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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 8  |  Issue : 1  |  Page : 65

Comparison of Interleukin-33 serum levels in asthmatic patients with a control group and relation with the severity of the disease


1 Division of Asthma, Allergy and Clinical Immunology, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan; FASA University of Medical Sciences, FASA, Iran
2 Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
3 Department of Pediatric Pulmonology, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
4 Department of Immunology, Gasteroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
5 Child Growth and Development Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

Date of Submission15-May-2016
Date of Acceptance06-Mar-2017
Date of Web Publication31-Aug-2017

Correspondence Address:
Seyedeh Azra Shamsdin
Department of Immunology, Gasteroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpvm.IJPVM_179_16

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  Abstract 


Background: The relation between interleukin-33 (IL-33) and asthma is not precisely known yet. The present study set to compare the serum level of IL-33 in patients with asthma and controls and study the relation with the severity of disease. Methods: The serum level of IL-33 and total IgE in 89 asthmatic patients and 57 controls were analyzed. The association of levels of IL-33 with the severity of disease, levels of total IgE, measures of spirometry (forced expiratory volume in 1 s [FEV1]), age, sex, presence or absence of other allergic diseases, and the disease duration was evaluated. Results: Higher levels of IL-33 and total IgE were detected in asthmatic patients compared with controls (P = 0.0001 and P = 0.008, respectively). In the asthmatic group, a significant direct association of IL-33 with age (P = 0.02, R = 0.23) and with total IgE level (P = 0.003, R = 0.31) were observed, but there was no relationship between other variables. Comparison of mean level of IL-33 in different asthma groups concerning the disease severity showed the statistically significant difference between them and a significant increased serum level of total IgE was observed in more severe disease. The results showed a significant negative correlation between FEV1 and total IgE (P = 0.028, R = −0.23) and IL-33 level (P = 0.0001, R = −0.83). Conclusions: IL-33 is suggested as a new inflammatory marker of severe and refractory asthma. Therefore, it may be a unique therapeutic target in these patients.

Keywords: Asthma, interleukin-33, severity


How to cite this article:
Momen T, Ahanchian H, Reisi M, Shamsdin SA, Shahsanai A, Keivanfar M. Comparison of Interleukin-33 serum levels in asthmatic patients with a control group and relation with the severity of the disease. Int J Prev Med 2017;8:65

How to cite this URL:
Momen T, Ahanchian H, Reisi M, Shamsdin SA, Shahsanai A, Keivanfar M. Comparison of Interleukin-33 serum levels in asthmatic patients with a control group and relation with the severity of the disease. Int J Prev Med [serial online] 2017 [cited 2019 Nov 17];8:65. Available from: http://www.ijpvmjournal.net/text.asp?2017/8/1/65/213814




  Introduction Top


Asthma is the lungs' chronic inflammatory disease characterized by variable airflow closure. Airway inflammation and injury are critical indicators of asthma pathogenesis.[1] In this regard, T-helper type 2 (TH2) lymphocyte-mediated immune responses and their cytokines are crucial in the disease pathogenesis. Interleukin (IL)-33 was used to be described as an IL-1 type cytokine associated with TH2 inflammation. However, since then, further evidence suggested the essential role of IL-33 in asthma and allergies as an initiator of the so-called responses.[2],[3]

IL-33 expression increases in the epithelial cells and bronchoalveolar lavage fluid of bronchial asthma patients, as compared with healthy individuals, correlating with the disease severity.[4],[5] In another study there was not any relation between serum total IgE level and exhaled nitric oxide, result of skin test and also severity of asthma.[6]

The primary goal of this survey was to analyze the serum levels of IL-33 in adult patients with asthma and compare the results with healthy controls. Furthermore, the association of IL-33 serum level and disease severity of asthma was investigated.


  Methods Top


This case–control study was carried out on 89 adult asthmatic patients referred to Allergy Clinic of University of Medical Sciences of FASA, Iran, during summer 2013. The study protocol was approved by the local Ethics Committee. Asthma was diagnosed based on history and clinical examination and by inclusion of reversible airway obstruction, defined as an increase of forced expiratory volume in 1 s (FEV1) by 12%, 15 min after salbutamol inhalation (400 μg/spacer).[7]

The patients with asthma were classified into four groups regarding the disease severity: intermittent, mild persistent, moderate persistent, and severe persistent (Expert Panel Report 3, 2007).[7] Patients who suffered from any chronic disease were excluded from the study.

Fifty-seven healthy individuals were selected with no signs of allergic or inflammatory diseases. After obtaining written informed consents, patients were visited by a physician, and their demographic information, respiratory data, duration of their disease, and concurrent other allergic diseases including allergic rhinitis and atopic dermatitis were recorded in a questionnaire. Both groups of patients and control were age and sex matched.

IL-33 level and total IgE between asthmatic and control groups were compared. Furthermore, the comparison was performed in patients with asthma between different groups regarding the levels of disease severity.

Furthermore, in the asthmatic group, the levels of IL-33 and other measures were compared: age, sex, levels of total IgE, FEV1, duration of disease, and association with allergic rhinitis and atopic dermatitis.

Measurement of serum levels of interleukin-33 and total IgE

Commercial enzyme-linked immunosorbent assays (ELISA) were applied to measure serum levels of IL-33 (BioLegend, USA). The assay was conducted using the protocols recommended by the manufacturers (standard range: 15.6–1000 pg/ml sensitivity: 4.14 pg/ml).

Level of total IgE was determined using ELISA (Monobind, USA). Levels of total IgE level were regarded as a marker of severity of disease in asthmatic patients. Spirometry was done with a portable spirometer (MIR, Italy) in asthmatic patients. The best FEV1 value was selected for analysis.

Statistical analysis

For basic comparison of IL-33, total IgE, and age between two groups of patients and control and also in asthmatic group for comparison of level of IL-33 in both sex and in patients with or without allergic rhinitis and eczema, independent t-test was used. The relationship between IL-33 with age, IgE, and disease duration and also the relation of FEV1 with IL-33 and IgE in asthmatic patients were analyzed by bivariate correlation and Pearson coefficient. For comparison levels of IL-33 and total IgE in different severity groups of asthma, one-way ANOVA test was used. IL-33 and IgE were normalized by one-sample Kolmogorov–Smirnov test. Significant level was considered as P< 0.05. Data were analyzed using SPSS software version 16 (SPSS Inc., Chicago, USA).


  Results Top


In this study, 89 asthmatics (49 women and 40 men, with a mean age of 41 ± 14.5 years [age range: 22–65]) and 57 nonasthmatics (34 women and 23 men, age range of 18–67, and mean age 41 ± 15 years) were examined. [Table 1] shows the characteristics of nonasthmatic and asthmatic patients and the comparisons of mean age, IL-33, total IgE level, and sex ratio between the groups. Higher levels of IL-33 were detected in asthmatic patients compared with controls (322.6 ± 241 vs. 139.7 ± 68.1 pg/ml; P = 0.0001). Furthermore, the patients with asthma had a significantly higher level of total IgE than healthy control (169.8 ± 153 vs. 108.42 ± 118 IU/ml; P = 0.008).
Table 1: Patients' demographics

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The correlation between IL-33 and total IgE revealed significantly direct associations between them (P = 0.003, R = 0.31). Furthermore, the association of IL-33 with age showed that older age asthmatics had significantly higher levels of IL-33 (P = 0.02, R = 0.23), but there was not any association with disease duration and IL-33 level [Table 2]. The level of IL-33 did not show significant differences between both sex, and in the patients with or without allergic rhinitis and atopic dermatitis [Table 3].
Table 2: Association of interleukin-33 level with age, total IgE level, and disease duration

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Table 3: Comparison association of the mean level interleukin-33 level in both sex and in patients with or without allergic rhinitis and atopic dermatitis with sex, presence or absence of allergic rhinitis, and atopic dermatitis

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In the asthmatic patients, 21 intermittent, 28 mild persistent, 21 moderate persistent, and 20 severe persistent patients entered the study. The mean IL-33 levels and total IgE levels between different groups of asthma were compared in terms of disease severity. The results showed that the mean level of IL-33 and total IgE had statistically significant differences between these groups [Table 4] and [Figure 1].
Table 4: Comparison the mean levels of interleukin-33 and total IgE with severity classification in asthmatic patients

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Figure 1: Mean values of interleukin 33 (ng/ml). In different groups of asthma according to severity assessment

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In asthmatic patients, there was a significant negative correlation between FEV1 and total IgE (P = 0.028, R = −0.23). In addition, a significant negative correlation was observed between FEV1 and IL-33 (P = 0.0001, R = −0.83).


  Discussion Top


The relation of IL-33 with asthma and allergies is still uncertain. Several studies on animals, applying recombinant protein to leukocyte cultures, support the role of IL-33 in promotion of Th2-type immune responses; however, only a few studies have been conducted in humans.[8] The impact of IL-33 has been proved in some allergic diseases such as anaphylaxis, atopic dermatitis, allergic rhinitis, and allergic conjunctivitis.[9],[10],[11],[12]

A number of candidate genes have identified by genome-wide association studies that contribute to asthma. Recently, studies suggested that variation in genes encoding IL-33 and IL-1 receptor-like 1 (IL-1RL1) has association with asthma. IL-1RL1 is a part of the IL-33 receptor complex.[13] IL-33 is a member in IL-1 family of cytokines such as IL-1β and IL-18, but IL-33 promotes Th2 cells, unlike other members which mostly create TH1 inflammation.[14],[15] After epithelial cell injury, Il33 releases as an alarm signal and activates other immune cells such as basophils, Th2 cells and mast cells, leading to the secretion of other cytokines like as IL5 and IL13 which have major role in starting allergic inflammation in asthma.[16]

In the current study, a significant rise was reported in serum levels of IL-33 in the asthmatic patients compared with the healthy participants. Furthermore, higher serum IL-33 levels were correlated with disease severity because the serum from moderate and severe asthmatic patients indicated a significant strong trend of IL-33 serum levels and negative correlation between IL-33 and FEV1.

Some studies showed higher levels of IL-33 in asthmatic patients and propose its relationship with disease severity, as one survey showed elevated expression of IL-33 in the epithelial cells and on bronchoalveolar lavage fluid of 25 cases with asthma against to healthy controls. Furthermore, this study found a direct correlation between higher levels of IL-33 and severity of asthma.[5] Hamzaoui et al. showed higher levels of IL-33 in the serum and sputum of 37 asthmatic children compared with controls.[17] Another study revealed significant increased levels of IL-33 in 30 asthmatic patients (15 stable asthma and 15 asthma patients in exacerbation subjects), particularly in the exacerbation group.[18] In another article there was not any relation between serum total IgE level and exhaled nitric oxide, result of skin test and also severity of asthma.[6]

The current study revealed a direct relationship between IL-33 serum levels and total IgE levels. Many studies confirm the relationship of total IgE and the severity of asthma. IL-33 stimulates B-cell expansion and IgE synthesis causing IL-4 secretions by innate cells. Simultaneously IL4 triggers production of total serum IgE by promoting interaction of CD40 on B-cells and CD40 ligand on T-cells. Thus, IL-33 may have a role in all IgE-mediated allergic diseases.[19]

In this work, a larger sample of participants with asthma was examined compared with the previous studies. A cross-sectional study was conducted which is considered as a limitation.

Growing evidence has proposed IL-33 a novel therapeutic target for allergic diseases such as asthma. Recent studies have shown beneficial effects of the IL-33 antagonist in murine models of allergic rhinitis, lower airway inflammation, and allergic contact dermatitis, suggesting IL-33 a potential therapeutic target against allergies.[20],[21],[22]

Some patients with severe refractory asthma respond poorly to high-dose inhaled or systemic glucocorticoid treatment.[23] The mechanisms regarding the inadequate control of symptoms are poorly understood. The majority of biologics are inadequate regarding the clinical setting in asthma.[24] Finding a target as a central trigger of inflammation in asthma is effective to develop novel treatment strategies against IgE-mediated allergies. IL-33 is possibly such a molecule, acting early in the allergic cascade following epithelial damage in response to different environmental stimuli or cellular damage. It recruits and activates the cells responsible for the disease, indicating a fundamental role in the pathophysiology of asthma.[24],[25]

It was speculated that IL-33 elevation is responsible for the maintenance of airway inflammation and hypersensitivity, especially in severe asthmatic cases.


  Conclusions Top


The results approve the role of IL-33 in the pathogenesis of airway inflammation and remodeling in severe and poorly controlled asthmatic patients. Further studies are required to prove the role of this cytokine as a new therapeutic target in asthma and other allergic diseases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Sly PD, Flack F. Susceptibility of children to environmental pollutants. Ann N Y Acad Sci 2008;1140:163-83.  Back to cited text no. 1
    
2.
Komai-Koma M, Xu D, Li Y, McKenzie AN, McInnes IB, Liew FY. IL-33 is a chemoattractant for human Th2 cells. Eur J Immunol 2007;37:2779-86.  Back to cited text no. 2
    
3.
Borish L, Steinke JW. Interleukin-33 in asthma: How big of a role does it play? Curr Allergy Asthma Rep 2011;11:7-11.  Back to cited text no. 3
    
4.
Préfontaine D, Nadigel J, Chouiali F, Audusseau S, Semlali A, Chakir J, et al. Increased IL-33 expression by epithelial cells in bronchial asthma. J Allergy Clin Immunol 2010;125:752-4.  Back to cited text no. 4
    
5.
Préfontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ, et al. Increased expression of IL-33 in severe asthma: Evidence of expression by airway smooth muscle cells. J Immunol 2009;183:5094-103.  Back to cited text no. 5
    
6.
Hastie AT, Rector B, Moore WC, Li H, Peters SP, Meyers DA, et al. Serum and sputum interleukin-33 (IL-33) levels show no association with serum total IgE, positive skin test number, exhaled nitric oxide, or increasing severity of atopic asthma. Am J Respir Crit Care Med 2013;187:A1008.  Back to cited text no. 6
    
7.
National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Bethesda: National Heart, Lung, and Blood Institute; 2007. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Available from: http://www.nhlbi.nih.gov/guidelines/asthma/. [Last accessed on 2017 Jan 23].  Back to cited text no. 7
    
8.
Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005;23:479-90.  Back to cited text no. 8
    
9.
Shimizu M, Matsuda A, Yanagisawa K, Hirota T, Akahoshi M, Inomata N, et al. Functional SNPs in the distal promoter of the ST2 gene are associated with atopic dermatitis. Hum Mol Genet 2005;14:2919-27.  Back to cited text no. 9
    
10.
Sakashita M, Yoshimoto T, Hirota T, Harada M, Okubo K, Osawa Y, et al. Association of serum interleukin-33 level and the interleukin-33 genetic variant with Japanese cedar pollinosis. Clin Exp Allergy 2008;38:1875-81.  Back to cited text no. 10
    
11.
Rogala B, Glück J. The role of interleukin-33 in rhinitis. Curr Allergy Asthma Rep 2013;13:196-202.  Back to cited text no. 11
    
12.
Matsuda A, Okayama Y, Terai N, Yokoi N, Ebihara N, Tanioka H, et al. The role of interleukin-33 in chronic allergic conjunctivitis. Invest Ophthalmol Vis Sci 2009;50:4646-52.  Back to cited text no. 12
    
13.
Grotenboer NS, Ketelaar ME, Koppelman GH, Nawijn MC. Decoding asthma: Translating genetic variation in IL33 and IL1RL1 into disease pathophysiology. J Allergy Clin Immunol 2013;131:856-65.  Back to cited text no. 13
    
14.
Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol 2008;121:1484-90.  Back to cited text no. 14
    
15.
Louten J, Rankin AL, Li Y, Murphy EE, Beaumont M, Moon C, et al. Endogenous IL-33 enhances Th2 cytokine production and T-cell responses during allergic airway inflammation. Int Immunol 2011;23:307-15.  Back to cited text no. 15
    
16.
Saluja R, Ketelaar ME, Hawro T, Church MK, Maurer M, Nawijn MC. The role of the IL-33/IL-1RL1 axis in mast cell and basophil activation in allergic disorders. Mol Immunol 2015;63:80-5.  Back to cited text no. 16
    
17.
Hamzaoui A, Berraies A, Kaabachi W, Haifa M, Ammar J, Kamel H. Induced sputum levels of IL-33 and soluble ST2 in young asthmatic children. J Asthma 2013;50:803-9.  Back to cited text no. 17
    
18.
Azazi EA, Elshora AE, Tantawy EA, Elsayd MA. Serum levels of interleukin-33 and its soluble receptor ST2 in asthmatic patients. Egypt J Chest Dis 2014;63:279-84.  Back to cited text no. 18
    
19.
Komai-Koma M, Brombacher F, Pushparaj PN, Arendse B, McSharry C, Alexander J, et al. Interleukin-33 amplifies IgE synthesis and triggers mast cell degranulation via interleukin-4 in naïve mice. Allergy 2012;67:1118-26.  Back to cited text no. 19
    
20.
Kim YH, Yang TY, Park CS, Ahn SH, Son BK, Kim JH, et al. Anti-IL-33 antibody has a therapeutic effect in a murine model of allergic rhinitis. Allergy 2012;67:183-90.  Back to cited text no. 20
    
21.
Kim YH, Park CS, Lim DH, Ahn SH, Son BK, Kim JH, et al. Beneficial effect of anti-interleukin-33 on the murine model of allergic inflammation of the lower airway. J Asthma 2012;49:738-43.  Back to cited text no. 21
    
22.
Taniguchi K, Yamamoto S, Hitomi E, Inada Y, Sugioka T, Hamasaki, Y. Blockade of interleukin-33 attenuates allergic contact dermatitis in model mice: Possible mechanism via eosinophil infiltration. J Clin Exp Dermatol Res 2013;4:183.  Back to cited text no. 22
    
23.
Turner S, Paton J, Higgins B, Douglas G; British Guidelines on the Management of Asthma. British guidelines on the management of asthma: What's new for 2011? Thorax 2011;66:1104-5.  Back to cited text no. 23
    
24.
Walsh GM. An update on biologic-based therapy in asthma. Immunotherapy 2013;5:1255-64.  Back to cited text no. 24
    
25.
Lambrecht BN, Hammad H. The airway epithelium in asthma. Nat Med 2012;18:684-92.  Back to cited text no. 25
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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