Interleukin 9: A candidate gene for asthma

Nicolaides, Nicholas C.; Holroyd, Kenneth J.; Ewart, Susan; Eleff, Scott M.; Kiser, Matthew B.; Dragwa, Carl; Sullivan, Christine D.; Grasso, Luigi; Zhang, Liu Yi; Messler, Carol J.; Zhou, Tianlun; Kleeberger, Steven R.; Buetow, Kenneth H.; Levitt, Roy C.

doi:10.1073/pnas.94.24.13175

Cited by 216 publications

(155 citation statements)

References 34 publications

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“…Among other biological activities (10), it was recently suggested on the basis of genetic linkage analyses that IL-9 might play an important role in the pathogenesis of asthma (18,19). This assumption was supported by the lung-specific expression of IL-9 in transgenic mice, which was accompanied by airway inflammation, bronchial hyper-responsiveness, and mast cell hyperplasia (20) as well as the increased expression of IL-9 and its receptor in human patients with atopic asthma (21).…”

Section: Il-9 and Il-13 Production By Activated Mast Cells Is Stronglmentioning

confidence: 60%

IL-9 and IL-13 Production by Activated Mast Cells Is Strongly Enhanced in the Presence of Lipopolysaccharide: NF-κB Is Decisively Involved in the Expression of IL-9

Stassen

Müller

Arnold

et al. 2001

The Journal of Immunology

139

100

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Mast cells, due to their ability to produce a large panel of mediators and cytokines, participate in a variety of processes in adaptive and innate immunity. Herein we report that in primary murine bone marrow-derived mast cells activated with ionomycin or IgE-Ag the bacterial endotoxin LPS strongly enhances the expression of IL-9 and IL-13, but not IL-4. This costimulatory effect of LPS is absent in activated mast cells derived from the LPS-hyporesponsive mouse strain BALB/c-LPSd, although in these cells the proinflammatory cytokine IL-1 can still substitute for LPS. The enhanced production of mast cell-derived IL-13 in the presence of IL-1 is a novel observation. Coactivation of mast cells with LPS leads to a synergistic activation of NF-κB, which is shown by an NF-κB-driven reporter gene construct. In the presence of an inhibitor of NF-κB activation, the production of IL-9 is strongly decreased, whereas the expression of IL-13 is hardly reduced, and that of IL-4 is not affected at all. NF-κB drives the expression of IL-9 via three NF-κB binding sites within the IL-9 promoter, which we characterize using gel shift analyses and reporter gene assays. In the light of recent reports that strongly support critical roles for IL-9 and IL-13 in allergic lung inflammation, our results emphasize the potential clinical importance of LPS as an enhancer of mast cell-derived IL-9 and IL-13 production in the course of inflammatory reactions and allergic diseases.

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Section: Il-9 and Il-13 Production By Activated Mast Cells Is Stronglmentioning

confidence: 60%

IL-9 and IL-13 Production by Activated Mast Cells Is Strongly Enhanced in the Presence of Lipopolysaccharide: NF-κB Is Decisively Involved in the Expression of IL-9

Stassen

Müller

Arnold

et al. 2001

The Journal of Immunology

139

100

View full text Add to dashboard Cite

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“…RC strains are a powerful tool to unravel the genetics of genetically complex processes as it allows mapping of the genes involved. For example, Nicolaides et al 45 could identify IL-9 as a quantitative trait locus implicated in the normal airway response to acetylcholine. Also, the CcS/ Dem strains, which were also used in our experiments, have already been successfully used by different groups.…”

Section: Discussionmentioning

confidence: 99%

Mouse genetic model for antigen-induced airway manifestations of asthma

et al. 2006

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Allergic asthma is a genetically complex disease characterized by allergen-specific immunoglobulin (Ig)E, eosinophilic inflammation of the lungs and airway hyper-responsiveness to bronchospasmogenic stimuli. In this study, we compared 13 recombinant congenic (RC) mouse strains in an ovalbumin model of allergic asthma. Different intensities and types of responses are observed throughout the RC strains. Intensities range from resistance to asthma in CcS05, to a very severe bronchoconstrictive reaction upon methacholine challenge for the parental STS strain. All strains show a 'modified' Th2 response except CcS14, which shows a 'true' Th2 response. When data from all strains are pooled, airway reactivity shows significant correlations with the serum Ig levels and the levels of interleukin (IL)-4, IL-5 and IL-13 in the broncho-alveolar lavage (BAL), at low dosage of methacholine (below 25 mg/ml), whereas at high dosage airway reactivity only correlates with BAL neutrophil levels. This indicates that at least two different mechanisms are involved in the airway reactivity to methacholine. None of these correlations can be found in every individual strain, which demonstrates that the asthma traits in this mouse model are genetically dissociated and that the loci can be genetically mapped.

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“…Studies in mice have shown association of differences in expression of IL9 gene with biological variability in bronchial responsiveness. 18,19 In humans, IL9 was found to influence chemokine release from bronchial epithelial cell 20,21 and airway smooth muscle, 22 and has also been shown to induce goblet cell hyperplasia during repair of human airway epithelia. 23 This pleiotropic effect of IL9 is in agreement with our findings.…”

Section: Sex-specific Qtl Underlying Asthma Phenotypes H Aschard Et Almentioning

confidence: 99%

Sex-specific effect of IL9 polymorphisms on lung function and polysensitization

et al. 2009

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Sex differences in asthma-associated phenotypes are well known but the genetic factors that may account for these differences have received little attention. This study aimed to characterize sex-specific and pleiotropic genetic factors underlying four quantitative phenotypes involved in the main asthma physiopathological pathways: immunoglobulin E levels, a measure of polysensitization (SPTQ), eosinophil counts and a measure of lung function FEV 1 /H 2 (forced expiratory volume in one second divided by height square). Sex-stratified univariate and bivariate linkage analyses were conducted in 295 families from the Epidemiological study on the Genetics and Environment of Asthma study. We found genome-wide significant evidence for a male-specific pleiotropic QTL (quantitative trait loci) on 5q31 (P ¼ 7 Â 10 À9 ) influencing both FEV 1 /H 2 and SPTQ and for a female-specific pleiotropic QTL on 11q23 underlying SPTQ and immunoglobulin E (P ¼ 2 Â 10 À5 ). Three other sexspecific regions of linkage were detected for eosinophil: 4q24 and 22q13 in females, and 3p25 in males. Further, bivariate association analysis of FEV 1 /H 2 and SPTQ with 5q31 candidate genes in males showed a significant association with two single-nucleotide polymorphisms within IL9 gene, rs2069885 and rs2069882 (P ¼ 0.02 and P ¼ 0.002, respectively, after Bonferroni's correction). This study underlies the importance of taking into account complex mechanisms, such as heterogeneity according to sex and pleiotropy to unravel the genes involved in asthma phenotypes.

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Interleukin 9: A candidate gene for asthma

Cited by 216 publications

References 34 publications

IL-9 and IL-13 Production by Activated Mast Cells Is Strongly Enhanced in the Presence of Lipopolysaccharide: NF-κB Is Decisively Involved in the Expression of IL-9

IL-9 and IL-13 Production by Activated Mast Cells Is Strongly Enhanced in the Presence of Lipopolysaccharide: NF-κB Is Decisively Involved in the Expression of IL-9

Mouse genetic model for antigen-induced airway manifestations of asthma

Sex-specific effect of IL9 polymorphisms on lung function and polysensitization

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