The Detection of IRF-1 Promoter Polymorphisms and Their Possible Contribution to T Helper 1 Response in Chronic Hepatitis C

Abstract

We described the interferon (IFN) regulatory factor-1 (IRF-1) promoter single nucleotide polymorphisms (SNPs), and the clinical and immunologic implications of these SNPs have been investigated. We successfully determined the mutation at -300 of the IRF-1 promoter by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and this mutation linked with other mutations in the promoter region. In our Japanese population, the frequency of the type -300*A/A was 11.9%, type A/G was 54.2%, and type G/G was 33.9%. We found no significant difference without IFN stimulation in the production levels of IFN-gamma and interleukin-10 (IL-10) from peripheral blood mononuclear cells (PBMC) between subjects with -300*A/A and those with other types. IFN-alpha stimulation, however, increased the levels of IFN-gamma significantly and decreased the IL-10 production level significantly only in the subject with -300*A/A type. Flow cytometric analysis showed that the Th1-type CD4(+) cell population was significantly increased by IFN-beta administration only in the patient with chronic hepatitis C with -300*A/A type. These results suggest that the IRF-1 promoter SNP types are positively involved in Th1-type response and, consequently, the -300*A/A type may be beneficial for viral elimination in chronic hepatitis C and IFN therapy.

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

“…Polymorphisms in the promoter region may affect the transcriptional activation of IRF-1 and its subsequent expression. Supporting evidence comes from a study that demonstrated that a particular promoter polymorphism (SNP at À300G/A) was shown to be correlated with cellular immunity to HIV infection (Saito et al 2002). Our data demonstrates that promoter polymorphism is common in the Kenyan IRF-1 gene sequences.…”

“…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.…”

Possible molecular mechanism of the relationship between NS5B polymorphisms and early clearance of hepatitis C virus during interferon plus ribavirin treatment

“…There are, however, many factors that influence the success of IFN and RBV combination therapy. The resistance or sensitivity to IFN or peg-IFN, not to RBV, might also affect the early viral response, and many factors in both viral and host sides are known to affect IFN responsiveness, such as NS5A mutations [Enomoto et al, 1996], immunological status [Saito et al, 2000], or irf-1 gene promoter polymorphisms [Saito et al, 2002. Together, these factors might determine the efficacy of anti-viral therapy in vivo, and the present in vitro data provides evidence partially supporting our clinical observations that NS5B polymorphisms are associated with early viral clearance during IFN and RBV therapy.…”

Polymorphisms in the Interferon Regulatory Factor-1 Promoter Are Not Associated with Psoriasis and Do Not Influence IFN-α-Induced Th1 Polarization

“…19 Furthermore, polarization toward the Th1 phenotype by in vitro or in vivo administration of type I IFN was more pronounced in individuals carrying the A/A single nucleotide polymorphism (SNP) at position Ϫ300. 20,21 Based on the central role of IFN-␣ in both the development of psoriasis and Th1 polarization, combined with the role of the IRF-1 promoter SNPs on the extent of IFN-␣-induced Th1 skewing, we hypothesized that IFN-␣ stimulation of psoriatic peripheral blood mononuclear cells (PBMC) results in a more pronounced Th1 polarization due to SNPs in the IRF-1 promoter. To test this, PBMCs from healthy donors and psoriasis patients were cultured for 24 h in the presence or absence of 500 U/mL IFN-␣, and the concentration of prototypic type 1 (IFN-␥ and IL-12p40) and type 2 (IL-10 and IL-4) cytokines was measured in the culture supernatant by ELISA.…”