Chronic obstructive pulmonary disease is associated with the -1055 IL-13 promoter polymorphism

Kraan, Tineke C. T. M. van der Pouw; Küçükaycan, Mehmet; Bakker, Aleida M.; Baggen, JM; Zee, Jaring S. van der; Dentener, Mieke A.; Wouters, Emiel F.M.; Verweij, C. L.

doi:10.1038/sj.gene.6363896

Cited by 87 publications

(56 citation statements)

References 28 publications

(23 reference statements)

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“…We did not replicate the association between the IL13-1111CT polymorphism and COPD that was previously reported in the Dutch population (31). However, in that study the positive association could be due to the relatively small sample size (151 COPD patients and 78 healthy control smokers).…”

Section: Discussioncontrasting

confidence: 52%

“…Interestingly, we found a positive association between IL13 R130Q and COPD and impaired lung function that was not found in the Dutch study (31). Vladich et al (34) reported that an R fi Q replacement may amplify IL13 activity (e.g., STAT6 phosphorylation and CD23 expression in monocytes), particularly when associated with other SNPs in the IL13 pathway, such as -1111CT (often found in LD) or V50R551 of IL4Ra (35).…”

Section: Discussionmentioning

confidence: 52%

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Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease

Beghè¹,

Hall²,

Parker³

et al. 2010

Allergy

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Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory respiratory diseases that are most likely due to an interaction between genetic and environmental factors. Atopy is the most important risk factor of asthma (1) and tobacco smoking is the most important risk factor of COPD (2).Interleukin-13 (IL13) is a Th2 cytokine implicated in (i) recruitment of inflammatory cells from the blood to the lung, (ii) immunoglobulin (Ig) E production by B cells, (iii) regulation of matrix metalloproteinases and (iv) induction of mucin production and secretion (3, 4). IL13 is produced by a variety of cells, including Th2 CD4 + , Th1 CD4 + , CD8 + T cells, mast cells, basophils and eosinophils. IL13 mediates its effects by interacting with a complex receptor system comprising an IL4Ra/IL13Ra1 heterodimer and the IL13Ra2 receptor (3).The involvement of IL13 in the pathogenesis of asthma has been extensively documented (3-5). The administration of recombinant IL13 in the lungs of mice increases airway AbstractBackground: Asthma and chronic obstructive pulmonary disease (COPD) are chronic respiratory diseases involving an interaction between genetic and environmental factors. Interleukin-13 (IL13) has been suggested to have a role in both asthma and COPD. We investigated whether single nucleotide polymorphisms (SNPs) in the IL13 pathway may contribute to the susceptibility and severity of asthma and COPD in adults. Methods: Twelve SNPs in IL13 pathway genes -IL4, IL13, IL4RA, IL13RA1, IL13RA2 and STAT6 -were genotyped in subjects with asthma (n = 299) and in subjects with COPD or healthy smokers (n = 992). Genetic association was evaluated using genotype and allele models for asthma severity, atopy phenotypes and COPD susceptibility. Linear regression was used to determine the effects of polymorphism on baseline lung function (FEV 1 , FEV 1 /FVC). Results: In asthmatics, three IL13 SNPs -rs1881457(-1512), rs1800925(-1111) and rs20541(R130Q) -were associated with atopy risk. One SNP in IL4RA1 [rs1805010(I75V)] was associated with asthma severity, and several IL13 SNPs showed borderline significance. IL13 SNPs rs1881457(-1512) and rs1800925 (-1111) were associated with better FEV 1 and FEV 1 /FVC in asthmatics. IL13 SNPs rs2066960(intron 1), rs20541(R130Q) and rs1295685(exon 4) were associated with COPD risk and lower baseline lung function in the recessive model. In females, but not in males, rs2250747 of the IL13RA1 gene was associated with COPD and lower FEV 1 . Conclusion: These data suggest that IL13 SNPs (promoter and coding region) and, to a lesser extent, IL4RA SNPs may contribute to atopy and asthma. We also provide tentative evidence that IL13 SNPs in the coding region may be of significance in COPD susceptibility.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 52%

Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease

Beghè¹,

Hall²,

Parker³

et al. 2010

Allergy

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“…The latter is nicely illustrated in studies from our laboratory and others that demonstrate that IL-13 is a potent stimulator of eosinophil-, macrophage-and lymphocyte-rich inflammation, mucus metaplasia, tissue fibrosis, and parenchymal proteolysis (5)(6)(7). In accord with these observations, IL-13 dysregulation has been documented, and IL-13 has been implicated in the pathogenesis of a variety of diseases characterized by inflammation and tissue remodeling including asthma, scleroderma, idiopathic pulmonary fibrosis, viral pneumonia, hepatic fibrosis, nodular sclerosing Hodgkin's disease, and chronic obstructive pulmonary diseases (COPD) (1)(2)(3)(4)(7)(8)(9)(10)(11)(12)(13). Studies from our laboratory and others have demonstrated that IL-13 mediates its tissue effects by activating a broad array of downstream target genes including chemokines, matrix metalloproteinases (MMPs), transforming growth factor (TGF)-␤ 1 , and chitinases (6, 14 -17).…”

mentioning

confidence: 50%

Role of Early Growth Response-1 (Egr-1) in Interleukin-13-induced Inflammation and Remodeling

Cho

Kang

Homer

et al. 2006

Journal of Biological Chemistry

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IL-13 is an important stimulator of inflammation and tissue remodeling at sites of Th2 inflammation, which plays a key role in the pathogenesis of a variety of human disorders. We hypothesized that the ubiquitous transcription factor, early growth response-1 (Egr-1), plays a key role in IL-13-induced tissue responses. To test this hypothesis we compared the expression of Egr-1 and related moieties in lungs from wild type mice and transgenic mice in which IL-13 was overexpressed in a lung-specific fashion. We simultaneously characterized the effects of a null mutation of Egr-1 on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 stimulates Egr-1 via an Erk1/2-independent Stat6-dependent pathway(s). They also demonstrate that IL-13 is a potent stimulator of eosinophil-and mononuclear cell-rich inflammation, alveolar remodeling, and tissue fibrosis in mice with wild type Egr-1 loci and that these alterations are ameliorated in the absence of Egr-1. Lastly, they provide insights into the mechanisms of these processes by demonstrating that IL-13 stimulates select CC and CXC chemokines (MIP-1␣/CCL-3, MIP-1␤/CCL-4, MIP-2/CXCL2/3, MCP-1/ CCL-2, MCP-2/CCL-8, MCP-3/CCL-7, MCP-5/CCL-12, KC/CXCL-1, and Lix/CXCL-5), matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and apoptosis regulators (caspase-3, -6, -8, and -9 and Bax) and activates transforming growth factor-␤ 1 and pulmonary caspases via Egr-1-dependent pathways. These studies demonstrate that Egr-1 plays a key role in the pathogenesis of IL-13-induced inflammatory and remodeling responses. Interleukin (IL2 )-13 is a 12-kDa product of a gene on chromosome 5q31 that is produced in large quantities by stimulated Th2 cells. It was originally described as an IL-4-like molecule based on shared effector properties including the ability to stimulate IgE production. Subsequent studies demonstrated that IL-13 and IL-4 play distinct roles in biology with IL-4 contributing to Th2 cell differentiation and response generation, whereas IL-13 contributes as a major effector of Th2 inflammation and tissue remodeling (1-4). The latter is nicely illustrated in studies from our laboratory and others that demonstrate that IL-13 is a potent stimulator of eosinophil-, macrophage-and lymphocyte-rich inflammation, mucus metaplasia, tissue fibrosis, and parenchymal proteolysis (5-7). In accord with these observations, IL-13 dysregulation has been documented, and IL-13 has been implicated in the pathogenesis of a variety of diseases characterized by inflammation and tissue remodeling including asthma, scleroderma, idiopathic pulmonary fibrosis, viral pneumonia, hepatic fibrosis, nodular sclerosing Hodgkin's disease, and chronic obstructive pulmonary diseases (COPD) (1-4, 7-13). Studies from our laboratory and others have demonstrated that IL-13 mediates its tissue effects by activating a broad array of downstream target genes including chemokines, matrix metalloproteinases (MMPs), transforming growth factor (TGF)-␤ 1 , and chitinases (6, 14 -17). ...

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“…Exaggerated levels of IL-13 production have been implicated in the pathogenesis of a variety of disorders, including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, scleroderma, hepatic fibrosis, and nodular sclerosing Hodgkin's disease (37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). The remarkable effects that IL-13 can have in these disorders can be appreciated in studies that highlighted the ability of IL-13 to induce tissue inflammation, cathepsin-and MMP-mediated proteolysis, and TGF-␤1-induced tissue fibrosis (25,32,48).…”

Section: Discussionmentioning

confidence: 99%

IL-13 Receptor α2 Selectively Inhibits IL-13-Induced Responses in the Murine Lung

Zheng

Liu²,

et al. 2008

The Journal of Immunology

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IL-13 is a critical cytokine at sites of Th2 inflammation. In these locations it mediates its effects via a receptor complex, which contains IL-4Rα and IL-13Rα1. A third, high-affinity IL-13 receptor, IL-13Rα2, also exists. Although it was initially felt to be a decoy receptor, this has not been formally demonstrated and the role(s) of this receptor has recently become controversial. To define the role(s) of IL-13Rα2 in IL-13-induced pulmonary inflammation and remodeling, we compared the effects of lung-targeted transgenic IL-13 in mice with wild-type and null IL-13Rα2 loci. We also investigated the effect of IL-13Rα2 deficiency on the OVA-induced inflammatory response. In this study, we show that in the absence of IL-13Rα2, IL-13-induced pulmonary inflammation, mucus metaplasia, subepithelial fibrosis, and airway remodeling are significantly augmented. These changes were accompanied by increased expression and production of chemokines, proteases, mucin genes, and TGF-β1. Similarly, an enhanced inflammatory response was observed in an OVA-induced phenotype. In contrast, disruption of IL-13Rα2 had no effect on the tissue effects of lung-targeted transgenic IL-4. Thus, IL-13Rα2 is a selective and powerful inhibitor of IL-13-induced inflammatory, remodeling, and physiologic responses in the murine lung.

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Chronic obstructive pulmonary disease is associated with the -1055 IL-13 promoter polymorphism

Cited by 87 publications

References 28 publications

Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease

Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease

Role of Early Growth Response-1 (Egr-1) in Interleukin-13-induced Inflammation and Remodeling

IL-13 Receptor α2 Selectively Inhibits IL-13-Induced Responses in the Murine Lung

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