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• W1571725334 startingPage "1062" @default.
• W1571725334 abstract "Abstract The human IL23R gene single nucleotide polymorphism rs11209026 A allele confers protection against inflammatory diseases. However, although this difference has been associated with reductions in IL-23–induced IL-17A production and STAT3 phosphorylation, the molecular mechanism underlying these changes remains undefined. Th17 cell maturation depends on IL-23 signaling. Multiple splice forms of the human IL23R transcript exist, and one, Δ9, encodes a soluble form of the receptor. In this study, we asked whether this protective allele was associated with mRNA splicing. Using mini-gene constructs and competitive oligonucleotide binding, we showed that the A allele alters IL-23R α-chain mRNA splicing and favors exon 9 skipping by reducing the binding of the splicing enhancer SF2. This enhances expression of the Δ9 mRNA and consequently diminishes IL-23 signaling. Thus, the presence of the A allele increases expression of the soluble form of IL23R mRNA (which then functions as a decoy receptor) and lowers the ability to develop a Th17 phenotype upon IL-23 stimulation. We further showed that antisense oligonucleotides targeting the SF2 binding site could efficiently induce exon 9 skipping in the presence of the G allele, and thereby replicate the effect of the A allele. Antisense oligonucleotide treatment caused dose-responsive induction of the IL23RΔ9 mRNA and interfered with in vitro differentiation of human Th17 cells, reducing their expression of the signature Th17 cytokines IL-17A and IL-17F. This may represent a novel approach to therapy of Th17-mediated diseases by elevating soluble IL-23R while simultaneously reducing the remaining cell surface receptor density." @default.
• W1571725334 created "2016-06-24" @default.
• W1571725334 creator A5003390449 @default.
• W1571725334 creator A5038792820 @default.
• W1571725334 creator A5088933102 @default.
• W1571725334 date "2015-02-01" @default.
• W1571725334 modified "2023-09-26" @default.
• W1571725334 title "The Human IL-23 Receptor rs11209026 A Allele Promotes the Expression of a Soluble IL-23R–Encoding mRNA Species" @default.
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• W1571725334 doi "https://doi.org/10.4049/jimmunol.1401850" @default.
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