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.
Subject(s)
Gene Expression Regulation/immunology , Inflammation Mediators/physiology , Receptors, Interleukin-12/biosynthesis , Receptors, Interleukin-12/genetics , Signal Transduction/immunology , Adult , Alternative Splicing/genetics , Alternative Splicing/immunology , Amino Acid Sequence , Base Sequence , Chromosomes, Human, Pair 19/genetics , Chromosomes, Human, Pair 19/immunology , Exons/genetics , Exons/immunology , Genome, Human/genetics , Genome, Human/immunology , HEK293 Cells , Humans , Inflammation Mediators/isolation & purification , Jurkat Cells , Molecular Sequence Data , Protein Isoforms/biosynthesis , Protein Isoforms/genetics , Protein Isoforms/isolation & purification , RNA Processing, Post-Transcriptional/genetics , RNA Processing, Post-Transcriptional/immunology , Receptors, Interleukin-12/isolation & purification , Signal Transduction/geneticsABSTRACT
BACKGROUND: No consensus evidence-based guidelines for the routine laboratory monitoring of children with JIA receiving non-steroidal anti-inflammatory drugs (NSAIDs) exist. The purpose of this study is to evaluate the clinical utility of routine laboratory monitoring of hemoglobin, transaminases, blood urea nitrogen, serum creatinine, and urinalysis in patients with juvenile idiopathic arthritis (JIA) receiving NSAIDs. METHODS: The medical records of 91 children with JIA followed between 1996 and 2006 were retrospectively reviewed for laboratory results and clinically significant adverse effects attributed to NSAID use. Laboratory abnormalities were documented, with potential adverse clinical sequelae, including if NSAID use was discontinued. RESULTS: Abnormal laboratory results were recorded for 24 of 91 patients. Nearly all abnormalities were mild and not associated with adverse clinical sequelae. All patients but one continued to receive NSAID therapy after the abnormality was detected. CONCLUSIONS: Although detection of abnormal laboratory values occurred while on NSAIDs, these abnormalities did not correlate with adverse clinical signs and symptoms. The routine monitoring of laboratory tests in asymptomatic children treated with NSAIDs is of questionable utility.
