IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity

被引:228
作者
Kawaguchi, M
Takahashi, D
Hizawa, N
Suzuki, S
Matsukura, S
Kokubu, F
Maeda, Y
Fukui, Y
Konno, S
Huang, SK
Nishimura, M
Adachi, M
机构
[1] Hokkaido Univ, Grad Sch Med, Dept Med 1, Kita Ku, Sapporo, Hokkaido 0608638, Japan
[2] Showa Univ, Sch Med, Dept Internal Med 1, Tokyo 142, Japan
[3] Johns Hopkins Univ, Ctr Asthma & Allergy, Baltimore, MD 21224 USA
关键词
asthma; candidate gene; case-control association analysis; IL-17F; single nucleotide polymorphism;
D O I
10.1016/j.jaci.2005.12.1346
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
Background: IL-17F is a recently discovered cytokine that plays a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. Upregulated IL17F gene expression has been observed at sites of allergen challenge in the airways of patients with asthma, suggesting that IL-17F is involved in the pathophysiology of asthma. Objective: To investigate the role of IL-17F in asthma pathogenesis, we conducted genetic analyses of association of asthma with the common variants of IL17F, using 867 unrelated Japanese subjects. Methods: Five polymorphisms were studied, including the coding-region sequence variant single nucleotide polymorphism rs763780 (7488T/C), which causes a His-to-Arg substitution at amino acid 161 (H 161 R). Functional consequences of the H161R substitution were examined by using recombinant wild-type and mutant IL-17F proteins. Results: Homozygosity of the H 161 R variant was inversely associated with asthma; the odds ratio (95% CI) for asthma was 0.06 (0.01-0.43) for the H 161 R homozygote compared with the wild-type homozygote (P =.0039). This result remains significant (P =.0079) after adjustment for the presence of atopy using the Mantel-Haenszel chi(2) test. In addition, in vitro functional experiments demonstrated that the H161R variant of IL-17F lacks the ability to activate the mitogen-activated protein kinase pathway, cytokine production, and chemokine production in bronchial epithelial cells, unlike wild-type IL-17F. Furthermore, the H161R variant blocked induction of IL-8 expression by wild-type IL-17F. Conclusion: The current findings indicate that the IL-17F H161R variant influences the risk of asthma and is a natural IL-17F antagonist, suggesting a potential role for IL-17F in the etiology of asthma.
引用
收藏
页码:795 / 801
页数:7
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