Advances in Natural and Applied Sciences

Advances in Natural and Applied Sciences, 9(2) February 2015, Pages: 39-44
AENSI Journals
Advances in Natural and Applied Sciences
ISSN:1995-0772 EISSN: 1998-1090
Journal home page: www.aensiweb.com/ANAS
Effect of the Use of Propolis on Serum Levels of Interleukin-17 and Clinical Symptoms
and Signs in Patients with Ulcerative Oral Lichen Planus
1
6
Ali Taghavi Zonouz , 2Masoumeh Mehdipour, 3Reza Tavakoli Ata Abadi, 4 Javad Shokri , 5Mehrangiz Rajaee,
Marziyeh Aghazadeh
1
Associate Professor, Department of Oral Medicine, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran.
Associate Professor, Deportment of Oral Medicine, Faculty of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
3
Postgraduate Student, Department of Oral Medicine, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran.
4
Associate Professor, Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
5
Assistant Professor, Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
6
Assistant Professor, Department of Oral Medicine, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran.
2
ARTICLE INFO
Article history:
Received 25 August 2014
Received in revised form
17 November 2014
Accepted 23 November 2014
Available online 10 December 2014
Keywords:
Interleukin-17,
lichen planus.
Propolis,Ulcerative
ABSTRACT
Background and aims: Ulcerative oral lichen planus is a relatively common
symptomatic condition with a potential for malignant transformation. Interleukin-17 is
a cytokines, which has attracted the attention of researchers as a factor effective in its
etiology. Therefore, recent research in relation to the treatment of inflammatory and
immunologic diseases has focused on techniques to decrease and regulate cytokines,
especially interleukin-17. Propolis is one of the products of honeybees and has anti
inflammatory, antineoplastic and antimicrobial properties and an effect on decreasing
IL-17 levels. The aim of the present study was to evaluate the effect of propolis on
serum levels of IL-17 and clinical symptoms and signs in patients with ulcerative oral
lichen planus. Materials and methods: In this clinical trial, 25 patients with ulcerative
lichen planus were included. Blood samples were taken to determine IL-17 serum
levels. Then 500-mg capsules of propolis were given for 30 days a capsule daily. After
a month, serum levels of IL-17 were determined once again. In addition, pain severity
(VAS) and the maximum sizes of lesions before and after administration of propolis
were determined. Results: Mean serum levels of IL-17 before and after intervention
were 135±16.5 and 127±12 pg/mL, respectively, demonstrating statistically significant
differences. In addition, VAS means before and after treatment were 4.2±3.6 and
3.3±2.8, respectively, with statistically significant differences. The means of maximum
lesion sizes before and after treatment were 14±7.7and 9.8±7.6 mm, revealing
statistically significant differences. Conclusion: Administration of propolis decreased
IL-17 serum levels, pain and burning sensation severity (based on VAS) and the
maximum of lesion diameters in patients with ulcerative oral lichen planus.
© 2015 AENSI Publisher All rights reserved.
To Cite This Article: Ali Taghavi Zonouz, Masoumeh Mehdipour, Reza Tavakoli Ata Abadi, Javad Shokri, Mehrangiz Rajaee, Marziyeh
Aghazadeh, Effect of the Use of Propolis on Serum Levels of Interleukin-17 and Clinical Symptoms and Signs in Patients with Ulcerative
Oral Lichen Planus. Adv. in Nat. Appl. Sci., 9(2): 39-44, 2015
INTRODUCTION
Ulcerative oral lichen planus is a T lymphocyte disease with a chronic inflammatory nature, which does not
respond well to routine treatments. Specific and non-specific antigenic mechanisms are involved in its
pathogenesis. In the non-specific mechanism, a reciprocal reaction between mast cells and T cells results in the
release of cytokines, chemokines and metalloproteinases from mast cells, which result in an increase in the
activity, migration ad differentiation of T lymphocytes. (Kuo, R.C., et al., 2012)
Increased attention to the etiopathogenesis of immunologic and inflammatory conditions has highlighted the
role of chemokines and cytokines. (Mesquita, D., et al., 2009)
Interleukin-17 family consists of cytokines which are secreted by T helper-17 cells and have an important
role in the regulation of mucous and epithelial immune responses.( Pappu, R., et al., 2012) The role of IL-17 has
been demonstrated in the etiology and pathogenesis of a number immunologic and inflammatory disease,
including psoriasis (Leonardi, C., et al., 2012), rheumatoid arthritis (Xie, Q., Cunsh, li J., 2012), Behçet’s
diseases (Liu, X., et al., 2011), multiple sclerosis (Pollinger, B., 2012), and recurrent aphthous stomatitis.
(Lewkowicz, N., et al., 2011) On the other hand, in a number of animal and human studies, a definite and
purposeful treatment strategy to neutralize or decrease IL-17 has resulted in attention to anti-IL-17 human
Corresponding Author: RezaTavakoli Ata Abadi, Postgraduate Student, Department of Oral Medicine, Faculty of
Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran.
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Reza Tavakoli Ata Abadi, et al. 2015
Advances in Natural and Applied Sciences, 9(2) February 2015, Pages: 39-44
monoclonal antibodies and other medications or natural products such as cyclosporins.( Nair, N., et al, 2013),
vidofludimus. (Herlinger, K.R., et al., 2012), ginseng. (Cho, I.H., I.K. Hyun, 2012) and propolis. (Moriasi, C., et
al., 2012) Propolis is the generic name of a resin material produced by honeybees from different plants and is
used to protect the beehive against bacteria, fungi and other pathogens. (Poralia, A., et al., 2010) Propolis has
antiinflammatory and antineoplastic properties and regulates the immune system and stabilizes the cell division
cycle; it also has antibacterial, antifungal and antiviral activity. (Sawicka, D., et al., 2012).
Several animal and in vitro studies have shown the preventive, anti-tumoral and antioxidative effects of
propolis in relation to prevention of conversion of premalignant lesions to malignant lesions in laboratory
animals and human cell lines in vitro. (Solaiman, G.H., et al., 2012; MohammadzadehSh, M. et al., 2007). The
decreasing effect of propolis on interleukins, especially IL-17, has been reported in animal studies (Tanaka, M.,
et al., 2012) and human cell lines in vitro. (Szliszka, E., et al., 2013) Propolis has been used in dentistry in
wound healing processes of the oral cavity and in controlling gingivitis. (Handa, A., et al., 2011) Based on data
available, no studies have to date evaluated the effect of oral propolis in patients with ulcerative oral lichen
planus. The present study was designed to evaluate the effect of oral propolis on the serum levels of IL-17 and
the clinical signs of ulcerative oral lichen planus.
MATERIALS AND METHODS
The present clinical trial was carried out in the Department of Oral Medicine, Faculty of Dentistry, Tabriz
University of Medical Sciences. The study was registered in the Iranian Clinical Trial Center and was allocated
the unique code of IRCT 201301011976N1. A total 27 patients (7 males and 20 females) were included in the
study by simple sampling technique.
The minimum and maximum ages of the participants were 37 and 69 years, respectively. The condition was
diagnosed clinically and histopathologically. None of the subjects in the present study had taken any
corticosteroids or immunosuppressives during the previous 2 months to control oral lichen planus or other
medical conditions. In addition, biopsies were not contraindicated for any of the subjects. None of the patients
had lichenoid lesions due to contact with amalgam or drug lichenoid reactions.
Blood samples (5 mL) were taken at 9‒11 in the morning from the cubitus veins and after isolation of the
blood serum, the samples were stored at -80ᵒC. After the initial blood sampling procedure, each patient was
given thirty 500-mg propolis capsules to be taken orally after breakfast with a glass of water for 30 days. The
patients were instructed to take the capsules daily and regularly. Patients who did not take the capsules or
exhibited allergic reactions or untoward drug reactions such as gastrointestinal problems were excluded from the
study.
On the days 10 and 20 the patients were contacted and questioned in relation to the correct use of the
medication, any side effects and the clinical status of each patient.
The propolis used in the present study was fresh green propolis produced from the Sabalan Mountain foots,
near Ardebil, in the NW of Iran. The propolis was prepared in the Faculty of Pharmaceutics, using extraction
technique by immersing in ethanol in three steps. Each 500-mg capsule contained 325 mg of pure extract and
175 mg of neutral filing material.
After one month the patients were recalled and once again 5 mL of blood sample were taken. During the
study one patient was excluded due to headache and another was excluded due to gastrointestinal disturbances
(abdominal pain).
The special human kit for measuring IL-17 serum level (eBioscience, USA) and an ELISA equipment
(Elisa Awareness, USA) were used to determine IL-17 serum levels. The assay was carried out according to the
standard technique and based on the special instructions of the kit. At the end of the assay, the optical densities
on the plates were read by the equipment at a wavelength of 450 nm and IL-17 serum levels were determined at
weight scales in terms of pg/mL based on standard concentrations after drawing graphs for each optical density.
Results:
The means of IL-17 serum levels before and after treatment with propolis were 135±16.5 and 127±13
pg/mL, respectively, demonstrating a decrease in IL-17 serum levels after treatment with propolis. Normal
distribution of data was evaluated by Kolmogorov-Smirnov test using SPSS 13, which revealed that data were
parametric. Therefore, paired t-test was used to evaluate data, which demonstrated significant differences in IL17 serum levels before and after treatment at a significant level of P<0.05.
In addition, the means of pain and burning sensation severity based on VAS before and after treatment with
propolis were 4.2±3.6 and 3.3±2.8, respectively, indicating a decrease in pain and burning sensation severity
after treatment with propolis, with statistically significant differences between the two periods, before and after
treatment (P=0.049).
Wilcoxon’s test was used to evaluate the diameters of lesions because data were non-parametric. The means
of lesion diameters before and after treatment were 14±7.7 and 9.8±7.6 mm, respectively, indicating a decrease
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Reza Tavakoli Ata Abadi, et al. 2015
Advances in Natural and Applied Sciences, 9(2) February 2015, Pages: 39-44
IL-17 serum level (pgr/
ml)
in the mean lesion diameter after treatment, with statistically significant differences between the two periods
(P=0.03).
Fig. 1: The error barsof IL-17 serum levels.
Fig. 2: The error bars of pain severity before and after treatment with propolis.
Fig. 3: The errorbars of lesion sizes before and after treatment with propolis.
Discussion:
Based on data available, the present study is the first study on the use of a natural product (propolis) with
the aim of decreasing IL-17 serum levels in patients with ulcerative oral lichen planus, given the
etiopathogenesis of the disease, i.e. the role of proinflammatory cytokines. The role of proinflammatory
cytokines has been shown in the etiology and pathogenesis of a large number of immunologic and inflammatory
conditions. (Gaffen, S., 2008) In animal studies by Pollinger et al in 2012 the effective and intensifying role of
IL-17 in laboratory rats with multiple sclerosis (MS) and rheumatoid arthritis was evaluated. (Pollinger, B.,
2012) In a study by Rafa et al in 2013 the role of IL-23/IL-17 axis in inducing bowel inflammatory diseases and
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Advances in Natural and Applied Sciences, 9(2) February 2015, Pages: 39-44
the pathogenic and intensifying role of these cytokines in Crohn disease and ulcerative colitis was emphasized.
(Rafa, H., et la., 2013)
In another animal study by Bosman et al in 2013 the role of catecholamines and glucocorticoids in
controlling proinflammatory cytokines, including IL-17 family, in rats artificially afflicted with disseminated
sepsis was evaluated and it was shown that when the adrenal gland is removed, rat mortality rate increases and
the serum levels of IL-17 increase 3 to 10 folds. The study showed the important role of IL-17 in inflammatory
diseases and also showed an increase in the serum levels of this cytokine in such diseases. (Bosmann, M., et al.,
2013)
In a human study by Wang Hu et al in 2013 the reciprocal interaction between lichen planus and chronic
periodontitis and serum levels of IL-17 was evaluated and the results showed significantly higher serum levels
of IL-17 in patients with concomitant oral lichen planus and chronic periodontitis compared to the healthy
controls. The highest serum levels of IL-17 were reported in female patients with concomitant ulcerative oral
lichen planus and chronic periodontitis. The results also showed that an increase in the serum levels of IL-17 in
the ulcerative type of lichen planus was higher than those with lower levels of inflammation, somehow
demonstrating the proportionality of IL-17 and the inflammation severity. (Wang, H., et al., 2013)
One of the materials referred to in various animal and laboratory studies and a few human studies in relation
to its antiinflammatory and antineoplastic effects is propolis.
In a study on human cell lines by Zukowska et al in 2013 the effective and antineoplastic role of propolis in
glioblastoma cell lines was emphasized. (Zukowsk, R.M., et al., 2013) In an animal study by Okzyk et al in
2013 the regenerative and reconstructive effect of propolis on type I and type II collagen in burns artificially
induced in pigs was evaluated and the results showed the positive effect of propolis on regeneration of these
wounds. (Olczyk, P., et al., 2013) In an animal study by Tanaka et al in Japan in 2012 the effect of propolis on
decreasing IL-17 serum levels was shown in rats experimentally afflicted with arthritis. Systemic administration
of propolis in rats resulted in the improvement of clinical signs of arthritis in rats. (Tanaka, M., et al., 2012)
In an in vitro study on human cell lines by Szliszka et al in 2013 the effective role of propolis and its
antiinflammatory and antioxidative effect and also its role in decreasing proinflammatory cytokines, such as IL17, was shown on human cell lines. (Szliszka, E., et al., 2013) In the present study, too, the antiinflammatory
properties of propolis and its effect on decreasing serum levels of IL-17 and on the clinical signs in patients with
ulcerative oral lichen planus were shown.
In a human clinical trial by Samet et al in Britain in 2007 the effect of 500-mg oral capsules of propolis on
the healing of recurrent aphthous stomatitis ulcers was evaluated and the results showed a decrease in the
recurrence rate and an improvement in the patients’ quality of life. (Samet, N., et al., 2007) In another human
study, the effect of anti-IL-17 (anti-IL-17 monoclonal antibody) on the healing of chronic cutaneous psoriasis
plaques was evaluated and the results showed that anti-IL-17 human monoclonal antibody (Ixekizumb)
improved the clinical symptoms and signs in patients with psoriasis . 4The study is important because of the
similarities between psoriasis and its inflammatory and chronic nature to those of lichen planus and the results
can be effective for the treatment of lichen planus. Hofstetter et al evaluated the role of IL-17 on rats with MS in
2009 and the results showed that T helper-17 cells can be considered a cell population effective in the
pathogenesis of MS. Therefore, adoption of a definitive purposeful treatment strategy to neutralize IL-17 can be
a promising and new treatment modality for this condition. (Hofstetter, H.H., et al., 2009)
Considering the results of studies mentioned above it appears the serum levels of interleukins, especially
IL-17, increase in a wide range of inflammatory and immunologic conditions. Therefore, finding techniques and
materials that can control and decrease IL-17 serum levels can open new horizons for the treatment of such
medical conditions. No side effects have been reported for the oral administration of propolis and the majority
of articles available have reported a limited number of contact allergic reactions and a few cases of generalized
dermatitis. In some reports, too, a few cases of gastrointestinal disorders have been mentioned. Budmir et al
reported a case of perioral dermatitis and contact cheilitis in an 18-year-old female patient who had used
propolisspray. (Budimir, V., et al., 2012) Cho et al reported a case of generalized dermatitis in a 36-year-old
female patient who had practiced self-treatment by taking propolis for a few weeks. (Cho, E., et al., 2011)
In the present study, two subjects were excluded from the study; one of the subjects developed headaches
after taking propolis capsules but recovered after discontinuing the medicine and re-developed headaches after
taking the medicine again. The other patient developed abdominal pain after taking propolis capsules. These two
patients received routine treatment for lichen planus. Headaches have not been reported as a side effect for
propolis and they might be considered one of the side effects for propolis.
In a human clinical trial by Hueber et al in 2012 the effect of scukinmab which is an anti-IL-17 monoclonal
antibody was evaluated in patients with moderate-to-severe Crohn disease and no significant clinical results
were reported. (Hueber, W., et al., 2012) Based on data available no studies to date have shown a significant
decrease in IL-17 levels in inflammatory or immunologic conditions. In addition, no reports are available on the
effect of propolis on increasing the serum levels of IL-17 in animal, in vitro or human studies.
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From the results of previous studies and those of the present study, which is the first human study on the
effect of propolis on interleukin serum levels and clinical signs of ulcerative lichen planus, it can be concluded
that propolis, a natural product, has a decreasing effect on IL-17 levels, which has a background role in inducing
lichen planus; therefore, propolis might be considered a medication, which apart from its symptomatic effects,
can have an effect on the main course of ulcerative oral lichen planus.
The importance of this consideration is obvious when it is noted that there are no known cures for oral
lichen planus with minimum side effects .31However, more studies are necessary to further evaluate the effect of
propolis on the ulcerative oral lichen planus itself.
Conclusion:
Oral administration of propolis in patients with ulcerative oral lichen planus results in a significant decrease
in IL-17 serum levels and an improvement in clinical symptoms and signs (a decrease in pain severity based on
VAS and a decrease in wound diameters) compared to the period before treatment.
ACKNOWLEDGEMENT
This study was performed based on a thesis submitted to the Department of Oral Medicine,Faculty of
Dentistry, Tabriz University of Medical Sciences, in partial fulfillment of the requirements for an MS degree.
Authors would like to thank Vice Chancellor for Research for their financial support.
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