Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma.
BACKGROUND
A substantial body of evidence exists to support the pivotal role of IL-13 in the pathogenesis of bronchial asthma. We recently found that a variant of the IL13 gene (Arg110Gln) is genetically associated with bronchial asthma, which is concordant with animal experiments using IL-13 in the development of asthma.


OBJECTIVE
To address whether the Gln110 variant of IL13 influences IL-13 function, contributing to the pathogenesis of bronchial asthma, we studied the functional properties of the variant.


METHODS
We generated 2 types of recombinant IL-13 proteins, the amino acids of which at 110 were arginine or glutamine, and analyzed the binding affinities with the IL-13 receptors, as well as the stability of the proteins. We further compared the relationship between the genotype and serum levels of IL-13.


RESULTS
The variant showed a lower affinity with the IL-13 receptor alpha2 chain, a decoy receptor, causing less clearance. The variant also demonstrated an enhanced stability in both human and mouse plasma. We further identified that asthmatic patients homozygous for the Gln110 variant have higher serum levels of IL-13 than those without the variant.


CONCLUSIONS
These results suggested that the variant might act as a functional genetic factor of bronchial asthma with a unique mechanism to upregulate local and systemic IL-13 concentration in vivo.
Arima
Kazuhiko
K
Department of Biochemistry, Saga Medical School, Saga, Japan.
Umeshita-Suyama
Ritsuko
R
Sakata
Yasuhisa
Y
Akaiwa
Mina
M
Mao
Xiao-Quan
XQ
Enomoto
Tadao
T
Dake
Yoshio
Y
Shimazu
Shin-ichiro
S
Yamashita
Tetsuji
T
Sugawara
Naoto
N
Brodeur
Scott
S
Geha
Raif
R
Puri
Raj K
RK
Sayegh
Mohamad H
MH
Adra
Chaker N
CN
Hamasaki
Naotaka
N
Hopkin
Julian M
JM
Shirakawa
Taro
T
Izuhara
Kenji
K
D019943:Amino Acid Substitution; D001249:Asthma / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000502:physiology; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin / Q000378:metabolism; D053660:Receptors, Interleukin-13; D011994:Recombinant Proteins / Q000378:metabolism; D015854:Up-Regulation
C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D011994:Recombinant Proteins