IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation.
Genetic factors are known to strongly influence susceptibility to allergic inflammation. The Th2 cytokine IL-13 is a central mediator of allergy and asthma, and common single-nucleotide polymorphisms in IL13 are associated with allergic phenotypes in several ethnically diverse populations. In particular, IL13+2044GA is expected to result in the nonconservative replacement of arginine 130 (R130) with glutamine (Q). We examined the impact of IL13+2044GA on the functional properties of IL-13 by directly comparing the activity of WT IL-13 and IL-13 R130Q on primary human cells involved in the effector mechanisms of allergic inflammation. Our results show that IL-13 R130Q was significantly more active than WT IL-13 in inducing STAT6 phosphorylation and CD23 expression in monocytes and hydrocortisone-dependent IgE switching in B cells. Notably, IL-13 R130Q was neutralized less effectively than WT IL-13 by an IL-13R2 decoy. Decreased neutralization of the minor variant could contribute to its enhanced in vivo activity. Neither IL-13 variant was able to engage T cells, which suggests that increased allergic inflammation in carriers of IL13+2044A depends on enhanced IL-13-mediated Th2 effector functions rather than increased Th2 differentiation. Collectively, our data indicate that natural variation in the coding region of IL13 may be an important genetic determinant of susceptibility to allergy.
Vladich
Frank D
FD
Functional Genomics Laboratory, Arizona Respiratory Center and Department of Cell Biology, College of Medicine, University of Arizona, Tucson, Arizona 85724, USA.
Brazille
Susan M
SM
Stern
Debra
D
Peck
Michael L
ML
Ghittoni
Raffaella
R
Vercelli
Donata
D
D000818:Animals; D001249:Asthma / Q000276:immunology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D007073:Immunoglobulin E / Q000096:biosynthesis; D007249:Inflammation / Q000276:immunology*; D018793:Interleukin-13 / Q000235:genetics* / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000502:physiology; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D017455:Receptors, IgE / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
D018793:Interleukin-13; D017455:Receptors, IgE; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D007073:Immunoglobulin E