Interferon regulatory factor 1 promoter polymorphism and response to type 1 interferon

Abstract

The clinical success of interferon-treatment has been found to vary in different individuals. To explain this, we hypothesized that responses to type 1 interferons could be partly determined by interferon regulatory factor-1 gene transcription, because the latter is an important transcription factor in the interferon system. We demonstrated that the antiproliferative effect of type 1 interferons on human liver cancer cells correlates with levels of transcription of the interferon regulatory factor-1 gene in parallel with those of p21 WAF-1 expression. Here, we investigated whether mutations in the interferon regulatory factor-1 gene cause different responses to type 1 interferons. DNA from several human liver cancer cell lines and peripheral blood mononuclear cells was investigated. Nucleotide sequences of the interferon regulatory factor-1 gene and polymerase chain reaction products of its upstream region were determined directly and after cloning. The promoter activity of the upstream region of this gene was measured by the luciferase reporter assay. We found 4 point mutations in the upstream (À 1 $ À 495) region, and the luciferase promoter assay demonstrated that these mutations did modify promoter activity. Analysis of DNA from healthy volunteers showed that these mutations are single nucleotide polymorphisms. These results suggest that single nucleotide polymorphisms of the interferon regulatory factor-1 promoter contribute, at least in part, to determining responses to type 1 interferons.

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

“…In the IRF-1 -/-NOD mouse, insulitis and diabetes were decreased accompanied by an increased survival [21]. Additional studies have suggested a role of IRF-1 and IFN-regulated genes in mediating human lupus [22][23][24]. Based on the knowledge that IRF-1 modulates inflammatory mediator production, we sought to determine whether IRF-1 gene deletion alters the severity of lupus nephritis in MRL/lpr mice.…”

Novel interferon regulatory factor-1 polymorphisms in a Kenyan population revealed by complete gene sequencing

“…The genotype and allelic frequencies of each SNP were calculated and depicted in Table 2. Twenty-seven of these SNPs have been previously reported either in publications or by the International Human Genome Sequencing Consortium through the NCBI-based SNP database (Database1;Database2;Donn et al 2001;Nakao et al 2001;Noguchi et al 2000;Saito et al 2001Saito et al , 2002. A number of previously reported SNPs were not observed in the subjects from this study, including 5551T/G, 4950A/G, 5558T/C, 5636G/A, 7662C/-and 6355G/A, demonstrating the high degree of IRF-1 genetic polymorphism in different ethnic populations.…”

“…Beside the well-studied different ''GT'' dinucleotides repeats in intron 7 of IRF-1, 31 single nucleotide polymorphisms (SNPs) in IRF-1 have been identified in human subjects or cell lines by other researchers (Database1;Database2;Donn et al 2001;Nakao et al 2001;Noguchi et al 2000;Saito et al 2001Saito et al , 2002. Due to the potential role that IRF-1 may play in HIV-1 replication and its importance in the antiviral immune response, it is important to identify genetic polymorphisms in IRF-1 and determine if these mutations result in coding changes in expressed IRF-1 protein.…”

Associations between interferon regulatory factor–1 polymorphisms and Behçet’s disease

“…Saito et al showed the promoter activity of an IRF-1 promoter with the -415C/-410A/-300A haplotype was higher than that of one with the -415A/-410G/-300G haplotype [17,18]. Donn et al reported that IRF-1 3=-UTR polymorphisms might confer susceptibility to JIA and suggested that 3=-UTR polymorphisms could affect IRF-1 mRNA stability [12].…”

“…In addition, IRF-1 promoter functional polymorphisms have been found to be associated with antiviral activity against hepatitis C infection [17,18], and the 3=-untranslated region (UTR) polymorphism was suggested to be associated with disease susceptibility to JIA [12].…”