title: IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Mio
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takahashi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hizawa
authors.forename: Shintaro
authors.initials: S
authors.lastname: Suzuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsukura
authors.forename: Fumio
authors.initials: F
authors.lastname: Kokubu
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Maeda
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Fukui
authors.forename: Satoshi
authors.initials: S
authors.lastname: Konno
authors.forename: Shau-Ku
authors.initials: SK
authors.lastname: Huang
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nishimura
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Adachi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D001249:Asthma / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D066298:In Vitro Techniques; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D007564:Japan; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C440021:IL17F protein, human; D020381:Interleukin-17; D011994:Recombinant Proteins