期刊
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
卷 44, 期 6, 页码 787-793出版社
AMER THORACIC SOC
DOI: 10.1165/rcmb.2009-0418OC
关键词
asthma; TSLP; bronchial epithelial cells; combination therapy; genetic polymorphisms
资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Ministry of Health, Labor, and Welfare of Japan
- Mary Beryl Patch Turnbull Scholar Program
- GlaxoSmithKline
- Boehringer Ingelheim
- Abbott Japan Co., Ltd.
- AstraZeneca
- Sanofi-Aventis
- National Institutes of Health [HL087699]
- Canadian Institute of Health Research
- Kyowa Hakko Kirin Pharma
- Dainippon Sumitomo Pharma
- Ono Pharmaceutical Co., Ltd.
- Japanese Society for the Promotion of Science
- Schering-Plough
- Dainippon Sumitomo Pharma Co., Ltd.
- Banyu
- Merck
- Genentech
- Amgen Corp.
- Immgenix
- Juvenile Diabetes Research Foundation
- Food Allergy Initiative
- Grants-in-Aid for Scientific Research [21591290, 21390303, 23791204, 22590834] Funding Source: KAKEN
Thymic stromal lymphopoietin(TSLP) triggers dendritic cell-mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)-1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter-reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting beta(2)-agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I: C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P = 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14-1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I: C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.
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