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

Research output: Contribution to journalArticle

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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

Fingerprint

Interleukin-17
Asthma
Homozygote
Cytokines
Amino Acid Substitution
Mitogen-Activated Protein Kinases
Interleukin-8
Chemokines
Allergens
Single Nucleotide Polymorphism
Neutrophils
Epithelial Cells
Odds Ratio
Inflammation
Gene Expression

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity. / Kawaguchi, Mio; Takahashi, Daisuke; Hizawa, Nobuyuki; Suzuki, Shintaro; Matsukura, Satoshi; Kokubu, Fumio; Maeda, Yukiko; Fukui, Yoshinobu; Konno, Satoshi; Huang, Shau Ku; Nishimura, Masaharu; Adachi, Mitsuru.

In: Journal of Allergy and Clinical Immunology, Vol. 117, No. 4, 01.04.2006, p. 795-801.

Research output: Contribution to journalArticle

Kawaguchi, M, Takahashi, D, Hizawa, N, Suzuki, S, Matsukura, S, Kokubu, F, Maeda, Y, Fukui, Y, Konno, S, Huang, SK, 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, vol. 117, no. 4, pp. 795-801. https://doi.org/10.1016/j.jaci.2005.12.1346
Kawaguchi, Mio ; Takahashi, Daisuke ; Hizawa, Nobuyuki ; Suzuki, Shintaro ; Matsukura, Satoshi ; Kokubu, Fumio ; Maeda, Yukiko ; Fukui, Yoshinobu ; Konno, Satoshi ; Huang, Shau Ku ; Nishimura, Masaharu ; Adachi, Mitsuru. / IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity. In: Journal of Allergy and Clinical Immunology. 2006 ; Vol. 117, No. 4. pp. 795-801.
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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.",
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T1 - IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity

AU - Kawaguchi, Mio

AU - Takahashi, Daisuke

AU - Hizawa, Nobuyuki

AU - Suzuki, Shintaro

AU - Matsukura, Satoshi

AU - Kokubu, Fumio

AU - Maeda, Yukiko

AU - Fukui, Yoshinobu

AU - Konno, Satoshi

AU - Huang, Shau Ku

AU - Nishimura, Masaharu

AU - Adachi, Mitsuru

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N2 - 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.

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KW - single nucleotide polymorphism

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