An Atopy-Associated Polymorphism in the Ectodomain of the IL-4Rα Chain (V50) Regulates the Persistence of STAT6 Phosphorylation

Abstract

Several commonly occurring polymorphisms in the IL-4Rα have been associated with atopy in humans; the Q576R and the S503P polymorphisms reside in the cytoplasmic domain, whereas the I50 to V50 polymorphism resides in the extracellular domain of the IL-4Rα. The effects of these polymorphisms on signaling remain controversial. To determine the effect of the polymorphisms on IL-4 signaling in human cells, we stably transfected the human monocytic cell line U937 with murine IL-4Rα cDNA bearing the I or V at position 50 and the P503/R576 double mutant. Each form of the murine IL-4Rα mediated tyrosine phosphorylation of STAT6 in response to murine IL-4 treatment similar to the induction of tyrosine phosphorylation by human IL-4 signaling through the endogenous human IL-4Rα. After IL-4 removal, tyrosine-phosphorylated STAT6 rapidly decayed in cells expressing I50 or P503R576 murine IL-4Rα. In contrast, STAT6 remained significantly phosphorylated for several hours after murine IL-4 withdrawal in cells expressing the V50 polymorphism. This persistence in tyrosine-phosphorylated STAT6 was associated with persistence in CIS mRNA expression. Blocking IL-4 signaling during the decay phase using the JAK inhibitor AG490 or the anti-IL-4Rα Ab M1 abrogated the persistence of phosphorylated STAT6 observed in the V50-IL-4Rα-expressing cells. These results indicate that the V50 polymorphism promotes sustained STAT6 phosphorylation and that this process is mediated by continued engagement of IL-4Rα, suggesting enhanced responses of V50 IL-4R when IL-4 is limiting.

Donor Polymorphisms in Genes Related to B-Cell Biology Associated With Antibody-Mediated Rejection After Heart Transplantation

“…41- 43 The p.Ile75Val polymorphism, named rs180510 on dbSNP, has been described as a gain-offunction mutation due to a sustained STAT6 phosphorylation. 44 This variant was associated with an increase in total serum IgE in atopic asthma, related to its active role in isotype class-switch recombination. 42 Thus, to identify a Most of the studies conducted in B-cell genes in different organ transplantation found an association with IL genes or tumor necrosis factor-α ( Table 1).…”

The Type I and Type II Receptor Complexes for IL-4 and IL-13 Differentially Regulate Allergic Lung Inflammation

“…We analyzed the impact of the Q576R, S503P, and I50V polymorphisms on signal transduction by the Type I receptor complex in vitro. While the R 576 and P 503 polymorphisms had no effect on STAT6 or IRS2 activation induced by IL-4 , we found that the V 50 polymorphism located in the extracellular domain of the IL-4R mediated a prolonged STAT6 signaling induced by IL-4 through the Type I receptor (Ford, et al, 2009). This was associated with a prolonged expression of the SOCS family member Cis.…”

Il-4Rα, TNF-α,TNF-α Receptor, and CD4 Enhancer Genes Polymorphisms in Rheumatoid Arthritis Saudi Female Patients

“…The association of IL-4R I50V and RA may be explained by recent study of Ford et al, which found a direct effect of the V50 polymorphism in the IL-4Rα as it led to persistence of STAT6 activation in response to IL-4 and persistence activation of a STAT6-dependentgene [48].Since the V50 polymorphism is located in the extracellular domain of the IL-4Rαchain, the prolongation of STAT6 phosphorylationin V50-IL-4Rα was likely not due to modulation of these intracellular mechanisms [48]. The prolongation of STAT6 phosphorylationin V50-IL-4Rαwas dependent upon continued JAK activity [49].…”

“…The prolongation of STAT6 phosphorylationin V50-IL-4Rαwas dependent upon continued JAK activity [49]. Nevertheless, Ford et al, speculated that the V50 polymorphism may also impact glycosylation of the human IL-4Rαandthat the relative impact may be cell type specific [48]. This glycosylation could influence IL-4 binding parameters leading to alterations in persistence of IL-4 signaling and gene expression in human patients.…”