An IL-4R alpha allelic variant, I50, acts as a gain-of-function variant relative to V50 for Stat6, but not Th2 differentiation.
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.
Stephenson
Linda
L
Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
Johns
Mary H
MH
Woodward
Emily
E
Mora
Ana L
AL
Boothby
Mark
M
D000483:Alleles; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D014644:Genetic Variation; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006801:Humans; D015847:Interleukin-4 / Q000502:physiology; D053662:Interleukin-4 Receptor alpha Subunit; D007532:Isoleucine / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011956:Receptors, Cell Surface; D019948:Receptors, Interleukin-4 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014633:Valine / Q000235:genetics
D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C504000:IL4R protein, human; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; D021122:Protein Subunits; D011956:Receptors, Cell Surface; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D007532:Isoleucine; D015847:Interleukin-4; D014633:Valine