title: Inflammatory signals direct expression of human IL12RB1 into multiple distinct isoforms.
abstract: IL12RB1 is essential for human resistance to multiple intracellular pathogens, including Mycobacterium tuberculosis. In its absence, the proinflammatory effects of the extracellular cytokines IL-12 and IL-23 fail to occur, and intracellular bacterial growth goes unchecked. Given the recent observation that mouse leukocytes express more than one isoform from il12rb1, we examined whether primary human leukocytes similarly express more than one isoform from IL12RB1. We observed that human leukocytes express as many as 13 distinct isoforms, the relative levels of each being driven by inflammatory stimuli both in vitro and in vivo. Surprisingly, the most abundant isoform present before stimulation is a heretofore uncharacterized intracellular form of the IL-12R (termed "isoform 2") that presumably has limited contact with extracellular cytokine. After stimulation, primary PBMCs, including the CD4(+), CD8(+), and CD56(+) lineages contained therein, alter the splicing of IL12RB1 RNA to increase the relative abundance of isoform 1, which confers IL-12/IL-23 responsiveness. These data demonstrate both a posttranscriptional mechanism by which cells regulate their IL-12/IL-23 responsiveness, and that leukocytes primarily express IL12RB1 in an intracellular form located away from extracellular cytokine.
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Ford
authors.forename: Halli E
authors.initials: HE
authors.lastname: Miller
authors.forename: Allison E
authors.initials: AE
authors.lastname: Reeme
authors.forename: Jill
authors.initials: J
authors.lastname: Waukau
authors.forename: Christine
authors.initials: C
authors.lastname: Bengtson
authors.forename: John M
authors.initials: JM
authors.lastname: Routes
authors.forename: Richard T
authors.initials: RT
authors.lastname: Robinson
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D001483:Base Sequence; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics / Q000276:immunology; D005091:Exons / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D015894:Genome, Human / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000302:isolation & purification / Q000502:physiology*; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics / Q000276:immunology; D053707:Receptors, Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics* / Q000302:isolation & purification; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: C508438:IL12RB1 protein, human; D018836:Inflammation Mediators; D020033:Protein Isoforms; D053707:Receptors, Interleukin-12