Imbalance Production between Interleukin-1β (IL-1β) and IL-1 Receptor Antagonist (IL-1Ra) in Bronchial Asthma

doi:10.1006/bbrc.2000.3516

Biochemical and Biophysical Research Communications

Volume 276, Issue 2, 24 September 2000, Pages 607-612

https://doi.org/10.1006/bbrc.2000.3516 Get rights and content

Abstract

Genes of the IL-1 family encode three different peptides, IL-1α, IL-1β, and IL-1Ra, respectively. IL-1 operates through IL-1RI, and is involved in airway inflammation in asthmatic subjects, whereas IL-1Ra appears to be a specific competitive inhibitor of IL-1. All genes are on chromosome 2q12-21 where genomewide searches have identified linkage for asthma. To test whether variants of IL-1 relate to asthma, we conducted a genetic association study in a Japanese population. We show that the A2 allele of IL1RN (encoding IL-1Ra) associates with nonatopic asthma [OR = 5.71, 95% CI: 1.63–19.8, Pc = 0.007]. Both atopic and nonatopic asthmatics with the A2 allele had significantly lower serum IL-1Ra levels in both types of asthmatics. Peripheral blood cells from asthmatics with A2 alleles, however, produced as much IL-1 as did those with A1 homozygotes. Since Th1 and Th2 cytokines differentially regulate the ratio between IL-1β and IL-1Ra, these findings suggest that dysregulation of IL-1β/IL-1Ra, probably due to interaction between epithelium and immuno-competent cells in the airway, is important in asthma inflammation.

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Cited by (57)

Classifications of moderate to severe asthma phenotypes in Japan and analysis of serum biomarkers: A Nationwide Cohort Study in Japan (NHOM Asthma Study)
2023, Allergology International
Citation Excerpt :
Interestingly, the tree analysis in this study revealed that the cytokine that was useful in assigning clusters was IL-1RA, which was high among the more severe clusters 2, 3, and 5. Although the relationships of IL-1RA with asthma and airway inflammation have been reported,41–43 the precise role of IL-1RA need to be further evaluated. One of the purposes of this study was to improve our understanding of the basis for GINA 4 and 5 and to develop an asthma classification algorithm using comprehensive phenotyping approaches that reflect pathophysiology and disease heterogeneity.
Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes.
Adult asthma patients (n = 1925) from 27 national hospitals in Japan were enrolled and divided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1–3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5 patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis were performed for phenotyping. Analysis of variance, the Kruskal–Wallis, and chi-square tests were used to compare cluster differences.
The following five clusters were identified: 1) late-onset, old, less-atopic; 2) late-onset, old, eosinophilic, low FEV₁; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young, female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers, FEV₁, body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes.
Five distinct phenotypes were identified for moderate to severe asthma and may be classified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.)
The common genetic variants in IL-1Β and IL-1RN may have no predisposition to alcoholic liver disease: A meta-analysis
2017, Meta Gene
Citation Excerpt :
Results of these studies suggest that IL-1β plays critical roles in the pathogenesis of ALD and inhibition of IL-1 signaling may be beneficial for various stage of ALD, including fatty liver, steatohepatitis, and fibrosis (Mathews and Gao, 2013). IL-1β and IL-1Ra are encoded by IL-1Β and IL-1RN genes, respectively, which share the same region of chromosome 2q12-21(Mao et al., 2000). Several functionally relevant genetic variants in these genes have been identified.
Interleukin-1β (IL-1β) has been demonstrated to play critical roles in the development of alcoholic liver disease (ALD). However, the association studies about functional polymorphisms of interleukin-1β gene (IL-1Β) and interleukin-1 receptor antagonist gene (IL-1RN) and individual susceptibility to ALD produced conflicting results. Thus, a systematic review and meta-analysis was performed to investigate the associations between IL-1Β and IL1RN polymorphisms and ALD risks.
Relevant studies were retrieved from six database including PubMed, Web of Science, Scopus, China Biology Medical literature database (CBM), Database of Chinese Scientific and Technical Periodicals (VIP), and Wanfang Data. Pooled odds ratio (OR) and 95% confidence interval (95%CI) were calculated by random-effects model.
A total of 10 studies (including 825 ALD patients, 470 alcoholics without ALD and 743 health controls) were identified and included in the meta-analysis. The combined results showed that there were no significant associations between IL-1Β (− 511C > T and + 3953T > C) polymorphisms and ALD susceptibility, or between IL-1RN VNTR polymorphism and ALD susceptibility. Moderate to higher heterogeneity was detected in most comparisons. No obvious publication bias was observed in all the genetic models.
The common genetic variants in IL-1Β and IL-1RN may have no predisposition to ALD. Large and well-designed epidemiological studies are needed to confirm these results.
High risk association of IL-1 receptor antagonist (IL-1RN) VNTR polymorphism with asthma in a North Indian population: A pilot study
2013, Cytokine
Citation Excerpt :
While another Finnish [35] study conducted on patients with allergic rhinitis, the homozygous *2/2 genotype predisposed towards greater risk of allergic rhinitis with OR = 2.8, 95% CI (1.3–6.2) and p < 0.05 while in our study the *2/2 genotype also predisposed towards greater risk of rhinitis with OR = 1.53, 95% (1.19–1.97) and p = 0.001. A Japanese [6] study has also reported the role of *2 allele in bronchial asthma, predisposing towards risk with OR = 5.71, 95% CI (1.63–19.80) and p = 0.007 while another Japanese study finds no association of the IL-1RN VNTR polymorphism with the disease altogether [36]. In contrast to the risk posed by IL-1RN polymorphism towards asthma in most of the research conducted worldwide, an American study has reported no association of the IL-1RN genotypes with the rate of lung function decline in smokers [37].
A pilot case-control study was conducted to evaluate the role of IL-1 receptor antagonist (IL-1RN) VNTR penta-allelic polymorphism in asthma that has been associated with various inflammatory diseases worldwide. This is the first case-control study conducted in India, investigating the role of IL-1RN VNTR polymorphism in asthma pathogenesis.
A case-control study was performed with a total of 824 adult subjects, inducting 410 asthma patients and 414 healthy controls from North India. The genotypes were identified by polymerase chain reaction.
Statistical analysis for the IL-1RN VNTR polymorphism revealed that the IL-1RN^*2 allele was significantly associated with asthma with OR = 1.45, 95% CI (1.15–1.85) and p = 0.001. The IL-1RN^*2/2 genotype posed a risk towards asthma with OR = 1.66, 95% CI (0.97–2.86) and p = 0.048. Most of the phenotypic traits were significantly associated with the disease.
IL-1RN^*2 allele is a high risk factor for asthma in the studied North Indian population.
Inflammatory cytokines (TNFα and IL1) polymophisms in asthma
2011, Revue Francaise d'Allergologie
Le TNFα et l’IL1 sont deux cytokines pro-inflammatoires impliquées dans la phase tardive inflammatoire au cours de l’asthme allergique.
Le but de ce travail était d’étudier les polymorphismes génétiques de ces deux cytokines qui pourraient modifier leur taux de production et ainsi influencer la susceptibilité à cette maladie et/ou son expression clinique.
Les polymorphismes du TNFα (G/A-308), de l’IL1β (C/T −511), de l’IL1β (C/T +3954), de l’IL1α (C/T −889) et le polymorphisme de l’IL1-Ra au niveau de l’intron 2 ont été analysés par biologie moléculaire chez 107 malades atteints d’asthme allergique et 168 sujets appariés en âge et en sexe.
La prévalence de l’allèle T du polymorphisme de l’IL1β (C/T +3954) était significativement moins élevée chez les malades par rapport aux témoins (p = 0,002 ; OR : = 0,423 ; IC : [0,239–0,746]) alors que la fréquence du génotype homozygote IL1Ra*2/2 était significativement plus élevée chez les malades par rapport aux témoins (p = 0,0056 ; OR : = 11,57 ; IC : [1,4–25,44]). L’analyse des polymorphismes du TNFα (A/G-308), de l’IL1α (C/T –889) et de l’IL1β (C/T –511) n’a montré aucune différence statistiquement significative concernant les fréquences alléliques et génotypiques entre les malades et les témoins. L’allèle IL1Ra*2 était significativement plus fréquent chez les malades ayant un taux élevé des IgE [supérieur à 200 UI/mL (25 %)] par rapport aux malades ayant un taux normal des IgE (16,7 %), p = 0,031 ; OR : = 3,5 ; IC : [1,064–11,5]. Toutefois, l’analyse multivariée n’a pas confirmé ces résultats.
Dans la population tunisienne, le polymorphisme de l’IL1Ra (intron 2) semble prédisposer à l’asthme allergique alors que celui de l’IL1β (C/T +3954) serait plutôt protecteur.
TNFα and IL1 are two inflammatory cytokines involved in the late inflammatory stage of asthma.
We aimed to detect genetic polymorphisms of those two cytokines which can modify the rate of their expression and thus influence the disease predisposition and its clinical outcome.
Polymorphisms of TNFα (G/A-308), IL1β (C/T –511), IL1β (C/T +3954), IL1α (C/T –889) and IL1Ra (intron 2) were analyzed by polymerase chain reaction in 107 patients with asthma and 168 controls.
The frequency of the allele T of IL1β (C/T +3954) was significantly lower in patients than in controls (P = 0.002; OR: = 0.423; CI: [0.239–0.746]) while the homozygous genotype IL1Ra*2/2 was significantly more frequent in patients comparatively to controls (P = 0.0056; OR: = 11.57; CI: [1.4–25.44]). There were no significant differences in genotypic and allelic frequencies in polymorphisms of TNFα (G/A -308), IL1α (C/T –889) and IL1β (C/T –511) between patients and controls. IL1Ra*2 allele was significantly more frequent in patients with high levels of IgE (> 200 UI/mL) (25%) comparatively to patients with normal levels (16.7%) P = 0.031; OR: = 3.5; CI: [1.064–11.5]. Nevertheless, adjustments for known covariates factors (age and gender) had not confirmed these univariate findings.
In Tunisia, IL1Ra polymorphism seems to predispose to asthma while the IL1β (C/T +3954) is rather protecting.
Effects of low molecular weight fungal compounds on inflammatory gene transcription and expression in mouse alveolar macrophages
2011, Chemico-Biological Interactions
Citation Excerpt :
IL1β dysregulation has been observed in other studies involving use of mouse in vitro AM and in vivo models of lung disease [11,14,42,43] (Fig. 4). For example, IL1β down-regulation has been linked to up-regulated expression of IL1ά and IL1r1, a specific competitive inhibitor of IL1β [42]. IL1β repression has also been linked to up-regulated IL4 [44] and IL10 [45] expression.
The inflammatory potential and molecular mechanisms underscoring inflammatory responses of lung cells to compounds from fungi that grow on damp building materials is poorly understood in vitro. In this study we evaluated the effect of pure fungal compounds on potentiating acute inflammatory response in primary mouse alveolar macrophages (AMs) and tested the hypothesis that AM responses to low molecular weight fungal compounds exhibit temporal and compound specificity that mimic that observed in the whole lung. Transcriptional responses of 13 inflammation/respiratory burst-associated genes (KC=Cxcl1, Cxcl2, Cxcl5, Cxcl10, Ccl3, Ccl112, Ccl20, IL-1β, Il-6, ifi27 Tnfα, iNOS and Blvrb) were evaluated in mouse AMs exposed to a 1 ml (10⁻⁸ mol) dose of either pure atranone C, brevianimide, cladosporin, curdlan, LPS, neoechinulin A & B, sterigmatocystin or TMC-120A for 2 h, 4 h and 12 h PE using customized reverse transcription (RT)-PCR based arrays. Multianalyte ELISA was used to measure expression of 6 pro-inflammatory cytokines common to the transcriptional assays (Cxcl1, Cxcl10, Ccl3, IL1β, Ifn-λ and Tnf-α) to determine whether gene expression corresponded to the transcription data. Compared to controls, all of these compounds induced significant (≥2.5-fold or ≤−2.5-fold change at p ≤ 0.05) time- and compound-specific transcriptional gene alterations in treatment AMs. The highest number of transcribed genes were in LPS treatment AMs at 12 h PE (12/13) followed by neoechinulin B at 4 h PE (11/13). Highest fold change values (>30) were associated with KC, Cxcl2, Cxcl5 and IL1β genes in cells exposed to LPS. Compound exposures also induced significant (p ≤ 0.05) time- and compound-specific pro-inflammatory responses manifest as differentially elevated Cxcl1, Cxcl10, Ccl3, Ifn-λ and Tnf-α concentrations in culture supernatant of treatment AMs. Dissimilarity in transcriptional responses in AMs and our in vivo model of lung disease is likely attributable to whole lung vs. isolated cell responsive and dose differences between the two studies. The results not only indicate that low molecular weight compounds from fungi that grow in damp built environments are potently pro-inflammatory in vitro, it further highlights the important role AMs play in innate lung defence, and against exposure to low molecular weight fungal compounds. These observations further support our position that exposure to low molecular weight compounds from indoor-associated fungi may provoke some of the inflammatory health effects reported from humans in damp building environments. They also open up a hypothesis building process that could explain the rise of non-atopic asthma associated with fungi.
Development of an inhaled endotoxin challenge protocol for characterizing evoked cell surface phenotype and genomic responses of airway cells in allergic individuals
2008, Annals of Allergy, Asthma and Immunology
Citation Excerpt :
Loss of an IL-1Ra response in asthma may facilitate increased inflammation, with exacerbants such as rhinovirus leading to acute disease exacerbation. Furthermore, evidence suggests that the balance between proinflammatory IL-1β and anti-inflammatory IL-1Ra may be more important than the individual cytokine levels themselves in modulating airway inflammation in asthma. 12,13 If IL-1Ra plays a role in controlling allergen-induced inflammation, then reduction of this protein by endotoxin might contribute to the enhancement of allergen-induced inflammation by LPS.
Environmental exposure to endotoxin is a known cause of exacerbation of asthma. Inhaled endotoxin protocols have been used to evaluate airway cell surface phenotypes associated with antigen presentation and innate immunity in healthy volunteers, but not in allergic volunteers.
To establish the safety of challenge with low-dose endotoxin (10,000 endotoxin units) (lipopolysaccharide [LPS]) inhalation in allergic individuals, to measure airway cell surface phenotypes associated with antigen presentation and innate immunity in induced sputum (IS) after LPS challenge, and to conduct gene expression profiling in IS cells to determine which host genetic networks are modified by LPS inhalation.
Induced sputum was obtained before and 6 hours after LPS inhalation in 10 allergic volunteers (8 with asthma and 2 with rhinitis). Flow cytometry was used to examine cell surface phenotypes on IS cells. Genomic expression was analyzed on a subset of IS samples (n = 10) using microarray and ingenuity pathway analysis.
A total of 10,000 endotoxin units of LPS induced significant up-regulation of membrane CD14, CD11b, CD16, HLA-DR, CD86, and Fcɛ receptor 1 on sputum phagocytes and increased expression of genes that influence antigen-presenting surface molecules (HLA-DR, chemokine ligand 2 or monocyte chemoattractant protein 1, v-rel reticuloendotheliosis viral oncogene homolog, prostaglandin-endoperoxide synthase 2 or cyclooxygenase 2, and transforming growth factor β), immune activation (CD14, interleukin 1β, and regulated upon activation, normal T cell expressed and secreted), and inflammation (intracellular adhesion molecule 1 and inhibitory κBα). Gene profiles for nuclear factor κB, interleukin 1, and tumor necrosis factor pathways were also significantly affected.
Low-dose inhaled endotoxin challenge is safe in allergic individuals with mild to moderate disease. It enhances airway cell surface phenotypes and expression of genes associated with antigen presentation, innate immunity, and inflammation. Microarray with ingenuity pathway analysis can be successfully applied to sputum cells to characterize genetic responses to inhaled exacerbants.

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¹: To whom correspondence and reprint requests should be addressed. E-mail: [email protected].

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Regular ArticleImbalance Production between Interleukin-1β (IL-1β) and IL-1 Receptor Antagonist (IL-1Ra) in Bronchial Asthma

Abstract

Immunol. Today

Gastroenterology

Genomics

Genomics

Genomics

J. Biol. Chem.

Blood

Cytokine

Lancet

Cytokine

Int. J. Mol. Med.

Thorax

J. Clin. Invest.

Gut

Scand. J. Gatroenterol.

J. Exp. Med.

Regular Article
Imbalance Production between Interleukin-1β (IL-1β) and IL-1 Receptor Antagonist (IL-1Ra) in Bronchial Asthma