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

Mio Kawaguchi, Daisuke Takahashi, Nobuyuki Hizawa, Shintaro Suzuki, Satoshi Matsukura, Fumio Kokubu, Yukiko Maeda, Yoshinobu Fukui, Satoshi Konno, Shau Ku Huang, Masaharu Nishimura, Mitsuru Adachi

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192 Citations (Scopus)

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 χ 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.

Original languageEnglish
Pages (from-to)795-801
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Volume117
Issue number4
DOIs
Publication statusPublished - Apr 1 2006
Externally publishedYes

Keywords

  • Asthma
  • candidate gene
  • case-control association analysis
  • IL-17F
  • single nucleotide polymorphism

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Kawaguchi, M., Takahashi, D., Hizawa, N., Suzuki, S., Matsukura, S., Kokubu, F., Maeda, Y., Fukui, Y., Konno, S., Huang, S. K., Nishimura, M., & Adachi, M. (2006). IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity. Journal of Allergy and Clinical Immunology, 117(4), 795-801. https://doi.org/10.1016/j.jaci.2005.12.1346