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RESEARCH ARTICLE Br J Med Health Res. 2015; 2(6) ISSN: 2394-2967
Please cite this article as: Al-Rekabi MD et al., Immunomodulatory Effects of Quercetin in Patient with
Active Rheumatoid Arthritis. British Journal of Medical and Health Research 2014.
BJMHR
British Journal of Medical and Health Research
Journal home page: www.bjmhr.com
Immunomodulatory Effects of Quercetin in Patient with Active
Rheumatoid Arthritis
Mohammad D. Al-Rekabi1*, Shatha H. Ali2, Hamadallah Al-Basaisi3, Furqan Hashim4,
Ahmed H. Hussein5, Hayder K. Abbas5
1. Clinical Pharmacy Dept., Faculty of Pharmacy, Kufa University, Iraq.
2. Clinical Lab. Sciences Dept., College of pharmacy, Baghdad University, Iraq.
3. Orthopedic Dept., Faculty of Medicine, Kufa University, Iraq.
4. Scientific and Humanity university college, Najaf, Iraq.
5. Pharmaceutics Dept., Faculty of pharmacy, Kufa University, Iraq.
ABSTRACT
Rheumatoid arthritis is an autoimmune systemic inflammatory disease primarily affecting the
joints as well as other extra-articular tissues. This study was designed to evaluate the
immunomodulatory effect of different doses of quercetin(500mg, 1000mg, 1500mg/day) for
rheumatoid arthritis in patients treated with the conventional disease modifying antirheumatic
drugs (DMARDs). This project was performed on 160 rheumatoid arthritis patients who
fulfilled the American College of Rheumatology (ACR) criteria for the diagnosis of
rheumatoid arthritis. In addition to 30 healthy volunteers were invited to participate in the
study and served as a control group. The selected patients were allocated randomly into four
groups, group (A) treated with azathioprine(100 mg/day) plus a placebo( starch containing
capsules), group (B) treated with azathioprine (100mg/day) plus quercetin (500mg/day),
group (C) treated with azathioprine (100mg/day) plus quercetin (1000mg/day) and group (D)
patients treated with azathioprine (100mg/day) plus quercetin (1500mg/day). Serum level of
interleukin-6, interleukin-10, intercellular adhesion molecule I (ICAM-1), complements
proteins pretreatment and after eight weeks of treatment. It was found that quercetin at doses
of 1500mg/ day, when added to 100mg azathioprine, significantly(p< 0.05) reduced
interleukin-6, complement protein 3 (C3) & complement protein 4 (C4) levels and elevated
interleukin-10 level more than when azathioprine had combined with placebo or with lower
doses of quercetin(500, 1000mg). However, all of tested doses of quercetin in this study were
able to significantly (p< 0.05) reduce the level of intercellular adhesion molecule-1 as
compared to the quercetin-free treated group. Oral administration of different daily doses of
quercetin (500, 1000, 1500mg) in combination with azathioprine (100 mg) produced an
immunomodulatory action through the reduction of interleukin-6, intercellular adhesion
molecule-1 and complement proteins while elevating the serum level of interleukine-10.
Keywords: Immunomodulatory, Quercetin, Rheumatoid Arthritis, Interleukins,
Complements protein.
*Corresponding Author Email: mohammed.matrood@uokufa.edu.iq
Received 21 April 2015, Accepted 28 April 2015
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Al-Rekabi et. al., Br J Med Health Res. 2015; 2(6) ISSN: 2394-2967
INTRODUCTION
The focusing on plant research has been increased all over the world in last decade and a
large amount of evidences has been collected to show the potential of medicinal plant in
various traditional systems1. Most of the immunomodulatory agents are of plant origins
which are appealed to induce paraimmunity, the nonspecific immunomodulation of
essentially granulocyte, macrophage, and natural killer cells and complement function2. It is
now being documented that immunomodulatory therapy could provide an alternative to
conventional chemotherapy to a variety of disease conditions3. Quercetin is a member of the
class of flavonoids called flavanols and forms the backbone for many other flavonoids
including the citrus flavonoids like rutin, hesperidins, naringenin and tangeritin4. The best
described property of quercetin is its ability to act as antioxidant5. Quercetin-induced
suppression of TNF-α can result in the stimulation of anti-inflammatory cytokines via
inhibiting the activation of NF-κβ, and therefore, one can anticipate that quercetin could be
widely used as an anti-TNF-α therapy6. It has also found that quercetin reduced visceral
adipose tissue TNf- α and nitric oxide production and downregulated nitric oxide synthase
expression in obese zucker rats7. Quercetin exerts immune and inflammation modulating
effect in several murine models of autoimmunity. In experimental allergic
encephalomyelitis(EAE) a T-helper 1 (Th1) cell-mediated inflammatory demyelinating
autoimmune disease model of multiple sclerosis-quercetin ameliorated EAE by blocking
interleukin-12( IL-12) signaling and Th1 differentiation8 Kaneuchi et al showed that
quercetin has anti-proliferative activity and the mechanisms of quercetin action may be
through modulation of cell cycle and cell growth regulatory genes9. Quercetin has also been
shown to limit the function of adhesion molecules on endothelial cells10. When activated
inappropriately, the complement system may evoke pathologic reactions in a variety of
inflammatory and degenerative diseases such as systemic lupus erythematosus (SLE),
rheumatoid arthritis (RA), as well as acute respiratory distress syndrome (ARDS)11
Therefore, inhibition of individual complement is a promising approach for the prevention
and treatment of these diseases and numerous natural products have been reported to possess
anti-complementary effect12. In this study , we investigated the effect of different doses of
quercetin on interleukin-6 (IL-6), interleukin-10 (IL-10), intracellular adhesion molecule-
1(ICAM-1) and complement proteins, C3 & C4 in patient with rheumatoid arthritis treated
with conventional DMARD, azathioprine .
MATERIALS AND METHOD
This study was performed on (190) subjects. 30 (10 male and 20 female) apparently healthy
control and 160 randomly selected RA patients (55 males and 105 females) with active
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Al-Rekabi et. al., Br J Med Health Res. 2015; 2(6) ISSN: 2394-2967
rheumatoid arthritis, at the out patient clinics in Al-Hakeem and Al-Sader hospitals in Najaf-
Iraq during the period December-2008 - October-2009, with age range (32 -71) years, mean
age ± SEM; (52.9±2.2), mean disease duration is 12 years (range 7-20 years). (111) patient
only completed the study. All patients have active rheumatoid arthritis and fulfill the 1987
revised criteria for the diagnosis of rheumatoid arthritis, set by the American College of
Rheumatology (ACR) (13). All selected patient are informed about the nature and aim of the
study. None of the patients had received any other specific anti-rheumatoid therapy during
the three months prior to the present study. Some of them were on intermittent use of one or
more NSAIDs, and those were informed to leave one week after the last dose of those
medications to ensure complete clearance. This research was approved by postgraduate
research committee at college of pharmacy Baghdad University.
Study design
The selected RA patient were allocated into 4 groups ,each of 40 patients , groups A, B, C
and D that received azathioprine 50mg(Glaxo Wellcome Inc.) plus placebo( starch containing
capsules), quercetin 250mg (Jarrow formulas, USA) plus azathioprine 50mg , quercetin
500mg plus azathioprine 50 mg and quercetin 750mg plus azathioprine 50 mg, respectively.
All treatments are given twice daily for eight weeks. In addition to 30 age- and sex- matched
healthy subjects that did not received any medications including those used in the study. This
group served as a control. Fasting blood samples were taken from patients and control. Serum
was obtained and analyzed for measurements of sIL-6, sIL-10, sICAM, C3 and C4, Patients
samples were analyzed at zero time ( pre-treatment) and after 8 weeks ( the end of the study).
Statistical analysis
SPSS (version 20.0 IBM, USA) software for windows was used to analyze the results of this
study. All results are expressed as Mean ± SEM. Student t-test and ANOVA was used to
examine the difference in the mean of parameters tested between studied groups. P value
<0.05 was considered significant.
RESULTS AND DISCUSSION
Effects of 8 Weeks Treatment of RA Patients with Azathioprine alone and its
Combination with Different Doses of Quercetin on Serum levels of IL-6, IL-10 and
ICAM-1:
The data presented in table (1) clearly showed that both IL-6 and ICAM-1 levels in all RA
patients groups enrolled in this study were significantly (P<0.05) elevated as compared to
healthy untreated volunteers. However, IL-10 level seems to be not altered significantly
(P<0.05) in patients baseline samples after 8 weeks. Table (1) also demonstrated a significant
(P<0.05) reduction in the serum level of IL-6 in all patients groups after treatment with
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Al-Rekabi et. al., Br J Med Health Res. 2015; 2(6) ISSN: 2394-2967
respect to the pre-treatment values of each group. It was also found that only patients treated
with 1500 mg quercetin plus azathioprine showed a significant(P<0.05) reduction in serum
level of IL-6 with respect to both azathioprine only treated group or quercetin
500mg/azathioprine 100mg treated patients. Regarding the level of IL-10, it was indicated
that there was a significant (P<0.05) increase in this cytokine in patients receiving either
azathioprine alone or combined with quercetin and, similar to IL-6, except for patients
receiving the highest quercetin dose showed a significant difference with respect to both
azathioprine only treated patients or those treated with quercetin 500mg/azathioprine 100 mg
regimen. Treatment with azathioprine alone did not significantly affect the level of ICAM-1
with respect to the pre-treatments values. Whereas, other groups that were treated with
different doses of quercetin showed significant reduction (P<0.05) in this adhesion molecule
compared with azathioprine only treated group, with the highest dose among them was
significantly different from other doses.( Figure 1)
Effects of 8 Weeks Treatment of RA Patients with Azathioprine alone and its Combination
with Different Doses of Quercetin on Serum Levels of Complement Proteins, C3 and C4.
Table 1: Effects of treatment of RA patients with azathioprine alone and its
combination with different doses of quercetin on serum level of IL-6, IL-10 and sICAM.
Group
IL-6(pg/ml)
IL-10(pg/ml)
sICAM(pg/ml)
Healthy control
Untreated
146.9 ± 8.3
140.1 ± 6.44
106.4 ± 4.45
Azathioprine (100mg/day)
Pre-treatment
354.1 ± 14.4*
159.1 ± 8.74
446.3 ± 21.5*
Post-treatment
238.7 ± 14.0*†
175.7 ±16.4*†
431.7 ± 20.7*
Azathioprine + Quercetin
(100/500mg/day)
Pre-treatment
332.1 ± 15.2*
156.9 ± 8.27
485.7 ± 21.0*
Post-treatment
218.8 ± 14.5*†
242.6 ±14.7*†
388.0 ± 15.9*†a
Azathioprine+ Quercetin
(100/1000mg/day)
Pre-treatment
352.0 ±13.3*
160.4 ± 7.74
435.5 ± 19.7*
Post-treatment
208.0 ± 14.7*†
244.6 ± 14.0*†
310.6 ± 15.9*†a
Azathioprine+ Quercetin
(100/1500mg/day)
Pre-treatment
341.6 ± 11.81*
150.5 ± 5.77
448.6 ± 18.89*
Post-treatment
171.6 ± 11.52†a,b
237.0 ±13.6*†a,b
279.6 ± 15.5*†a,b
-Data are expressed as mean ±SEM
-*P<0.05 with respect to healthy control group.
-†P<0.05 with respect to pretreatment value.
-aP<0.05 with respect to azathioprine treated group.
-bP<0.05 with respect to azathioprine +Quercetin (100/500mg/day) treated group.
Data presented in table (2) showed no significant differences in the levels of complement
proteins, C3 and C4, in RA patients compared to the healthy untreated control group. Table
(2) also indicated that treating RA patients with azathioprine alone or combined with 500 mg
/day quercetin for eight weeks resulted in slight, non-significant reduction in the serum level
of both complement proteins, C3 and C4. Data also demonstrated a significant reduction in
serum level of both C3 and C4 in patient treated with 1000 or 1500 mg/day of quercetin plus
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Al-Rekabi et. al., Br J Med Health Res. 2015; 2(6) ISSN: 2394-2967
azathioprine with respect to both other groups treated with azathioprine only or azathioprine
plus 500 mg/day.(Figure 2)
(A)
(B)
(C)
Figure (1): Serum level of Il-6 (A), ICAM-1 (B) and Il-10(C) in RA patients after 8
weeks treatment with azathioprine and its combination with different doses of
quercetin.
Both IL-6 and ICAM-1 levels in all RA patients groups enrolled in this study were
significantly (P<0.05) elevated as compared to healthy untreated volunteers. However, IL-10
level seems to be not altered significantly (P<0.05) in patients baseline samples after 8 weeks.
Significant (P<0.05) reduction in the serum level of IL-6 in all patients groups after treatment
with respect to the pre-treatment values of each group. It was also found that only patients
treated with 1500 mg quercetin plus azathioprine showed a significant(P<0.05) reduction in
serum level of IL-6 with respect to both azathioprine only treated group or quercetin
500mg/azathioprine 100mg treated patients. Regarding the level of IL-10, it was indicated
0
50
100
150
200
250
300
350
400
IL-6 level (pg/ml)
Healthy control Pre Post
Healthy control Aza 100 mg/day
Aza + Quer (100/500 mg /day) Aza + Quer (100/1000 mg /day)
Aza + Quer (100/1500 mg /day)
0
50
100
150
200
250
300
350
400
450
sICAM level (pg /ml)
Healthy control Pre Post
Healthy control Aza 100 mg/day
Aza + Quer (100/500 mg /day) Aza + Quer (100/1000 mg /day)
Aza + Quer (100/1500 mg /day)
0
50
100
150
200
250
IL-10 level ( pg/ml)
Healthy control Pre Post
Healthy control Aza 100 mg/day
Aza + Quer (100/500 mg /day) Aza + Quer (100/1000 mg /day)
Aza + Quer (100/1500 mg /day)
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Al-Rekabi et. al., Br J Med Health Res. 2015; 2(6) ISSN: 2394-2967
that there was a significant (P<0.05) increase in this cytokine in patients receiving either
azathioprine alone or combined with quercetin and, similar to IL-6, except for patients
receiving the highest quercetin dose showed a significant difference with respect to both
azathioprine only treated patients or those treated with quercetin 500mg/azathioprine 100 mg
regimen. Treatment with azathioprine alone did not significantly affect the level of ICAM-1
with respect to the pre-treatments values. Whereas, other groups that were treated with
different doses of quercetin showed significant reduction (P<0.05) in this adhesion molecule
compared with azathioprine only treated group, with the highest dose among them was
significantly different from other doses.
Table 2: Effects of treatment of RA patients with azathioprine alone and its
combination with different doses of quercetin on serum level of complement proteins
(C3 & C4)
Group
C3 ( mg/dl)
C4 ( mg/dl)
Healthy control
Untreated
136.3 ± 7.71
77.4 ± 7.08
Azathioprine (100mg/day)
Pre-treatment
140.9 ± 8.44
93.6 ± 4.62
Post-treatment
115.5 ± 6.77
88.0 ± 4.21
Azathioprine+ Quercetin (100/500mg/day)
Pre-treatment
133.4 ± 7.68
89.3 ± 4.39
Post-treatment
111.3 ± 5.28*
86.9 ± 3.28
Azathioprine+ Quercetin
(100/1000mg/day)
Pre-treatment
120.5 ± 4.38
91.8 ± 3.55
Post-treatment
93.2 ± 3.66*†b
67.8 ± 3.12†ab
Azathioprine+ Quercetin
(100/1500mg/day)
Pre-treatment
121.6 ± 4.45
91.7 ± 3.50
Post-treatment
88.5 ± 3.66*†ab
62.3 ± 3.95†ab
Data are expressed as mean ±SEM
*P<0.05 with respect to healthy control group.
†P<0.05 with respect to pretreatment value.
aP<0.05 with respect to azathioprine treated group.
bP<0.05 with respect to azathioprine +Quercetin (100/500mg/day) treated group.
(A)
(B)
Figure (2): Serum level of C3 (A) and C4 (B) in RA patients after 8 weeks treatment
with azathioprine and its combination with different doses of quercetin.
0
20
40
60
80
100
120
140
160
C3 level (mg/dl)
Healthy control Pre Post
Healthy control Aza 100 mg/day
Aza + Quer (100/500 mg /day) Aza + Quer (100/1000 mg /day)
Aza + Quer (100/1500 mg /day)
0
10
20
30
40
50
60
70
80
90
100
C4 level (mg/dl)
Healthy control Pre Post
Healthy control Aza 100 mg/day
Aza + Quer (100/500 mg /day) Aza + Quer (100/1000 mg /day)
Aza + Quer (100/1500 mg /day)
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Al-Rekabi et. al., Br J Med Health Res. 2015; 2(6) ISSN: 2394-2967
No significant differences in the levels of C3 and C4, in RA patients compared to the healthy
untreated control group. A significant reduction was found in serum level of C3 and C4 in
patient treated with 1000 or 1500 mg/day of quercetin plus azathioprine with respect to both
other groups treated with azathioprine only or azathioprine plus 500 mg/day. It has been well
documented that synovial tissues are able to synthesize the mediators of inflammatory
cascade in the joint, which may play an important role in the pathophysiology of RA. While
no known biological marker to be definitive for the diagnosis or prognosis of RA, the levels
of biomarkers such as cytokines, chemokines, and metalloproteinases can potentially reflect
the inflammatory state in joints14. Several studies have addressed the feasibility of biomarker
analysis in serum and synovial fluids in arthritis15. IL-6 is derived from not only
immunocompetent cells but also from other cells, such as neoplastic cells, endothelial cells,
and muscle fibers16. It is well known that IL-6 plays an important role in acute-phase
inflammatory reaction through accelerating release of PMN from the bone marrow,
enhancing PMN adhesiveness and recruitment, activating PMN, and enhancing release of
cytotoxic contents17. Neutrophils are terminally differentiated cells and most important
inflammatory cells. On one hand, activated neutrophils defense against pathogenic micro
organisms; on the other hand, activated neutrophils may aggravate constitutive damage of
auto-tissues through producing various inflammatory mediators18. Therefore, the level of IL-6
in body or in local inflammatory sites may affect the solution of inflammation. In normal
situation of body, bone marrow, plasma and peripheral blood serum have low levels of IL-6
and this is clear from the analysis of the serum of the normal healthy volunteers invited for
this study that showed to be significantly lower than the level seen in RA patients. However,
in infectious situation of pathogenic bacteria, IL-6 producing cells synthesize and release IL-
6 in response to the stimuli. LPS, a potential pro-inflammatory factor derived from Gram
negative bacteria, induces IL-6 production by neutrophils and expedites neutrophil
recruitment by activating Toll-like receptor 4 (TLR4)19. In the present study we found that
treating RA patient with 1500mg/day of quercetin combined with 100mg azathioprine
resulted in a significant reduction in the level of the pro-inflammatory cytokines, IL-6, and
such reduction was significantly lower than that produced by azathioprine alone or when
combined with lower doses of quercetin( Table 1). It was also found that quercetin to exhibit
inhibitory effect on IL-6 production by LPS-stimulated neutrophils. They indicate that
quercetin might decrease the susceptibility of neutrophils to pro-inflammatory factors (e.g.,
LPS), or interfere with the response of neutrophils to pro-inflammatory factors. The
inhibitory effect of quercetin on LPS-induced IL-6 production by neutrophils might partially
eliminate the accumulation of neutrophils into the inflamed sites through inhibiting
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Al-Rekabi et. al., Br J Med Health Res. 2015; 2(6) ISSN: 2394-2967
neutrophil activation and neutrophil adhesion to endothelial cells. Thus, this process is much
beneficial to the resolution of inflammation20. Conducting such findings with the pro-
inflammatory activity of IL-6 level may explain the results of our study which involved a
significant dose dependent reduction in IL-6 in the serum of RA patient treated with quercetin
combined with azathioprine. On the other hand, IL-10 has been showed to inhibit the
production of pro-inflammatory cytokines by monocytes, as well as, inhibiting its own
production. While IL-10 is undetectable in the synovial fluid, it is clearly present in RA
synovial membrane and is detectable in macrophage and T-cells isolated from RA synovial
tissue21. Therefore, modulation of IL-10 production in RA synovial tissue could have a
significant effect on the chronic inflammatory process and may represent a potential
therapeutic target both for the existing and new treatments for RA22. Kojo et al (2005) had
found that IL-10 produced by iNKT cells induces regulatory dendritic cells, which in turn
generates CD4+ regulatory T cells known to suppress immune responses 23. It is clear from
the results of this study that IL-10 is significantly increased in response to quercetin
administration in a dose independent manner (Table 1). Furthermore, Sakaguchi (2000)
demonstrated that such increment may be related to the immunoregulatory T cells which are
characterized by their capability to synthesize and secrete latent TGF-1 and IL-10(24).
Additionally, Siegfried Ansorge et al (2003) had found that propolis and some of its
constituents like quercetin down-regulate DNA synthesis and decrease inflammatory
cytokine production but induce TGF-1 and IL-10 production of human immune cells Thus,
the bee product propolis can be considered as a powerful natural anti-inflammatory medicine
influencing different types of immune-responses probably via immune regulatory T cells25.
Azathioprine was found to had no significant effect on the level of IL-10(Figure.1 C). This
finding is in agreement with the result of Aurore et al (2005)26 and Chiba et al (2004)27. The
adhesion of leukocytes to the vascular endothelial cells is a critical step in the inflammatory
response and involves recruitment and infiltration of leukocytes to the site of tissue injury,
infection, or lesion formation. These processes are mediated by a wide variety of adhesion
molecules. Intercellular adhesion molecule-1 (ICAM-1, CD54) expressed on endothelial cells
is one of the major cell surface glycoproteins that contribute to the cell adhesion processes28.
Although ICAM-1 is constitutively expressed on endothelial cells, it can be significantly
induced in response to proinflammatory mediators such as tumor necrosis factor- α (TNF-α)
and interleukin-129, as well as phorbol 12-myristate 13-acetate (PMA)30, oxidants31, and
human immunodeficiency virus-1 tat proteins32. Elevated levels of ICAM-1 expression have
been shown to be critically involved in the development of a variety of autoimmune diseases
and pathologic inflammatory disorders, e.g., rheumatoid arthritis, psoriasis, and
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Al-Rekabi et. al., Br J Med Health Res. 2015; 2(6) ISSN: 2394-2967
atherosclerosis33. This fact also documented in RA patient participated in this study where
they showed a significantly increased level of this adhesion molecule compared with the
healthy control group (1). This table also indicated that combination of quercetin with
azathioprine results in a dose dependent reduction in ICAM-1 serum level with respect to
both, their pre-treatment values and azathioprine-only treated group. As shown in Figure (1
B), the highest quercetin dose in this study (1500mg/day) resulted in a significant reduction
in ICAM with respect to the lowest dose (500mg/day). Recently, ICAM-1 expression by
tumor cells has been reported to be a major contributing factor that facilitates metastatic
progression34. The modulation of ICAM-1 expression is therefore an important therapeutic
target, as shown by the beneficial effects of anti-ICAM-1 antibodies and other
pharmacological agents on the progression of inflammatory responses in several in vivo
studies35. The inhibitory effect of flavonoids on the expression of adhesion molecules has
been suggested to be mediated by down regulation of the induced NF-B activation36. Other
studies that support our findings were those indicated by Binwu Ying (2009) who reported
that quercetin attenuated IL-1 beta-induced expression of ICAM-1 mRNA and protein in a
dose-dependent manner. His experiment suggested that quercetin actively inhibited the
inhibitory protein of nuclear factor-kappa B (I kappa B) degradation, and nuclear factor-
kappa B (NF-kappa B) activity37. This inhibitory effect of quercetin on inducible ICAM-1
expression may represent a mechanism that contributes to the anti-inflammatory property of
this dietary flavonol. The elevated expression of sICAM-1 could also play a role in increasing
the risk of atherogenesis and cardiovascular diseases in patient with RA38. Table (2) had
showed that although azathioprine alone or its combination with low dose (250mg/day)
quercetin had lowered the level of both complement proteins (C3&C4), such reduction did
not reach the significant level. However, quercetin in higher doses (1000 or 1500mg/day),in
combination with azathioprine, resulted in significant reduction in both C3 and C4 with
respect to azathioprine only treated group or to a group receiving lower dose of
quercetin(Figure 2). These findings may be explained by the role of complement system in an
inflammatory process and immune response.
CONCLUSION
It is concluded that the use of quercetin in patient with rheumatoid arthritis that treated with
azathioprine resulted in dose dependent immunomodulatory actions regarding its effect on
cytokines, sICAM and complement proteins.
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