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Table of Contents   
ORIGINAL RESEARCH  
Year : 2014  |  Volume : 25  |  Issue : 3  |  Page : 284-289
Assessment of serum interleukin-8 as a sensitive serological marker in monitoring the therapeutic effect of levamisole in recurrent aphthous ulcers: A randomized control study


1 Department of Oral Medicine and Radiology, Peoples University, Bhopal, Madhya Pradesh, India
2 Bapuji Dental College and Hospital, Davangere, Karnataka, India

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Date of Submission15-Feb-2012
Date of Decision09-Jul-2013
Date of Acceptance18-Nov-2013
Date of Web Publication7-Aug-2014
 

   Abstract 

Aim: The study was designed to evaluate the serum interleukin-8 (IL-8) levels in patients with recurrent aphthous ulcer (RAU) and monitor the immunomodulation and altered IL-8 levels by levamisole before therapy and after levamisole therapy.
Materials and Methods: This study was carried as a randomized case-control study involving a study group of 30 patients diagnosed as RAUs and given levamisole (vermisole 150 mg, od for 1 st 3 days of 3 weeks in a month and for 3 months with a gap of 1 week) and these patients were recalled after 3 months and were subjected for estimation of serum IL-8 levels. Control group had 20 age and sex matched individuals with no systemic illness and were not given any levamisole. Good compliance was reported at the end of the study.
Results: Mild gastric irritation was reported and when severe it was managed by H1 blocker. Patients were reviewed after 3 months. The follow-up data at each visit with respect to each other and to base-line values was calibrated using a Students t-test. Highly significant comparisons were obtained in the serum IL-8 between study and control groups before the onset of levamisole (t = 6.53, P ≤ 0.001). IL-8 levels reduced by 72% after levamisole was instituted in RAU patients and comparison was highly significant for before and after levamisole onset (t = 5.54, P ≤ 0.001).
Conclusion: This study points to the effectiveness of levamisole as an effective adjunct therapy in the routine management of RAU.

Keywords: Interleukin-8, levamisole, recurrent aphthous ulcer, treatment

How to cite this article:
Gupta P, Ashok L, Naik SR. Assessment of serum interleukin-8 as a sensitive serological marker in monitoring the therapeutic effect of levamisole in recurrent aphthous ulcers: A randomized control study . Indian J Dent Res 2014;25:284-9

How to cite this URL:
Gupta P, Ashok L, Naik SR. Assessment of serum interleukin-8 as a sensitive serological marker in monitoring the therapeutic effect of levamisole in recurrent aphthous ulcers: A randomized control study . Indian J Dent Res [serial online] 2014 [cited 2020 Sep 26];25:284-9. Available from: http://www.ijdr.in/text.asp?2014/25/3/284/138293
Recurrent aphthous stomatitis (RAS) is a common condition, which is characterized by multiple recurrent small, round or ovoid ulcers with circumscribed margins, erythematous haloes and yellow or grey floors typically presenting first in childhood or adolescence. [1] It is one of the common disease affecting non-keratinized oral mucosa. [2] The etiology of recurrent aphthous ulcer (RAU) is not entirely clear. [1] Despite many studies trying to identify a causal microorganism, RAU does not appear to be infectious. [1] A genetic predisposition is present, as shown by strong associations with genotypes of interleukin (IL)-1b, -6 and -8 in RAU patients and a positive family history in about one-third of patients with RAU. [3] Etiopathogenesis of RAU is a very complicated process and involves a group of chemical mediators of inflammation. Various studies have demonstrated the role of cytokines in the pathogenesis of RAU. Cytokines are small, secreted proteins, which mediate and regulate immunity, inflammation and hematopoiesis. [4] Cytokines, their receptors and antagonists sometimes play a critical role in the pathogenesis of various diseases and the pathological condition is very closely correlated with serum cytokines level including aphthous ulcers. [4]

IL-8 also referred to as neutrophil chemotactic factor (NCF) and neutrophil activating factor (NAF) is a chemokine and an important mediator of host response to injury and inflammation. It acts as chemo-attractant for T cells and basophils as well. [3]

IL-8 level rapidly increases in response to pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α or IL-1 β, bacterial or viral products and cellular stress. [5] The spontaneous secretion and lipopolysaccharide stimulated production of IL-8 by peripheral blood monocytes are significantly increased in patients with Behcet's disease (BD) associated with the presence of oral aphthous ulcers. [5]

Keratinocytes, endothelial cells and neutrophils in pre-ulcerative oral aphthous lesion secrete significant amount of IL-8 which activates neutrophils and attract more T cells, including cytotoxic T cells to the aphthous lesion. IL-8 activates neutrophils, which produces enzymes causing tissue destruction. Thus IL-8 may be involved in the pathogenesis of RAU. [3]

This study was carried out as a randomized case control study to estimate the serum IL-8 levels before and after levamisole therapy in RAU patients. IL-8 is involved in the immunomodulation of RAU and plays a significant role in its pathogenesis. Levamisole is an immunomodulator which can have an effect on IL-8 levels. IL-8 causes tissue destruction and levamisole reduces these levels and thus prevents destruction.

Although in management of RAU, various medications have been tried in the management of RAU including antibiotics, corticosteroids and vitamins. [2]

Levamisole is a compound that possesses a wide variety of immunological effects. [2] Earlier it was used as an antihelminthic along with other drugs belonging to this class. It can restore the normal phagocytic activity of macrophages and neutrophils, modulate T cell mediated immunity and potentiate the activity of human interferons. [6] In cases of RAU it helps in normalization of CD4+/CD8 + cell ratio and increased serum level of IgA and IgM. Thus it helps in restoring the depressed T cell function. [6] It also helps in modulating the serum level of IL-6 and IL 8 in RAS. Therefore levamisole has been used in clinical trials in the treatment of RAU. [2],[7],[8],[9] Few of the adverse effects include nausea, hyperosmia, dysgeusia and agranulocytosis. During the course of our study, none of these were reported by patients probably owing to short and intermittent treatment duration.


   Materials and Methods Top


The study comprised a prospective clinical analysis of randomly selected RAU patients who were residents of Davangere district in Karnataka, who were either having major or minor or herpetiform types. All those included in the study had no systemic illness that could interfere with study. Such cases were not included in the study. The subjects were grouped as follows:

Group I: A control group of 20 healthy subjects, who had no history of systemic conditions.

Group IIA: 30 Patients with clinically diagnosed RAUs (IL-8 was assayed before levamisole).

Group IIB: 30 Patients (recalled of Group IIA) with clinically diagnosed RAUs who were subjected to 3 month of levamisole therapy after obtaining the consent from the local ethical committee.

All patients recruited to the study were of comparable disease progression and share the common demographic features of ethnicity, geographic localization and socio-economic status. Age and sex distribution of cases and controls are summarized in [Table 1], Graphs 1-3. Adequate history regarding mode of onset, duration and frequency regarding RAU was obtained. An informed consent was obtained from each subject for carrying out the clinical examination and the diagnostic procedures. Patients with medical illness such as liver cirrhosis, collagen and autoimmune disorders, diabetes mellitus, parkinsons disease, malabsorption syndrome, leukemia and myeloma were not included in the study. The Ethical Committee of Bapuji Dental College and Hospital, Davangere had given permission to carry out the study. Sampling was done after consulting a statistician who had then defined the sample size for the study.
Table 1: The general characteristics in terms of age and sex distribution of the 2 study groups involved in the study process


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All the RAU patients had at least one episode of oral ulceration per month during the preceding years; none of them had taken any prescription medication before entering the study. A complete systemic and hematological work-up was carried before any patient was included in the study. Levamisole was administered as vermisole 150 mg, once daily for 1 st 3 days of 1 st 3 weeks of a month and for 3 months with a gap of 1 week. A total volume of 5 ml blood sample was withdrawn from the patient during the active stage of the disease and after treatment with levamisole (3 month later). Compliance was monitored by asking the patient to record the time at which each drug was taken. Patients were monitored once in a month for the observation of changes in frequency, duration, severity and number of oral aphthous ulcerations. Patients were carefully warned regarding the serious side-effects and hence not to medicate themselves unless and until prescribed by any doctor. Recall was done through questionnaires and this was duly filled by the doctor itself. No adverse effects were noted by us during the course of study.

Serum IL-8 assay was done using immunotech IL-8 enzyme immunoassay (IM 2237) (Immunotech a Beckman coulter company, 130 av de latter de tassigny, B.P. 177, 13276 Marsielle cede × 9, France). Reagent consisted of bovine serum albumin. Reconstitute the serum with distilled water. After reconstitution use it immediately or store at 2-8°C. It can be calibrated later by reference to the World Health Organization IL-8 (89/520) standard. Biotinylated monoclonal IL-8 antibody (ready to use) - it contains biotinylated monoclonal IL-8 antibody and bovine serum albumin. Diluent (ready to use) - it contains bovine serum albumin. Streptavidin - Horseradish peroxidase (HRP) conjugate (ready to use) - it contains streptavidin - HRP conjugate and bovine serum albumin. Wash solution (50 ml) - it is diluted with 950 ml of distilled water. Substrate (ready to use). Stop solution (ready to use) - this solution is a 2 N sulfuric acid solution. It is classified irritant at this concentration.

Principle

The immunotech IL-8 enzyme immunoassay (IM 2237) is a two-step immunological sandwich type assay. In the first step the IL-8 is captured by a monoclonal antibody bound to the wells of a microtiter plate. In the second step, a biotinylated monoclonal antibody is added together with streptavidin-peroxidase conjugate. The biotinylated antibody binds to the solid phase antigen-antibody complex and in turn, binds to conjugate. After incubation, the wells are washed and the antigen complex bound to the well are detected by the addition of a chromogenic substrate. The intensity of the coloration is proportional to the IL-8 coloration in the sample or calibrator. The results in the package insert were calculated using a quadratic mode curve fit with absorbance values on the vertical axis and the IL-8 concentration of the calibrators on the horizontal axis (pg/ml). Statistical analysis was performed using Student's t-test (unpaired) to compare between cases and controls. Paired t-test was used for multiple group comparisons. P < 0.05 was considered for statistical significance.


   Results Top


Study variables were recorded under the following headings:

  • Serum IL-8 levels in cases (before levamisole therapy) and control groups.
  • Serum IL-8 levels in cases group after levamisole therapy.


Correlation of serum IL-8 levels between controls and study group

The base line serum level of IL-8 for age and sex matched controls (Group I) were lower when compared with cases of RAUs [Table 2], Graph 4]. The result when subjected to Student's t-test (unpaired), the value obtained was t = 6.53. The P value calculated was < 0.001. The difference was highly significant.
Table 2: Correlation of serum IL-8 levels between controls and study group with a highly significant P value


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Post treatment with levamisole changes in serum IL-8 levels in RAU

The serum level of IL-8 in RAS major patients had reduced after treatment with levamisole. Mean reduction in serum IL-8 in RAU major patients after levamisole therapy was by 80% [Table 3] and Graph 5]. These results when subjected to Student's t-test (paired) the value obtained was 4.48. The P value calculated was < 0.01 and hence the difference was significant.
Table 3: Post-treatment changes in serum IL-8 levels in RAS. Minor and major RAS has significant reduction in the post treatment levels of IL-8. Overall there was highly significant reduction in the IL-8 levels in all the types


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The serum level of IL-8 for RAU minor patients had reduced by 69% after levamisole therapy. These results when subjected to Student's t-test (paired) the value obtained was 3.72. The difference was significant (P < 0.01).

The serum level of IL-8 for RAS herpetiform ulcer patients after levamisole therapy had reduced by 58%. These results were not subjected to any statistical analysis because of less number of cases with herpetiform ulcers.

The serum level of IL-8 in patients during the active stage of the disease on treatment with levamisole for a period of 3 months was found to be reduced by 72%. The values when subjected to Student's paired t-test were found to be 5.54. The differences were found to be highly significant (P < 0.001). The study group had no major side-effects other than mild gastric irritation in which case the patient was put on H1 blockers (omeprazole 20 mg). Patients definitely had a reduction in the painful days during the subsequents episodes of RAU. When asked they reported that there was a difference in the earlier episodes of RAU prior to treatment and episodes after treatment saying that their painful days were reduced. This was suggestive of reduce healing time after therapy with levamisole.


   Discussion Top


RAU has got a diverse etiology and complex pathogenesis on which still research is going on to understand the immunopathogenesis and hence that the definite treatment plan can be formulated to reduce the duration, frequency and severity of the disease. Cytokines play a major role in immunopathogenesis of RAU. Cytokines are central to inflammation and there are indications that they play a crucial role in the pathogenesis of RAU. [10]

IL-8 also referred as NCF and NAF is a recently characterized cytokine. [11] Originally described as neutrophil chemo attractant, it is now known to possess more diverse functions as a neutrophil activator and chemo attractant of other cells including T cells and basophils. [11]

Earlier studies have shown the presence of CD4+, CD8 + cells and B lymphocytes, mature tissue macrophages, recently recruited monocytes and activated T cells in oral aphthous lesion. [12] Activated T cells are found in the peripheral blood of RAU patients. [3] Increased production of TNF-α by peripheral blood leukocytes are found in active RAU patients. [13] This locally and systemically produced TNF-α can induce many cell types to secrete IL-8 in the local tissue and peripheral blood. [13]

Considering these findings, it was suggested that keratinocytes, tissue infiltrated mononuclear cells, endothelial cells and fibroblasts in RAU lesional oral mucosa may be the local cellular source of IL-8. [3] Thus IL-8 is produced by these cells through the stimulation of TNF-α and IL-1 in local tissues and in peripheral blood. The locally and systemically produced IL-8 finally results in an increased serum IL-8 level in RAU patients. [3]

IL-8 is a sensitive chemokine, its serum level will document the leukocyte recruitment and interaction with the blood vessel endothelial cells. [11] Interaction with the blood vessel endothelial cells has been suggested to be involved in the development of the lesions. [11]

In the present study, serum IL-8 was monitored in patients with the active stage of RAU and was compared with age and sex matched healthy controls, to assess the sensitivity of IL-8 in monitoring the disease activity in RAU patients. Furthermore the therapeutic effect of levamisole was assessed by monitoring serum level of IL-8 after treatment with levamisole for a period of 3 months.

Levamisole has been found to immunomodulate T cell-mediated immunity. [14] Normalization of the decreased CD4+/CD8 + cell ratio and increased serum levels of immunoglobulin IgA and IgM has been found in RAU patients after levamisole treatment. [15] The reversion of aberrant cellular and humoral immunities after levamisole therapy may explain why RAU patients experience marked improvement in symptoms. [15] Furthermore, healing or disappearance of RAU lesions after drug therapy may result in the reduction in the number of altered macrophages, lymphocytes, mast cells and vascular endothelial cells in RAU lesional oral mucosa, which in turn results in a decrease in the production of TNF-α because these cells can secrete TNF-α in the local lesional tissues. [7]

Correlation of serum IL-8 levels between controls and study group

The base line serum level of IL-8 for age and sex matched controls had a significantly lower value, which when compared with cases of RAUs.

In a study on patients with Bechets disease (BD) with aphthous ulcer serum level of IL-8 was found to be higher and it was very much increased as compared to the present study, but when serum IL-8 levels were monitored in BD patients without aphthous ulcer values obtained were lower. Thus, serum IL-8 levels are significantly lower in patients without aphthous ulcer. [5]

RAU has got multifactorial etiology and a lot of systemic diseases may be associated with the disease. Most of the studies monitoring serum level of IL-8 have been conducted on patients with BD which along with RAU involves genital lesions and neurological involvement and not only the intra-oral RAU, which can be attributed to high level of IL-8 in these patients. RAU immunopathogenesis involves mainly cell mediated immunity and host response to allergen, pathogen or foreign substance which varies from individual to individual and principally is governed by the immune status of the host. Serum levels of IL-8 are governed by TNF-α and IL-1 and these factors are mainly regulated by cell mediated immunity triggered before the onset of lesion. [14],[16] Increased production of TNF-α by peripheral blood leukocytes is found in active RAU patients. [7] It was suggested that macrophages, lymphocytes, mast cells and vascular endothelial cells in RAU lesional oral mucosa may be the local cellular sources of TNF-α and peripheral blood monocytes, lymphocytes, natural killer cells and other leukocytes as well as endothelial cells may be the systemic cellular sources of TNF-α. [7] The variation in the serum level of IL-8 is also controlled genetically as was discussed in a study that IL-1 β gene polymorphism is associated with the higher incidence of RAU. [17]

Therapeutic effect of levamisole in RAU patients

In the present study, there was a significant reduction in serum IL-8 after levamisole therapy and is in accordance with others. [3] Similarly, serum level of IL-6 is reduced and levamisole plus Chinese medicinal herbs helps in further reducing the serum level of IL-6. [6] Serum TNF-α levels of the treated RAU patients declined during the remission stage following treatment with levamisole for a period of 0.5-4 months. [7]

Healing of RAU lesions after levamisole therapy can give rise to reduction in the number of altered keratinocytes that can secrete IL-8 in the local lesional tissues. [15] Normalization of cellular immunity after levamisole therapy may also reduce the number of endothelial cells that are capable of producing IL-8 systemically or may reduce the secretion of cytokines such as TNF-α and IL-1 that are found to induce the production of IL-8 by keratinocytes, macrophages and endothelial cells. [11] Therefore, healing of RAU lesions and normalization of local and systemic cellular immunity may explain why treatment with levamisole can decrease serum IL-8 levels in RAU patients. [3]

There remains no safe therapy to ensure no recurrence of RAU; indeed there have been few studies that conclusively prove that any agent apart from anti-inflammatory agents can reduce the frequency and severity of RAU than can placebo.

One of the most effective systemic immunomodulator to be used in cases of RAU is levamisole. The exact mode of action of levamisole remains unclear, but the current data do not suggest being the clinical panacea once suggested. Levamisole reportedly has produced a decrease in the frequency, duration and number of oral ulcers.

However, the findings of this study needs to be carefully interpreted due to lack of studies involving the estimation of serum IL-8 levels in patients with RAU. Further research involving the larger samples and estimation of serum IL-8 and other cytokines like IL-6 levels during the course of disease and following treatment with levamisole is suggested along with extensive work involving specificity of estimation techniques before a definite statement on elevated serum IL-8 during the disease process and decreased levels following the course of levamisole so that their clinical applications can be made.

The following study found beneficiary effects in RAU patients after treating with levamisole. It had reduced the number of ulcers, its severity and duration, fastened healing (observed but not tabulated). Further studies involving the estimation of serum IL-8 and serum IL-6 levels in patients with RAU will definitely identify the more sensitive marker in monitoring the disease activity of RAU, because IL-6, like IL-8 is also a useful serum marker in evaluating the therapeutic effects of levamisole in RAU patients.


   Acknowledgment Top


The authors would like to thank Dr. Kishore Bhat, Department of Microbiology, Marata mandal, Belgaum, Karnataka.

 
   References Top

1.Jurge S, Kuffer R, Scully C, Porter SR. Mucosal disease series. Number VI. Recurrent aphthous stomatitis. Oral Dis 2006;12:1-21.  Back to cited text no. 1
    
2.Yamamoto T, Yoneda K, Ueta E, Osaki T. Serum cytokines, interleukin-2 receptor, and soluble intercellular adhesion molecule-1 in oral disorders. Oral Surg Oral Med Oral Pathol 1994;78:727-35.  Back to cited text no. 2
    
3.Sun A, Chang YF, Chia JS, Chiang CP. Serum interleukin-8 level is a more sensitive marker than serum interleukin-6 level in monitoring the disease activity of recurrent aphthous ulcerations. J Oral Pathol Med 2004;33:133-9.  Back to cited text no. 3
    
4.Available from: http://www.Microvet.arizona.edu/Courses/MIC419/Tutorials/cytokines.html-45k. [Last accessed on 2007 Jun 03]  Back to cited text no. 4
    
5.Katsantonis J, Adler Y, Orfanos CE, Zouboulis CC. Adamantiades-Behçet's disease: Serum IL-8 is a more reliable marker for disease activity than C-reactive protein and erythrocyte sedimentation rate. Dermatology 2000;201:37-9.  Back to cited text no. 5
    
6.Sun A, Chia JS, Chang YF, Chiang CP. Levamisole and Chinese medicinal herbs can modulate the serum interleukin-6 level in patients with recurrent aphthous ulcerations. J Oral Pathol Med 2003;32:206-14.  Back to cited text no. 6
    
7.Zouboulis CC, Katsantonis J, Ketteler R, Treudler R, Kaklamani E, Hornemann S, et al. Adamantiades-Behçet's disease: Interleukin-8 is increased in serum of patients with active oral and neurological manifestations and is secreted by small vessel endothelial cells. Arch Dermatol Res 2000;292:279-84.  Back to cited text no. 7
    
8.Wang LM, Kitteringham N, Mineshita S, Wang JZ, Nomura Y, Koike Y, et al. The demonstration of serum interleukin-8 and superoxide dismutase in Adamantiades-Behçet's disease. Arch Dermatol Res 1997;289:444-7.  Back to cited text no. 8
    
9.Häyrinen-Immonen R, Nordström D, Malmström M, Hietanen J, Konttinen YT. Immune-inflammatory cells in recurrent oral ulcers (ROU). Scand J Dent Res 1991;99:510-8.  Back to cited text no. 9
    
10.Taylor LJ, Bagg J, Walker DM, Peters TJ. Increased production of tumour necrosis factor by peripheral blood leukocytes in patients with recurrent oral aphthous ulceration. J Oral Pathol Med 1992;21:21-5.  Back to cited text no. 10
    
11.Sun A, Chiang CP, Chiou PS, Wang JT, Liu BY, Wu YC. Immunomodulation by levamisole in patients with recurrent aphthous ulcers or oral lichen planus. J Oral Pathol Med 1994;23:172-7.  Back to cited text no. 11
    
12.Sun A, Wang JT, Chia JS, Chiang CP. Levamisole can modulate the serum tumor necrosis factor-alpha level in patients with recurrent aphthous ulcerations. J Oral Pathol Med 2006;35:111-6.  Back to cited text no. 12
    
13.al-Dalaan A, al-Sedairy S, al-Balaa S, al-Janadi M, Elramahi K, Bahabri S, et al. Enhanced interleukin 8 secretion in circulation of patients with Behçet's disease. J Rheumatol 1995;22:904-7.  Back to cited text no. 13
    
14.Ozoran K, Aydintuð O, Tokgöz G, Düzgün N, Tutkak H, Gürler A. Serum levels of interleukin-8 in patients with Behcet's disease. Ann Rheum Dis 1995;54:610.  Back to cited text no. 14
    
15.Guimarães AL, de Sá AR, Victória JM, Correia-Silva JF, Pessoa PS, Diniz MG, et al. Association of interleukin-1beta polymorphism with recurrent aphthous stomatitis in Brazilian individuals. Oral Dis 2006;12:580-3.  Back to cited text no. 15
    
16.Sugermann PB, Savage NW, Seymour GJ, Walsh LJ. Is there a role for tumor necrosis factor-alpha (TNF-alpha) in oral lichen planus? J Oral Pathol Med 1996;25:219-24.  Back to cited text no. 16
    
17.Sun A, Chia JS, Chang YF, Chiang CP. Serum interleukin-6 level is a useful marker in evaluating therapeutic effects of levamisole and Chinese medicinal herbs on patients with oral lichen planus. J Oral Pathol Med 2002;31:196-203.  Back to cited text no. 17
    

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Correspondence Address:
Prashant Gupta
Department of Oral Medicine and Radiology, Peoples University, Bhopal, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9290.138293

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    Tables

  [Table 1], [Table 2], [Table 3]

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