IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation

Abstract

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+2044G→A is expected to result in the nonconservative replacement of arginine 130 (R130) with glutamine (Q). We examined the impact of IL13+2044G→A 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-13Rα2 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.

Computational analysis of multimorbidity between asthma, eczema and rhinitis

“…Furthermore, The associated region on chromosome 2q12 contains the family of IL1-r eceptor genes, IL1RL1 (IL1 receptor-like 1), IL18R1 (IL18 receptor 1), and IL18RAP (IL18 receptor accessory protein). Members of this family are abundantly expressed in the skin, and IL1RL1 i s involved in Th2 responses and is important for the pathogenesis of eczema [61, 62]. TSLP is an epithelial IL7 -like cytokine activating Th2 responses [63], and is responsible for a pattern of inflammation suggestive of multimorbidity between asthma and chronic obstructive pulmonary disease [64], and between different types of dermatitis [65].…”

Interleukin 13 and Interleukin 4 Receptor-α Polymorphisms in Rhinitis and Asthma

“…SNPs may have different biological effects depending on cell type or biological milieu. Functional studies have shown that IL13 –1111C/T [29] and Arg130Gln [30,31] and IL4R Gln551Arg [32,33], and Ile50Val [34] have functional consequences such as changes in transcription rates, enhanced activity or signaling through the protein, or changes in serum protein levels in diverse cell types. Some effects are suggested to depend on the biological context, e.g.…”

Importance of Cytokines in Murine Allergic Airway Disease and Human Asthma

“…Relatively few studies demonstrate a mechanism that explains how a cytokine or cytokine-related polymorphism can influence asthma frequency or severity; exceptions include demonstration of an IL-4 promoter polymorphism that appears to increase asthma frequency by increasing IL-4 production (226), an IL-13 polymorphism that appears to exacerbate asthma by enhancing IL-13 activation of Stat6 and decreasing IL-13 affinity for IL-13Rα2 (169, 227); an IL-17F polymorphism that protects against asthma by antagonizing wild-type IL-17F activity (208); an IL-18 polymorphism that appears to increase asthma severity by increasing IL-18 expression (228) and an IL-4Rα polymorphism that increases asthma severity by promoting signaling pathways that synergize with Stat6 activation to induce genes that contribute to allergic inflammation (18). …”