Interferon Receptor Gene Research Articles

Transcription termination/polyadenylation occurs at multiple sites in the human type I interferon receptor gene.

Based on the previously reported sequence, we isolated an independent cDNA clone encoding a binding component of the human type I interferon receptor (IFN-R). This cDNA is identical to the published sequence except that it lacks 62 bases of 5' untranslated sequence and terminates at the first of two potential polyadenylation sites. In Northern blot analyses of poly(A)+RNAs from both IFN-sensitive and IFN-resistant Daudi cells, this cloned cDNA hybridized to a predominant mRNA of 2.4 kb, as well as to mRNAs of 1.8, 4.8, and 5.6 kb, and occasionally 6.9 kb. These various transcripts, which were also observed at similar levels in Raji B cells and two T-cell lines, Jurkat and MOLT-4, were detected after high-stringency washes, and by alternate probes corresponding to subfragments of the cDNA. In contrast, only the 4.8- and 5.6-kb transcripts hybridized to a polymerase chain reaction (PCR)-derived probe that corresponded to genomic sequences immediately down-stream from the second polyadenylation site. These results indicate that the latter transcripts arise from the same gene as the predominant 2.4-kb mRNA due to incomplete transcription termination at either of the known polyadenylation sites. Finally, Northern blot analysis of total RNAs revealed the presence of the predominant 2.4-kb type I IFN-R transcript in numerous tissues from second trimester human fetuses, suggesting that the type I IFN-R gene is constitutively expressed in multiple cell types.

The mouse immune interferon receptor gene is located on chromosome 10.

When mouse L cells are incubated with 32P-labeled recombinant murine immune interferon ( [32P]Mu-IFN-gamma) and subsequently cross-linked with disuccinimidyl suberate, a major complex with an apparent molecular mass of 95,000-125,000 daltons can be visualized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The complex was not formed when the binding was performed in the presence of excess unlabeled Mu-IFN-gamma or when Chinese hamster ovary cells were used. This complex therefore represents the Mu-IFN-gamma receptor (or its interferon-binding subunit). The chromosomal location of the Mu-IFN-gamma receptor (or the binding subunit of the receptor) gene, termed Ifgr, was identified by performing the binding and cross-linking reactions on a series of mouse-hamster somatic cell hybrids with different subsets of mouse chromosomes. The presence of mouse chromosome 10 was shown to be necessary and sufficient for the formation of the cross-linked complex. Thus, the gene coding for the binding subunit of the Mu-IFN-gamma receptor was localized to mouse chromosome 10. The presence of this chromosome in the hybrid cells was not sufficient, however, to confer antiviral resistance to the hybrids when they were treated with Mu-IFN-gamma and challenged with encephalomyocarditis virus.

Sequential expression of genes involved in human T lymphocyte growth and differentiation.

Nuclear transcription assays were performed with isolated nuclei from human peripheral blood T lymphocytes stimulated with phytohemagglutinin and phorbol myristate acetate to determine the kinetics of transcriptional activity of various genes occurring in T cell activation. Although silent in resting T cells, the genes encoding c-myc and the interleukin 2 (IL-2) receptor were induced early, preceding gamma interferon (IFN-gamma), IL-2, and transferrin receptor gene transcription. Transcriptional activity of these genes fell after their respective peaks, indicating that the expression of these genes is a transient event during T cell activation. With the exception of the transferrin receptor gene, the kinetics of induction of these genes were not altered by concentrations of cycloheximide that inhibited protein synthesis. These data indicate that the induction of genes encoding c-myc, IL-2, IL-2 receptor, and IFN-gamma occur independently of the sequential production of the proteins they encode.

Interferon induction of (2??5?) oligoisoadenylate synthetase in diploid and trisomy 21 human fibroblasts: Relation to dosage of the interferon receptor gene (IRFC)

Trisomy 21 human fibroblasts are more sensitive to human interferon-alpha (IFN-alpha) than are diploid controls, consistent with the location of the gene (IFRC) which codes for the IFN-alpha receptor on chromosome 21. When compared in the antiviral assay, the difference in sensitivity is five- to tenfold, much greater than the 50% difference in IFRC gene dosage. An understanding of the mechanism by which this amplification of gene dosage occurs is relevant to the specific pathology of Down's syndrome and as a model system for studying the pathogenic effects of chromosomal aneuploidy. The enzyme (2'-5') oligoisoadenylate synthetase (2-5A synthetase), which is believed to be central to the interferon-induced antiviral response, is induced 50% more in trisomy 21 fibroblasts than in diploid controls. Thus the amplification in response occurs subsequent to the binding of IFN-alpha to its receptor and the triggering of the first set of intracellular events, the latter exemplified by the induction of 2-5A synthetase. Similar results were obtained with IFN-gamma, consistent with other evidence which indicates that a gene coding for a separate IFN-gamma receptor is also located on chromosome 21.

Rosette formation by circulating lymphocytes from rheumatoid and nonrheumatoid subjects.

<h3>Abstract</h3> Trisomy 21 causes Down syndrome, a condition characterized by cognitive impairments, immune dysregulation, and atypical morphogenesis. Using whole blood transcriptome analysis, we demonstrate that specific overexpression of four interferon receptors encoded on chromosome 21 associates with chronic interferon hyperactivity and systemic inflammation in Down syndrome. To define the contribution of interferon receptor overexpression to Down syndrome phenotypes, we used genome editing to correct interferon receptor gene dosage in mice carrying triplication of a large genomic region orthologous to human chromosome 21. Normalization of interferon receptor copy number attenuated lethal antiviral responses, prevented heart malformations, decreased developmental delays, improved cognition and normalized craniofacial anomalies. Therefore, interferon receptor gene dosage determines major hallmarks of Down syndrome, indicating that trisomy 21 elicits an interferonopathy amenable to therapeutic intervention. <h3>One-Sentence Summary</h3> Correction of interferon receptor gene dosage rescues multiple key phenotypes in a mouse model of trisomy 21.