title: The introduction of RNA-DNA differences underlies interindividual variation in the human IL12RB1 mRNA repertoire.
abstract: Human interleukin 12 and interleukin 23 (IL12/23) influence susceptibility or resistance to multiple diseases. However, the reasons underlying individual differences in IL12/23 sensitivity remain poorly understood. Here we report that in human peripheral blood mononuclear cells (PBMCs) and inflamed lungs, the majority of interleukin-12 receptor β1 (IL12RB1) mRNAs contain a number of RNA-DNA differences (RDDs) that concentrate in sequences essential to IL12Rβ1's binding of IL12p40, the protein subunit common to both IL-12 and IL-23. IL12RB1 RDDs comprise multiple RDD types and are detectable by next-generation sequencing and classic Sanger sequencing. As a consequence of these RDDs, the resulting IL12Rβ1 proteins have an altered amino acid sequence that could not be predicted on the basis of genomic DNA sequencing alone. Importantly, the introduction of RDDs into IL12RB1 mRNAs negatively regulates IL12Rβ1's binding of IL12p40 and is sensitive to activation. Collectively, these results suggest that the introduction of RDDs into an individual's IL12RB1 mRNA repertoire is a novel determinant of IL12/23 sensitivity.
authors.affiliation: Department of Pediatrics, Section of Genomic Pediatrics and Children's Research Institute, The Medical College of Wisconsin, Milwaukee, WI 53226; Human and Molecular Genetics Center, The Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Turner
authors.affiliation: Department of Pediatrics, Section of Genomic Pediatrics and Children's Research Institute, The Medical College of Wisconsin, Milwaukee, WI 53226; Human and Molecular Genetics Center, The Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Praful
authors.initials: P
authors.lastname: Aggarwal
authors.affiliation: Department of Microbiology and Molecular Genetics, The Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Halli E
authors.initials: HE
authors.lastname: Miller
authors.affiliation: Department of Pediatrics, Section of Asthma, Allergy and Clinical Immunology, The Medical College of Wisconsin, Milwaukee, WI 53226.
authors.forename: Jill
authors.initials: J
authors.lastname: Waukau
authors.affiliation: Department of Pediatrics, Section of Asthma, Allergy and Clinical Immunology, The Medical College of Wisconsin, Milwaukee, WI 53226.
authors.forename: John M
authors.initials: JM
authors.lastname: Routes
authors.affiliation: Department of Pediatrics, Section of Genomic Pediatrics and Children's Research Institute, The Medical College of Wisconsin, Milwaukee, WI 53226; Human and Molecular Genetics Center, The Medical College of Wisconsin, Milwaukee, WI 53226; rrobinson@mcw.edu ubroeckel@mcw.edu.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Broeckel
authors.affiliation: Department of Microbiology and Molecular Genetics, The Medical College of Wisconsin, Milwaukee, WI 53226; rrobinson@mcw.edu ubroeckel@mcw.edu.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Robinson
mesh_terms: D000328:Adult; D001483:Base Sequence; D004247:DNA / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D008969:Molecular Sequence Data; D010835:Phytohemagglutinins / Q000494:pharmacology; D011014:Pneumonia / Q000235:genetics / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D012313:RNA / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis
chemical_list: C508438:IL12RB1 protein, human; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D018664:Interleukin-12; D012313:RNA; D004247:DNA
keywords: IL-12; IL-23; IL12RB1; RDD; RNA