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J Allergy Clin Immunol. 2006 Apr;117(4):795-801. Epub 2006 Feb 14.

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

Author information

1
First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.

Abstract

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 (H161R). Functional consequences of the H161R substitution were examined by using recombinant wild-type and mutant IL-17F proteins.

RESULTS:

Homozygosity of the H161R variant was inversely associated with asthma; the odds ratio (95% CI) for asthma was 0.06 (0.01-0.43) for the H161R 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 chi2 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.

PMID:
16630936
DOI:
10.1016/j.jaci.2005.12.1346
[Indexed for MEDLINE]

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