 Nov;39(11):3134–46.
[62] Hanai H, Sugimoto K. Curcumin has bright prospects for the treatment of inflam-
matory bowel disease. Curr Pharm Des 2009;15:2087–94.
[63] Bhattacharyya S, Hossain DMS, Mohanty S, Sen GS, Chattopadhyay S, Banerjee S,
et al. Curcumin reverses T cell-mediated adaptive immune dysfunctions in
tumor-bearing hosts. Cell Mol Immunol 2010;7:306–15.
[64] Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature
1998;392:245–52.
[65] Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev
Immunol 1991;9:271–96.
[66] Lotze MT, Zeh HJ, Rubartelli A, Sparvero LJ, Amoscato AA, Washburn NR, et al. The
grateful dead: damage-associated molecular pattern molecules and reduction/oxi-
dation regulate immunity. Immunol Rev 2007;220:60–81.
[67] Kumar H, Kawai T, Akira S. Pathogen recognition in the innate immune response.
Biochem J 2009;420:1–16.
[68] Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. Int
Rev Immunol 2011;30:16–34.
[69] Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S. Antigen presentation
and T cell stimulation by dendritic cells. Annu Rev Immunol 2002;20:621–67.
[70] Winzler C, Rovere P, Rescigno M, Granucci F, Penna G, Adorini L, et al. Maturation
stages of mouse dendritic cells in growth factor-dependent long-term cultures. J
Exp Med 1997;185:317–28.
[71] Yoshida R, Imai T, Hieshima K, Kusuda J, Baba M, Kitaura M, et al. Molecular cloning
of a novel human CC chemokine EBI1-ligand chemokine that is a specific functional
ligand for EBI1, CCR7. J Biol Chem 1997;272:13803–9.
[72] Coates PT, Thomson AW. Dendritic cells, tolerance induction and transplant out-
come. Am J Transplant 2002;2:299–307.
[73] Wood KJ, Sakaguchi S. Regulatory Tcells in transplantation tolerance. Nat Rev
Immunol 2003;3:199–210.
[74] Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev
Immunol 2003;21:685–711.
[75] Lipscomb MF, Masten BJ. Dendritic cells: immune regulators in health and disease.
Physiol Rev 2002;82:97–130.
[76] Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback
in systemic autoimmune disease. Nat Rev Immunol 2001;1:147–53.
[77] Marrack P, Kappler J, Kotzin BL. Autoimmune disease: why and where it occurs. Nat
Med 2001;7:899–905.
[78] Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J. Induction of dendritic cell dif-
ferentiation by IFN-alpha in systemic lupus erythematosus. Science 2001;294:
1540–3.
[79] Stranges PB, Watson J, Cooper CJ, Choisy-Rossi CM, Stonebraker AC, Beighton RA,
et al. Elimination of antigen-presenting cells and autoreactive T cells by Fas contrib-
utes to prevention of autoimmunity. Immunity 2007;26:629–41.
[80] Kim GY, Kim KH, Lee SH, Yoon MS, Lee HJ, Moon DO, et al. Curcumin inhibits
immunostimulatory function of dendritic cells: MAPKs and translocation of NF-
kappa B as potential targets. J Immunol 2005;174:8116–24.
[81] Shirley SA, Montpetit AJ, Lockey RF, Mohapatra SS. Curcumin prevents human den-
dritic cell response to immune stimulants. Biochem Biophys Res Commun 2008;
374:431–6.
Please cite this article as: Momtazi-Borojeni AA, et al, Curcumin: A natural modulator of immune cells in systemic lupus erythematosus,
Autoimmun Rev (2017), https://doi.org/10.1016/j.autrev.2017.11.016
9
[82] Krasovsky J, Chang DH, Deng G, Yeung S, Lee M, Ping CL, et al. Inhibition of human
dendritic cell activation by hydroethanolic but not lipophilic extracts of turmeric
(Curcuma longa). Planta Med 2009;75:312–5.
[83] Zhao HM, Xu R, Huang XY, Cheng SM, Huang MF, Yue HY, et al. Curcumin improves
regulatory T cells in gut-associated lymphoid tissue of colitis mice. World J
Gastroenterol 2016;22:5374–83.
[84] Zhao HM, Xu R, Huang XY, Cheng SM, Huang MF, Yue HY, et al. Curcumin sup-
pressed activation of dendritic cells via JAK/STAT/SOCS signal in mice with exper-
imental colitis. Front Pharmacol 2016;7:455.
[85] Rogers NM, Kireta S, Coates PT. Curcumin induces maturation-arrested dendritic
cells that expand regulatory T cells in vitro and in vivo. Clin Exp Immunol 2010;
162:460–73.
[86] Panahi Y, Hosseini MS, Khalili N, Naimi E, Majeed M, Sahebkar A. Antioxidant and
anti-inflammatory effects of curcuminoid-piperine combination in subject with
metabolic syndrome: A randomized controlled trial and an updated meta-analysis.
Clin Nutr 2015 Dec;34(6):1101–8.
[87] Huang TS, Lee SC, Lin JK. Suppression of c-Jun/AP-1 activation by an inhibitor of
tumor promotion in mouse fibroblast cells. Proc Natl Acad Sci U S A 1991;88:
5292–6.
[88] Yang X, Lv JN, Li H, Jiao B, Zhang QH, Zhang Y, et al. Curcumin reduces lung inflam-
mation via Wnt/beta-catenin signaling in mouse model of asthma. J Asthma 2016:
1–6.
[89] Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of mu-
rine helper T cell clone. I. Definition according to profiles of lymphokine activities
and secreted proteins. J Immunol 1986;136:2348–57.
[90] Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine se-
cretion lead to different functional properties. Annu Rev Immunol 1989;7:145–73.
[91] Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcrip-
tion factor, T-bet, directs Th1 lineage commitment. Cell 2000;100:655–69.
[92] Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu
Rev Immunol 2009;28:445–89.
[93] Crane IJ, Forrester JV. Th1 and Th2 lymphocytes in autoimmune disease. Crit Rev
Immunol 2005;25:75–102.
[94] Akahoshi M, Nakashima H, Tanaka Y, Kohsaka T, Nagano S, Ohgami E, et al. Th1/Th2
balance of peripheral T helper cells in systemic lupus erythematosus. Arthritis
Rheum 1999;42:1644–8.
[95] Uhm WS, Na K, Song GW, Jung SS, Lee T, Park MH, et al. Cytokine balance in kidney
tissue from lupus nephritis patients. Rheumatology (Oxford) 2003;42:935–8.
[96] Masutani K, Akahoshi M, Tsuruya K, Tokumoto M, Ninomiya T, Kohsaka T, et al.
Predominance of Th1 immune response in diffuse proliferative lupus nephritis. Ar-
thritis Rheum 2001;44:2097–106.
[97] Haas C, Ryffel B, Le Hir M. IFN-gamma is essential for the development of autoim-
mune glomerulonephritis in MRL/Ipr mice. J Immunol 1997;158:5484–91.
[98] Schwarting A, Wada T, Kinoshita K, Tesch G, Kelley VR. IFN-gamma receptor signal-
ing is essential for the initiation, acceleration, and destruction of autoimmune kid-
ney disease in MRL-Fas(lpr) mice. J Immunol 1998;161:494–503.
[99] Al-Janadi M, Al-Balla S, Al-Dalaan A, Raziuddin S. Cytokine profile in systemic lupus
erythematosus, rheumatoid arthritis, and other rheumatic diseases. J Clin Immunol
1993;13:58–67.
[100] Gomez D, Correa PA, Gomez LM, Cadena J, Molina JF, Anaya JM. Th1/Th2 cytokines
in patients with systemic lupus erythematosus: is tumor necrosis factor alpha pro-
tective? Semin Arthritis Rheum 2004;33:404–13.
[101] Tokano Y, Morimoto S, Kaneko H, Amano H, Nozawa K, Takasaki Y, et al. Levels of
IL-12 in the sera of patients with systemic lupus erythematosus (SLE)—relation to
Th1- and Th2-derived cytokines. Clin Exp Immunol 1999;116:169–73.
[102] Kirou KA, Crow MK. New pieces to the SLE cytokine puzzle. Clin Immunol 1999;91:
1–5.
[103] Snapper CM, McIntyre TM, Mandler R, Pecanha LM, Finkelman FD, Lees A, et al. In-
duction of IgG3 secretion by interferon gamma: a model for T cell-independent
class switching in response to T cell-independent type 2 antigens. J Exp Med
1992;175:1367–71.
[104] Chan RW, Lai FM, Li EK, Tam LS, Chow KM, Li PK, et al. Imbalance of Th1/Th2 tran-
scription factors in patients with lupus nephritis. Rheumatology (Oxford) 2006;45:
951–7.
[105] Araujo CC, Leon LL. Biological activities of Curcuma longa L. Mem Inst Oswaldo Cruz
2001;96:723–8.
[106] Brouet I, Ohshima H. Curcumin, an anti-tumour promoter and anti-inflammatory
agent, inhibits induction of nitric oxide synthase in activated macrophages.
Biochem Biophys Res Commun 1995;206:533–40.
[107] Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, et al. Molecular mechanisms
underlying chemopreventive activities of anti-inflammatory phytochemicals:
down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation.
Mutat Res 2001;480–481:243–68.
[108] Castro CN, Barcala Tabarrozzi AE, Winnewisser J, Gimeno ML, Antunica Noguerol
M, Liberman AC, et al. Curcumin ameliorates autoimmune diabetes. Evidence in
accelerated murine models of type 1 diabetes. Clin Exp Immunol 2014;177:
149–60.
[109] Han F, Luo B, Shi R, Han C, Zhang Z, Xiong J, et al. Curcumin ameliorates rat exper-
imental autoimmune neuritis. J Neurosci Res 2014;92:743–50.
[110] Kang BY, Song YJ, Kim KM, Choe YK, Hwang SY, Kim TS. Curcumin inhibits Th1 cy-
tokine profile in CD4+ T cells by suppressing interleukin-12 production in macro-
phages. Br J Pharmacol 1999;128:380–4.
[111] Kang BY, Chung SW, Chung W, Im S, Hwang SY, Kim TS. Inhibition of interleukin-12
production in lipopolysaccharide-activated macrophages by curcumin. Eur J
Pharmacol 1999;384:191–5.
[112] Park MJ, Moon SJ, Lee SH, Yang EJ, Min JK, Cho SG, et al. Curcumin attenuates acute
graft-versus-host disease severity via in vivo regulations on Th1, Th17 and regula-
tory T cells. PLoS One 2013;8:e67171.
[113] Lee H, Kim H, Lee G, Chung HS, Bae H. Curcumin attenuates lupus nephritis upon
interaction with regulatory T cells in New Zealand black/white mice. Br J Nutr
2013;110:69–76.
10 A.A. Momtazi-Borojeni et al. / Autoimmunity Reviews xxx (2017) xxx–xxx
[114] Delitala M, Dianzani U, Lorenzi T, Melensi M. A mathematical model for immune
and autoimmune response mediated by T-cells. Comput Math Appl 2013;66:
1010–23.
[115] Wu B, Cheng Y. Upregulation of innate immune responses in a T cell/histiocyte-rich
large B cell lymphoma patient with significant autoimmune disorders mimicking
systemic lupus erythematosus. Ann Hematol 2014;93:353–4.
[116] Bystrom J, Clanchy F, Taher TE, Mangat P, Jawad AS, Williams RO, et al. TNFα in the
regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmune in-
flammatory diseases. Cytokine 2016. https://doi.org/10.1016/j.cyto.2016.09.001.
[117] Noma T. Helper T cell paradigm: Th17 and regulatory T cells involved in autoim-
mune inflammatory disorders, pathogen defense and allergic diseases. Nihon
Rinsho Meneki Gakkai Kaishi 2009;33:262–71.
[118] Purvis HA, Stoop JN, Mann J, Woods S, Kozijn AE, Hambleton S, et al. Low-strength
T-cell activation promotes Th17 responses. Blood 2010;116:4829–37.
[119] Maiti AK, Kim-Howard X, Viswanathan P, Guillén L, Rojas-Villarraga A, Deshmukh
H, et al. Confirmation of an association between rs6822844 at the Il2–Il21 region
and multiple autoimmune diseases: evidence of a general susceptibility locus. Ar-
thritis Rheum 2010;62:323–9.
[120] Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH. Interleukin-1
and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 re-
sponses and autoimmunity. Immunity 2009;31:331–41.
[121] Murphy SF, Schaeffer AJ, Done J, Wong L, Bell-Cohn A, Roman K, et al. IL17 mediates
pelvic pain in experimental autoimmune prostatitis (EAP). PLoS One 2015;
10:e0125623.
[122] Wong C, Ho CY, Li E, Lam C. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-
12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythe-
matosus. Lupus 2000;9:589–93.
[123] Wong CK, Lit LCW, Tam LS, Li EKM, Wong PTY, Lam CWK. Hyperproduction of IL-23
and IL-17 in patients with systemic lupus erythematosus: implications for Th17-
mediated inflammation in auto-immunity. Clin Immunol 2008;127:385–93.
[124] Zhang Z, Kyttaris VC, Tsokos GC. The role of IL-23/IL-17 axis in lupus nephritis. J
Immunol 2009;183:3160–9.
[125] Martin JC, Baeten DL, Josien R. Emerging role of IL-17 and Th17 cells in systemic
lupus erythematosus. Clin Immunol 2014;154:1–12.
[126] Garrett-Sinha LA, John S, Gaffen SL. IL-17 and the Th17 lineage in systemic lupus er-
ythematosus. Curr Opin Rheumatol 2008;20:519–25.
[127] Deng X-M, Yan S-X, Wei W. IL-21 acts as a promising therapeutic target in systemic
lupus erythematosus by regulating plasma cell differentiation. Cell Mol Immunol
2015;12:31–9.
[128] Nakou M, Papadimitraki E, Fanouriakis A, Bertsias G, Choulaki C, Goulidaki N, et al.
Interleukin-21 is increased in active systemic lupus erythematosus patients and
contributes to the generation of plasma B cells. Clin Exp Rheumatol 2013;31:
172–9.
[129] Zickert A, Amoudruz P, Sundström Y, Rönnelid J, Malmström V, Gunnarsson I. IL-17
and IL-23 in lupus nephritis-association to histopathology and response to treat-
ment. BMC Immunol 2015;16:7.
[130] Leng R-X, Pan H-F, Chen G-M, Wang C, Qin W-Z, Chen L-L, et al. IL-23: a promising
therapeutic target for systemic lupus erythematosus. Arch Med Res 2010;41:
221–5.
[131] Bettelli E, Sullivan B, Szabo SJ, Sobel RA, Glimcher LH, Kuchroo VK. Loss of T-bet, but
not STAT1, prevents the development of experimental autoimmune encephalomy-
elitis. J Exp Med 2004;200:79–87.
[132] Trinchieri G, Pflanz S, Kastelein RA. The IL-12 family of heterodimeric cytokines:
new players in the regulation of T cell responses. Immunity 2003;19:641–4.
[133] Kanakasabai S, Casalini E, Walline CC, Mo C, Chearwae W, Bright JJ. Differential reg-
ulation of CD4+ T helper cell responses by curcumin in experimental autoimmune
encephalomyelitis. J Nutr Biochem 2012;23:1498–507.
[134] Xie L, Li X-K, Funeshima-Fuji N, Kimura H, Matsumoto Y, Isaka Y, et al. Amelioration
of experimental autoimmune encephalomyelitis by curcumin treatment through
inhibition of IL-17 production. Int Immunopharmacol 2009;9:575–81.
[135] Bakr B, Ay ZY, Büyükbayram HI, Dogucx DK, Bayram D, Candan IA, et al. Effect of
curcumin on systemic t helper 17 cell response; gingival expressions of
interleukin-17 and retinoic acid receptor-related orphan receptor gt; and alveolar
bone loss in experimental periodontitis. J Periodontol 2016;87:e183–91.
[136] Palaniyandi S, Kumari R, Dalland J, Kesler M, Hildebrandt GC. Protective effect of
curcumin in murine graft versus host disease after allogeneic hematopoietic cell
transplantation. Biol Blood Marrow Transplantat 2017;23:S376–7.
[137] Zhang ZY, Zhang Z, Schluesener H. FTY720 attenuates lesional interleukin-17+ cell
accumulation in rat experimental autoimmune neuritis. Neuropathol Appl
Neurobiol 2009;35:487–95.
[138] Rautajoki KJ, Rautajoki KJ, Kyläniemi MK, Raghav SK, Rao K, Lahesmaa R. An insight
into molecular mechanisms of human T helper cell differentiation. Ann Med 2008;
40:322–35.
[139] Carbone F, De Rosa V, Carrieri PB, Montella S, Bruzzese D, Porcellini A, et al. Regu-
latory T cell proliferative potential is impaired in human autoimmune disease. Nat
Med 2014;20:69–74.
[140] Long SA, Buckner JH. CD4+ FOXP3+ T regulatory cells in human autoimmunity:
more than a numbers game. J Immunol 2011;187:2061–6.
[141] Nie J, Li YY, Zheng SG, Tsun A, Li B. FOXP3+ Treg cells and gender bias in autoim-
mune diseases. Front Immunol 2015;6:493.
[142] Schmidt A, Éliás S, Joshi RN, Tegnér J. In vitro differentiation of human CD4+
FOXP3+ induced regulatory T cells (iTregs) from naïve CD4+ T cells using a TGF-
β-containing protocol. J Vis Exp 2016;118:e55015. https://doi.org/10.3791/55015.
[143] Bento-de-Souza L, Victor JR, Bento-de-Souza LC, Arrais-Santos M, Rangel-Santos
AC, Pereira-Costa É, et al. Constitutive expression of genes encoding notch recep-
tors and ligands in developing lymphocytes, nTreg cells and dendritic cells in the
human thymus. Results Immunol 2016;6(118):15–20. https://doi.org/10.3791/
55015.
[144] Haribhai D, Chatila TA, Williams CB. Immunotherapy with iTreg and nTreg cells in a
murine model of inflammatory bowel disease. Gastrointestinal Physiology and Dis-
eases: Methods and Protocols; 2016. p. 197–211.
Please cite this article as: Momtazi-Borojeni AA, et al, Curcumin: A natural modulator of immune cells in systemic lupus erythematosus,
Autoimmun Rev (2017), https://doi.org/10.1016/j.autrev.2017.11.016
[145] Schmitt EG, Haribhai D, Williams JB, Aggarwal P, Jia S, Charbonnier L-M, et al. IL-10
produced by induced regulatory T cells (iTregs) controls colitis and pathogenic ex-
iTregs during immunotherapy. J Immunol 2012;189:5638–48.
[146] Blenman KR, Duan B, Xu Z, Wan S, Atkinson MA, Flotte TR, et al. IL-10 regulation of
lupus in the NZM2410 murine model. Lab Investig 2006;86:1136–48.
[147] Roncarolo M-G, Levings MK. The role of different subsets of T regulatory cells in
controlling autoimmunity. Curr Opin Immunol 2000;12:676–83.
[148] Letterio JJ. Murine models define the role of TGF-β as a master regulator of immune
cell function. Cytokine Growth Factor Rev 2000;11:81–7.
[149] Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA. A role for TGF-β in the generation
and expansion of CD4+ CD25+ regulatory T cells from human peripheral blood. J
Immunol 2001;166:7282–9.
[150] Kulkarni AB, Huh C-G, Becker D, Geiser A, Lyght M, Flanders KC, et al. Transforming
growth factor beta 1 null mutation in mice causes excessive inflammatory re-
sponse and early death. Proc Natl Acad Sci 1993;90:770–4.
[151] Prud'Homme GJ, Piccirillo CA. The inhibitory effects of transforming growth factor-
beta-1 (TGF-β1) in autoimmune diseases. J Autoimmun 2000;14:23–42.
[152] Sanjabi S, Zenewicz LA, Kamanaka M, Flavell RA. Anti-inflammatory and pro-
inflammatory roles of TGF-β, IL-10, and IL-22 in immunity and autoimmunity.
Curr Opin Pharmacol 2009;9:447–53.
[153] Kim G, Jang MS, Son YM, Seo MJ, Ji SY, Han SH, et al. Curcumin inhibits CD4+ T cell
activation, but augments CD69 expression and TGF-β1-mediated generation of
regulatory T cells at late phase. PLoS ONE 2013;8.
[154] Sancho D, Gómez M, Sánchez-Madrid F. CD69 is an immunoregulatory molecule
induced following activation. Trends Immunol 2005;26:136–40.
[155] Martín P, Gómez M, Lamana A, Marín AM, Cortés JR, Ramírez-Huesca M, et al. The
leukocyte activation antigen CD69 limits allergic asthma and skin contact hyper-
sensitivity. J Allergy Clin Immunol 2010;126:355–65.
[156] Sancho D, Gómez M, Viedma F, Esplugues E, Gordón-Alonso M, García-López MA,
et al. CD69 downregulates autoimmune reactivity through active transforming
growth factor-β production in collagen-induced arthritis. J Clin Invest 2003;112:
872–82.
[157] Martín P, Sánchez-Madrid F. CD69: an unexpected regulator of TH17 cell–driven
inflammatory responses. Sci Signal 2011;4:pe14.
[158] Martín P, Gómez M, Lamana A, Cruz-Adalia A, Ramírez-Huesca M, Ursa MÁ, et al.
CD69 association with Jak3/Stat5 proteins regulates Th17 cell differentiation. Mol
Cell Biol 2010;30:4877–89.
[159] Martin P, Gomez M, Lamana A, Cruz-Adalia A, Ramirez-Huesca M, et al. CD69 asso-
ciation with Jak3/Stat5 proteins regulates Th17 cell differentiation. Mol Cell Biol
2010;30:4877–89.
[160] Bereswill S, Muñoz M, Fischer A, Plickert R, Haag L-M, Otto B, et al. Anti-
inflammatory effects of resveratrol, curcumin and simvastatin in acute small intes-
tinal inflammation. PLoS One 2010;5:e15099.
[161] Forward NA, Conrad DM, Coombs MRP, Doucette CD, Furlong SJ, Lin T-J, et al.
Curcumin blocks interleukin (IL)-2 signaling in T-lymphocytes by inhibiting IL-2
synthesis, CD25 expression, and IL-2 receptor signaling. Biochem Biophys Res
Commun 2011;407:801–6.
[162] Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune toler-
ance. Cell 2008;133:775–87.
[163] Passerini L, Allan SE, Battaglia M, Di Nunzio S, Alstad AN, Levings MK, et al.
STAT5-signaling cytokines regulate the expression of FOXP3 in CD4 +
CD25 + regulatory T cells and CD4 + CD25 − effector T cells. Int Immunol
2008;20:421–31.
[164] Alunno A, Bartoloni E, Bistoni O, Nocentini G, Ronchetti S, Caterbi S, et al. Balance
between regulatory T and Th17 cells in systemic lupus erythematosus: the old
and the new. Clin Dev Immunol 2012:823085.
[165] Handono K, Hasanah D, Kalim H, Mawarti H. The association among serum levels of
vitamin D, TGf-β/IL-6 balance and Treg/Th17 balance in systemic lupus erythema-
tosus patients in Indonesia. Int J Biochem Biotechnol 2013;2:490–6.
[166] Handono K, Marisa D, Kalim H. Association between the low levels of vitamin D
and Treg function in systemic lupus erythematosus patients. Acta Med Indones
2016;45:26–31.
[167] Yang J, Yang X, Zou H, Chu Y, Li M. Recovery of the immune balance between Th17
and regulatory T cells as a treatment for systemic lupus erythematosus. Rheuma-
tology 2011;50:1366–72.
[168] Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol 2010;
40:1830–5.
[169] Gautam SC, Gao X, Dulchavsky S. Immunomodulation by curcumin. The Molecular
Targets and Therapeutic Uses of Curcumin in Health and Disease. Springer; 2007.
p. 321–41.
[170] Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned
from clinical trials. AAPS journal]–>AAPS J 2013;15:195–218.
[171] Jacob A, Wu R, Zhou M, Wang P. Mechanism of the anti-inflammatory effect of
curcumin: PPAR-γ activation. PPAR Res 2007:89369.
[172] Handono K, Pratama MZ, Endharti AT, Kalim H. Treatment of low doses curcumin
could modulate Th17/Treg balance specifically on CD4+ T cell cultures of systemic
lupus erythematosus patients. Cen Eur J Immunol 2015;40:461–9.
[173] Abbas Momtazi A, Sahebkar A. Difluorinated curcumin: a promising curcumin an-
alogue with improved anti-tumor activity and pharmacokinetic profile. Curr Pharm
Des 2016;22:4386–97.
[174] Asai A, Miyazawa T. Occurrence of orally administered curcuminoid as glucuronide
and glucuronide/sulfate conjugates in rat plasma. Life Sci 2000;67:2785–93.
[175] Ireson C, Orr S, Jones DJ, Verschoyle R, Lim C-K, Luo J-L, et al. Characterization of
metabolites of the chemopreventive agent curcumin in human and rat hepatocytes
and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-
induced prostaglandin E2 production. Cancer Res 2001;61:1058–64.
[176] Pan M-H, Huang T-M, Lin J-K. Biotransformation of curcumin through reduction
and glucuronidation in mice. Drug Metab Dispos 1999;27:486–94.
[177] Kurien BT, D'souza A, Scofield RH. Heat-solubilized curry spice curcumin inhibits
antibody–antigen interaction in in vitro studies: a possible therapy to alleviate au-
toimmune disorders. Mol Nutr Food Res 2010;54:1202–9.
 A.A. Momtazi-Borojeni et al. / Autoimmunity Reviews xxx (2017) xxx–xxx 11

[178] Kurien BT, Harris VM, Quadri SM, Coutinho-de Souza P, Cavett J, Moyer A, et al. Sig-
nificantly reduced lymphadenopathy, salivary gland infiltrates and proteinuria in
MRL-lpr/lpr mice treated with ultrasoluble curcumin/turmeric: increased survival
with curcumin treatment. Lupus Sci Med 2015;2:e000114.
[179] Foxley S, Zamora M, Hack B, Alexander RR, Roman B, Quigg RJ, et al. Curcumin ag-
gravates CNS pathology in experimental systemic lupus erythematosus. Brain Res
2013;1504:85–96.
[180] Abdollahi E, Momtazi AA, Johnston TP, Sahebkar A. Therapeutic effects of curcumin
in inflammatory and immune-mediated diseases: a nature-made jack-of-all-
trades? J Cell Physiol 2017. https://doi.org/10.1002/jcp.25778.
[181] Kulkarni AP, Ghebremariam YT, Kotwal GJ. Curcumin inhibits the classical and the
alternate pathways of complement activation. NY Acad Sci]–>Ann N Y Acad Sci
2005;1056:100–12.

Please cite this article as: Momtazi-Borojeni AA, et al, Curcumin: A natural modulator of immune cells in systemic lupus erythematosus,
Autoimmun Rev (2017), https://doi.org/10.1016/j.autrev.2017.11.016
View publication stats