|Year : 2017 | Volume
| Issue : 2 | Page : 86-93
Immune modulation effects of curcumin in pristane-induced lupus mice
Handono Kalim1, Kusworini Handono2, Takhta Khalasha3, Mirza Zaka Pratama3, Tri Wahyudi Iman Dantara3, Ayu Pramitha Wulandari3, Fahimma Albinsaid3, Sofi Nur Fitria3, Muhammad Vardian Mahardika3
1 Department of Internal Medicine, Rheumatology and Immunology Division, Faculty of Medicine Brawijaya University, Saiful Anwar General Hospital, Malang, East Java 65111, Indonesia
2 Department of Clinical Pathology, Faculty of Medicine Brawijaya University, Saiful Anwar General Hospital, Malang, East Java 65111, Indonesia
3 Department of Biomedical Sciences, Faculty of Medicine Brawijaya University, Saiful Anwar General Hospital, Malang, East Java 65111, Indonesia
|Date of Web Publication||26-May-2017|
Department of Internal Medicine, Rheumatology and Immunology Division, Faculty of Medicine Brawijaya University, Saiful Anwar General Hospital, Jalan JA Suprapto No. 2, Malang, East Java 65111
Source of Support: None, Conflict of Interest: None
Background: Curcumin, a polyphenolic compound derived from food spice turmeric has been widely used in Asian traditional medicine for its medicinal properties as antitumor, antioxidant, and anti-inflammatory properties. Meanwhile, intraperitoneal (i.p.) injection of the hydrocarbon oil pristane into normal mice leads to a lupus-like autoimmune syndrome. We aimed to investigate the effects of curcumin on systemic lupus erythematosus (SLE) clinical manifestation, adaptive immune system components, proinflammatory cytokines, and autoantibody production in pristane-induced lupus mice.
Methods: Fifty female BALB/c mice, 6–8 weeks old were divided into 2 groups: Forty mice received a single i.p. injection of 0.5 cc pristane for lupus induction and ten mice as healthy controls. Starting at 16 weeks after injection, forty pristane-induced lupus mice were divided into four groups based on doses of curcumin received intragastrically: 0, 12.5, 50, and 200 mg/kg bw/day daily for 16 weeks. At 32 weeks after injection, all of mice were assessed for arthritis score, proteinuria level, body weights, adaptive immune system components (Th1, Th2, Th17, and Treg percentages) from spleen using flow cytometry; proinflammatory cytokines and autoantibody production, including interleukin-6 (IL-6), interferon-alpha (IFN-α), and antinuclear antibody (ANA) from serum using enzyme-linked immunosorbent assay.
Results: Arthritis score and proteinuria level were decreased in curcumin-treated mice. However, body weights were not significantly different between the groups. The decreased of Th1, Th2, and Th17 percentages were seen after treatment with 200 mg/kg bw/day of curcumin (P = 0.031,P = 0.017, andP = 0.005, respectively). However, only slight increase of Treg percentages was seen after curcumin treatment. Treatment with 200 mg/kg bw/day of curcumin decreased serum IL-6 and IFN-α levels (P = 0.007 andP = 0.003). Furthermore, ANA levels were also decreased significantly after treatment with 200 mg/kg bw/day of curcumin (P = 0.013).
Conclusion: Our findings suggested that curcumin could prove useful as a therapeutic intervention in SLE.
Keywords: Curcumin, pristane, systemic lupus erythematosus
|How to cite this article:|
Kalim H, Handono K, Khalasha T, Pratama MZ, Dantara TW, Wulandari AP, Albinsaid F, Fitria SN, Mahardika MV. Immune modulation effects of curcumin in pristane-induced lupus mice. Indian J Rheumatol 2017;12:86-93
|How to cite this URL:|
Kalim H, Handono K, Khalasha T, Pratama MZ, Dantara TW, Wulandari AP, Albinsaid F, Fitria SN, Mahardika MV. Immune modulation effects of curcumin in pristane-induced lupus mice. Indian J Rheumatol [serial online] 2017 [cited 2021 Jan 19];12:86-93. Available from: https://www.indianjrheumatol.com/text.asp?2017/12/2/86/205759
| Introduction|| |
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with complex pathogenesis. In previous decades, many studies found that abnormal function and proportion of CD4+ T-cells subsets had major roles in the development of SLE. Increased Th1, Th2, and Th17 subsets and decreased regulatory of T-cells (Treg) have been reported in many studies to be correlated with activity index, tissue damage, and autoantibodies synthesis in SLE patients.,,
There are numerous murine models that have long been studied in an effort to understand pathogenesis and advances in SLE treatment. One SLE animal model is the pristane-induced lupus mice model. Pristane is an isoprenoid alkane found at high concentration in mineral oil and can induce autoantibodies and the clinical manifestations of SLE in murine models. Studies have shown that these mice have disparate T-cell requirements of two subsets of lupus-specific autoantibodies as well as the toll-like receptor 7-dependent and FcγR-independent production of Type I interferon.
The rapid advance in the treatment and diagnosis of SLE in recent few years has resulted in greater life expectancy of SLE patients. Current therapeutics used to treat SLE including glucocorticoids are directed at suppressing humoral immunity and the production of autoantibodies as well as helper T-cells (Th) and B-cells. However, the use of long-term glucocorticoids and immunosuppressant therapies for SLE may result in various side effects. Immunosuppressant agents are not widely available and affordable, especially in the developing country.
One of the current developments in autoimmune disease treatment field in developing country is nutraceutical product. One example of bioactive compound from plants that have immunomodulatory properties is curcumin, a phenolic compound which mainly can be found in turmeric. It has been shown that curcumin possesses many biological effects on cells, including anti-inflammatory, antioxidant, immunomodulator, and anticancer.,,, Curcumin is also proved to be able to modulate cellular response and the growth of various cell types in the immune system, including T-cells, B-cells, dendritic cells, macrophages, and natural killer cells.
Despite the wide range of curcumin effects on various biologic processes, the role of curcumin in SLE is rarely discussed. Therefore, this research aimed to investigate the role of curcumin on the clinical manifestations and adaptive immune responses as well as the production of proinflammatory cytokines in SLE animal model.
| Methods|| |
Mice and lupus induction
Totally, fifty female BALB/c mice that were 6–8 weeks old were obtained from Pusvetma Surabaya, East Java, Indonesia. All mice were housed in standard cages (5 mice/cage) in a climate-controlled environment. The mice were maintained on 12-h light/dark cycle and provided food and water ad libitum. Mice were habituated to the holding room for a minimum of 1 week before undergoing experimental procedures. Fifty female BALB/c mice were randomly divided into the following two groups: (1) pristane-induced mice group: Forty BALB/c mice received a single intraperitoneal injection of 0.5 ml of pristane (Sigma-Aldrich, USA) for lupus induction and (2) normal control group: 10 BALB/c mice not injected with pristane and not fed with curcumin.
Preparation and administration of curcumin
The curcumin was acquired from Sigma, St Louis, MO. Curcumin solutions of (1 or 5 mg/ml in filtered water) were prepared by dissolving it in hot distilled water (about 90°C); and subsequently heated for 10 min in a boiling water bath, and filtered using Sigma-Aldrich sintered glass funnel number three (pore size 16–40 μm). The precipitate was washed with additional amounts of hot distilled water then the solution was cooled. This procedure allowed the curcumin solubility to increase 12-fold in water based. Afterward, the solutions were emulsified with 0.5% carboxymethyl cellulose for intragastric administration to mice.
Sixteen weeks after pristane injection, pristane-induced mice group were randomly divided into the following four groups: (1) Curcumin A group: Ten pristane-induced mice were given curcumin 12.5 mg/kg bw/day daily for 16 weeks; (2) Curcumin B group: Ten pristane-induced mice were given curcumin 50 mg/kg bw/day daily for 16 weeks; (3) Curcumin C group: Ten pristane-induced mice were given curcumin 200 mg/kg bw/day daily for 16 weeks; (4) Model control group: Ten pristane-induced mice were not given curcumin. Intragastric administration of curcumin was carried out daily until 32 weeks postpristane injection. The mice were euthanized at the end of 32 weeks postpristane injection, then their spleen and serum had been obtained for further analyses.
Measurement of proteinuria
Beginning at 32 weeks postpristane injection, proteinuria was measured semi-quantitatively by impregnating wool paper test strips with spot urine sample (URiSCAN, Yeongdong Pharmaceutical Company). The color change of the strip infiltrated with the urine sample was visually judged against a standard strip and scored from 0 to 5+, according to manufacturer's instructions. The urinary protein content was graded according to the score as follows: 0 ≤100 mg/L, 1+ = 100 mg/L, 2+ = 300 mg/L, 3+ = 1000 mg/L, 4+ = 3000 mg/L, and 5+ = 10,000 mg/L. Significant proteinuria was characterized by more than positive two score on dipstick score (equivalent to >300 mg/dl protein in urine).
Scoring of arthritis
At 32 weeks postpristane injection, mice were examined for arthritis development after curcumin treatment. Scoring of animals was done blindly using a scoring system (arthritis score) based on the number of inflamed joints in each paw, inflammation being defined by swelling and redness. In this scoring system, each inflamed toe or knuckle gave one point, whereas an inflamed wrist or ankle gave five points, resulting in a score of 0–15 (five toes + five knuckles + one wrist/ankle) for each paw and 0–60 points for each mice. The individual mice arthritis score was obtained by summing the scores recorded for each limb. Clinical evaluations were performed by two investigators (anatomical pathology specialist) unaware of mice identity, and the mean of both scores was calculated.
Preparation from spleen tissue was done using previous protocol methods. Spleen tissues were harvested and teased apart into single-cell suspension by pressing them with the plunger of a 3 ml syringe. Tissues were collected in 10 ml of staining buffer and passed cell suspension through a cell strainer to eliminate clumps and debris, then collected cell suspension in a conical tube. The cell suspension was centrifuged for 4–5 min (300–400 xg) at 4°C and the supernatant was removed. Red blood cell lysis was performed. Samples were resuspended in 50 ml of staining buffer and cell count, and viability analyses were performed using Trypan Blue.
Flow cytometry analysis
Cells that had been taken from spleen were stained using antibody markers to assess CD4+ T cells subsets percentages, including Th1, Th2, Th17, and Treg by flow cytometry. Before Th1, Th2, and Th17 staining, cells were stimulated with phorbolmyristate acetate (50 ng/ml; Sigma, St. Louis, MO, USA) and ionomycin (1 μg/ml; sigma) in the presence of Brefeldin A (BD Pharmingen, San Diego, CA, USA) for at least 4 h. Subsequently, the cells were labeled with PE antimouse CD4 (Biolegend, USA). Intracellular staining was performed using FITC antimouse IFN-γ (Biolegend, USA), PerCP antimouse IL-4 (Biolegend, USA), and PerCP antimouse IL-17A to detect Th1, Th2, and Th17, respectively.
For the detection of Treg, cells were labeled with PE antimouse CD4 (Biolegend, USA), PerCP antimouse CD25 (Biolegend, USA), and FITC antimouse FoxP3 (Biolegend, USA). Staining was performed according to Biolegend manufacture protocols. All cells were analyzed using Cellquestpro software.
Proinflammatory cytokines and autoantibody assay
At 32 weeks postpristane injection, whole blood samples of the mice were collected from their heart following inhalation of chloroform anesthesia. The blood samples were allowed to clot by leaving it at room temperature for 15–30 min, and the clot was removed by centrifuging it at 1000–2000 à×g for 10 min. Proinflammatory cytokines levels (IL-6 and interferon-alpha [IFN-α]) from serum were determined using enzyme-linked immunosorbent assay (ELISA) kits (from Biolegend, USA). Antinuclear antibody (ANA) from serum was also determined using ELISA kits (MyBioSource, San Diego, CA, USA).
Comparison of all data between groups was done by one-way analysis of variance test followed by post hoc analysis. Parametric data were described as mean ± standard deviation; the statistical significance of the various tests was examined by two-sided hypothesis testing. P < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS for Windows version 16.0 (SPSS, Chicago, IL, USA).
All of the experiments were undertaken in certified in vivo laboratories at Pharmacology Laboratory of Brawijaya University Research Centre, Malang, East Java, Indonesia. The studies and animal care have been approved by the Health Research Ethics Committee, Faculty of Medicine, University of Brawijaya.
| Results|| |
Initially, ten mice were included in each group; however, four mice in model control group and one mice in curcumin A group were dead before reaching 32 weeks after pristane injection. Data from these mice were excluded from the analysis of treatment efficacy. Pristane-induced mice treated with curcumin gained weight in a manner similar to that of model control and normal control groups. There was no difference in body weight between various groups of mice. Mice treated with curcumin 200 mg/kg bw/day had the highest body weight [Table 1].
|Table 1: Clinical Characteristics of Pristane Induced Lupus Mice on Each Group (*P <0.05, **P < 0.01, and ***P < 0.001 compared to model control group)|
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Effect of curcumin on proteinuria
At the end of the study, urinalysis revealed that 2 out of 6 mice in model control group and 2 out of 9 mice in curcumin A group had significant proteinuria. One out of 10 mice in curcumin B group also had a significant proteinuria. Whereas, there was no mice from curcumin C group that had proteinuria. Therefore, curcumin can prevent the development of proteinuria in this pristane-induced lupus model.
Effect of curcumin on arthritis and autoantibody production
The presence of joint swelling and redness on all of the paws of the mice was assessed using arthritis score. Curcumin treatment reduced the arthritis score. With a dose-dependent manner [Table 1], (P < 0.001, P < 0.001, and P < 0.001 in groups treated with curcumin 12.5, 50, and 200 mg/kg bw/day, respectively, compared to model control group).
Curcumin, especially with administration of 50 mg/kg bw/day and 200 mg/kg bw/day, showed significantly lower serum ANA level compared to model control group [Table 1] (P = 0.008 and P = 0.013, respectively).
Effects of curcumin treatment on Th1 and Th2 percentages
Th1 (CD4+ IFNγ+) and Th2 (CD4+ IL4+) percentages were measured from spleen samples using flowcytometry [Figure 1]a and [Figure 1]b. Daily dose of curcumin treatment on pristane-induced lupus mice decreased both Th1 and Th2 percentages on dose-dependent manner. Only in curcumin C group that was able to decrease Th1 percentages significantly lower compared to model control group [Figure 2]a, (P = 0.031). However, in curcumin B and C group was able to decreased Th2 percentages significantly compared to model control group [Figure 2]b, (P = 0.045 and P = 0.017).
|Figure 1: Representative dot plots which illustrate (a) Th1 expressing CD4+ interferon γ+, (b) Th2 expressing CD4+ interleukin 4+, (c) Th17 expressing CD4+ interleukin-17A+, and (d) Treg expressing CD25+ FoxP3+|
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|Figure 2: Effect curcumin on (a) Th1 percentages, (b) Th2 percentages, (c) ratio of Th1/Th2 percentages in spleen. The curcumin group showed a significantly decreased in Th1 and Th2 percentages when compared with model control group. Values are means, with their standard errors represented by vertical bars (n = 7–8). Mean values were significantly different from that of model control group mice: *P < 0.05, **P < 0.01 (analysis of variance)|
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Curcumin did not alter the balance of Th1 and Th2 [Figure 2]c, (P = 0.898). These results indicated that curcumin reduced Th1 and Th2 percentages on pristane-induced lupus mice without altering Th1/Th2 balance.
Effect of curcumin treatment on Th17 and Treg percentages
A test had been conducted to prove whether curcumin could affect Th17 and Treg differentiation on pristane-induced lupus mice. [Figure 1]c showed Th17 expressed CD4+ IL-17A +, whereas [Figure 1]d showed Treg expressed CD4+ CD25+ FoxP3+.
Daily curcumin administration for 16 weeks decreased Th17 (CD4+ IL-17A +) percentages in the spleen of pristane-induced lupus mice in a dose-dependent manner [Figure 3]a. Administration 50 and 200 mg/kg bw/day of curcumin decreased Th17 percentages significantly compared to model control group [Figure 3]a, (P = 0.039 and P = 0.005). In contrast, curcumin tended to increase Treg (CD4+ CD25+ FoxP3+) percentages in the spleen of pristane-induced lupus mice in a dose-dependent manner [Figure 3]b.
|Figure 3: Effect curcumin on (a) Th17 percentages, (b) Treg percentages, and (c) ratio of Th17/Treg percentages in spleen. The curcumin group showed a significantly decreased in Th17 percentages and ratio of Th17/Treg percentages. However, the increased of Treg percentages were not significantly different between the groups. Values are means, with their standard errors represented by vertical bars (n = 7–8). Mean values were significantly different from that of model control group mice: *P < 0.05, **P < 0.01 (analysis of variance)|
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We also found that curcumin altered Th17/Treg balance by shifting it toward Treg differentiation in a dose-dependent manner [Figure 3]c. Th17/Treg ratios decreased significantly in curcumin C group compared to model control group (P = 0.024).
Effects of curcumin treatment on proinflammatory cytokines
Imbalance of CD4+ T-cells subsets in SLE might be the result of an increase in proinflammatory cytokines, such as IL-6 and IFN-α. We assessed serum IL-6 and IFN-α levels of each group to evaluate the role of curcumin on these cytokines production.
Doses of 12.5, 50, and 200 mg/kg bw/day curcumin reduced serum IL-6 levels significantly compared to model control group in a dose-dependent manner [Figure 4]a (P = 0.013, P = 0.011, and P = 0.007, respectively). Administration of 200 mg/kg bw/day showed significantly decreased IFN-α serum levels compared to model control group (P = 0.003) [Figure 4]b.
|Figure 4: Effect curcumin on (a) interleukin-6 (b) interferon-alpha levels in serum. The curcumin group showed a significantly decreased in interleukin-6 and interferon-alpha levels when compared with the model control group. Values are means, with their standard errors represented by vertical bars mean values were significantly different from that of model control group mice: *P < 0.05 (analysis of variance)|
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| Discussion|| |
Curcumin is an active principle component isolated from the rhizome of Curcuma longa which have been proven to be having anti-inflammatory, antioxidant, and antitumor activities. Various studies also found that curcumin could inhibit the complement cascade and alleviate a number of immune-mediated diseases.,, In this study, we explored the therapeutic effects of curcumin on SLE animal models. This is the first study that aimed to investigate in vivo effects of curcumin on pristane-induced lupus mice. We found that mice that were treated with curcumin showed significant decrease of arthritis score and ANA level compared to model control group. Our study results showed that there was no significant difference in body weight between various groups of curcumin-treated mice, similar with the finding of another studies.,
Although SLE pathophysiology is a complex process, many studies found that CD4+ T-cells have major roles in the pathogenesis of SLE.,, Clinical deteriorations of SLE have been reported to be correlated with the increase of Th1, Th2, and Th17 subsets and also the decrease of Treg populations. This study discovered that administration of high doses of curcumin (200 mg/kg bw/day) for 16 weeks decreased Th1, Th2, and Th17 populations in the spleen of pristane-induced lupus mice, but not significantly increased Treg populations.
Previously, SLE was thought to be a Th2-driven disease; however, recent reports showed that besides Th2, Th1 also has an abnormal response in SLE., Interestingly, in this study, curcumin reduced both Th1 and Th2 populations simultaneously in the same manner, which was showed by similar Th1/Th2 ratios to model control group. This result was somewhat different from the previous studies, where most of them indicate that curcumin regulates the shift from Th1 to Th2. However, these previous studies results were obtained from studies on Th1 dominant diseases., In contrast, in Th2-driven disease, such as allergic asthma, curcumin might reduce Th2 polarization. Added with our study results, it is possible that curcumin may act differently in Th1/Th2 balance, depending on the situation, in which component is dominant, Th1 or Th2. In fact, it confirms that curcumin does not only inhibiting Th1 but also inhibiting Th2. Therefore, in Th1- and Th2-driven disease such as SLE, curcumin may decrease both Th1 and Th2 populations simultaneously.
Other subsets of CD4+ T-cells which have important roles in the pathogenesis of SLE are Th17 and Treg. Recent reports suggested that improving Th17/Treg balance might help to reduce disease activity in SLE patients. From our study, we found that daily curcumin treatment for 16 weeks, especially 200 mg/kg bw/day, could decrease Th17 population and Th17/Treg ratios significantly compared to control. However, there was only slight enhancement of Treg population that can be seen after curcumin treatment. Previously, curcumin had been shown to be able to attenuate airway inflammation on mice models by increasing Treg and reducing Th17 functions. Another study also showed that curcumin might reduce the severity of acute graft-versus-host disease by regulating of Th17 and Treg functions. Another study investigating the effect of low doses curcumin treatment in human also revealed similar results. Despite the facts, the roles of curcumin treatment in mice model of SLE have never been published.
Imbalance of Th cells and Treg subsets on SLE are thought to be a complex phenomenon influenced by abnormal production of proinflammatory cytokines. Several of the proinflammatory cytokines that mediate the early and late immune response in SLE are IL-6 and Type I interferons, such as IFN-α. The raise in these cytokines levels had been reported to correlate with the increase in autoantibody productions, aggravating clinical manifestations, and tissue destructions in SLE.
Our present study has proved that curcumin might also decrease IL-6 and IFN-α serum concentration on pristane-induced lupus mice model, which was consistent with the previous studies. Das and Vinayak  reported that curcumin could regulate IL-6 expression through a regulation of nuclear factor-kB transcription factor. Another research carried out by Sordillo and Helson  also showed that curcumin suppressed cytokine release such as IL-6 and IFN-α in Ebola and other severe viral infections patients. Curcumin's ability to modulate various types of transcription factors is believed to be the molecular mechanisms of curcumin which may suppress cytokines production.,
Despite being an interesting subject to be studied, this study still had many limitations, such as immune modulation mechanism of curcumin which still need to be elucidated. Further research should be aimed particularly to monitor the effects of curcumin on organs, other proinflammatory cytokines on serum, and also the risk of long-term use of curcumin on the body. Although there are still many problems that need to be investigated, the use of curcumin as an immunomodulatory agent is very interesting to be developed as for the complementary treatment of SLE.
This report showed that curcumin protected pristane-induced lupus mice from arthritis and overproduction of ANA. Curcumin also modulated the abnormal immune response in mice model of SLE, shown by reduction of Th1 and Th2 population on spleen of pristane-induced lupus mice without affecting the balance between Th1 and Th2 subsets. Interestingly, administration of curcumin on pristane-induced lupus mice might also decrease Th17 percentages and Th17/Treg ratio. However, there was only slight raise of Treg percentages after curcumin treatment. Proinflammatory cytokines productions of IL-6 and IFN-α were also inhibited by curcumin. Thus, our observation revealed that curcumin could prove useful as a therapeutic intervention in SLE.
We are grateful to Brawijaya University and Directorate general of higher education (DIKTI), for providing the research funding.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]