IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity.
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.
Kawaguchi
Mio
M
First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
Takahashi
Daisuke
D
Hizawa
Nobuyuki
N
Suzuki
Shintaro
S
Matsukura
Satoshi
S
Kokubu
Fumio
F
Maeda
Yukiko
Y
Fukui
Yoshinobu
Y
Konno
Satoshi
S
Huang
Shau-Ku
SK
Nishimura
Masaharu
M
Adachi
Mitsuru
M
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
C440021:IL17F protein, human; D020381:Interleukin-17; D011994:Recombinant Proteins