An IL-4R alpha allelic variant, I50, acts as a gain-of-function variant relative to V50 for Stat6, but not Th2 differentiation.

Stephenson L, Johns MH, Woodward E, Mora AL, Boothby M
J Immunol. 2004 173 (7): 4523-8

PMID: 15383584 · DOI:10.4049/jimmunol.173.7.4523

Signaling through the IL-4R alpha-chain (IL-4Ralpha) is crucial for the development of Th2 cells, central effectors in atopic disease. Alleles of the IL-4Ralpha have been identified that have been variably associated with increased incidence of allergic disease, but there is little direct evidence that any variant is sufficient to alter a target that determines allergic pathophysiology or susceptibility. Variants of IL-4Ralpha encoding isoleucine instead of valine at position 50 (I50 vs V50, respectively) can signal increased Stat6-dependent transcriptional activity, whether in an I50, Q551 or I50, R551 haplotype. Strikingly, signaling through these receptors did not increase the efficiency of Th2 development or the IL-4 mediated repression of Th1 development or a target gene, IL-18Ralpha. Further, IL-4-induced proliferation was similar for Th2 cells independent of the variant expressed. Together these findings indicate that IL-4Ralpha variants that exhibit gain-of-function with respect to Stat6 do not act directly through alterations in Th2/Th1 induction after Ag exposure. The data further suggest that for such variants, any mechanistic involvement is based on a role in cellular targets of Th2 cytokines.

MeSH Terms (27)

Alleles Animals Cell Differentiation DNA-Binding Proteins Genetic Variation Growth Inhibitors Humans Interleukin-4 Interleukin-4 Receptor alpha Subunit Isoleucine Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Mutagenesis, Site-Directed Protein Subunits Receptors, Cell Surface Receptors, Interleukin-4 Signal Transduction STAT6 Transcription Factor Th1 Cells Th2 Cells Trans-Activators Transcription, Genetic Up-Regulation Valine

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