Effect Of Interferon Regulatory Factor 1 Research Articles

Autophagic activation of IRF-1 aggravates hepatic ischemia-reperfusion injury via JNK signaling.

Increasing evidence has accrued indicating that autophagy is associated with hepatic ischemia–reperfusion injury (IRI). This report demonstrates that interferon regulatory factor‐1 (IRF‐1) was upregulated in response to hepatic IRI and was associated with autophagic activation. As a result of these processes, there is an aggravation of liver damage, effects that can be offset by IRF‐1 depletion. In addition, these effects of IRF‐1 are associated with JNK pathway activation followed by increases in Beclin1 protein levels. This JNK‐induced autophagic cell death then leads to cell failure, and plays an important role in liver function damage. We conclude that IRF‐1 activates autophagy through JNK‐mediated autophagy. Accordingly, these findings indicating that the IRF‐1/JNK pathway activates autophagy to exacerbate liver IRI in this mouse model may provide new insights into novel protective therapies for hepatic IRI.

Interferon regulatory factor 1 marks activated genes and can induce target gene expression in systemic lupus erythematosus.

Interferon regulatory factor 1 (IRF-1) mediates both induction of interferons (IFNs) and responses to type I IFNs. It has been implicated as a critical mediator of inflammation in murine lupus models. In a previous study of chromatin modifications in monocytes from patients with systemic lupus erythematosus (SLE), IRF-1 was implicated as being associated with increased histone acetylation in this disease. The present study was undertaken to directly investigate IRF-1 binding sites on chromatin. Cells from 9 female SLE patients and 7 female controls were examined. Monocytes were purified from peripheral blood and subjected to library preparation using a validated antibody to IRF-1. IRF-1 binding sites on chromatin were identified by chromatin immunoprecipitation followed by sequencing. The effect of IRF-1 on target gene expression was confirmed using an overexpression system in cell lines, and coimmunoprecipitation was used to identify protein interactions. IRF-1 binding around transcribed regions was increased in SLE patient monocytes, but histone modifications at potential IRF-1 binding sites without detectable IRF-1 binding were increased as well. Overexpression of IRF-1 was sufficient to drive transcription of target genes. IRF-1 overexpression was also able to alter histone modifications at a focus set of target genes, and treatment with an IRF-1 inhibitor reduced both expression and histone modifications at target genes. IRF-1 was found to interact with a select set of histone-modifying enzymes and other transcription factors. IRF-1 is an important signaling protein in the interferon pathway. It not only activates gene expression as a transcription factor, but may perpetuate disease by leading to a dysregulated epigenome.

The effect of interferon regulatory factor-1 on apoptosis regulation in osteosarcomawith different p53 status

Objective Detect the effects of interferon regulatory factor-1 (IRF-1) gene on the apoptosisregulation in osteosarcoma with different p53 status and disclose the underlying mechnisms preliminarily.Methods To observe the effects of IRF-1 gene on the apoptosis effects induced by chemotherapeutic agent adriamycin in steosarcoma with different p53 status,p53 +/+ U2OS and p53-/-SaOS-2 were used.Western blotting analysis was firstly used to detect the expression of IRF-1 protein in adriamycin treated p53 +/+ U2OS and p53-/-SaOS-2 cells.And then IRF-1 gene was further overexpressed or knocked out for further detection the apoptosis effect induced by adriamycin respectively.Meanwhile,the target genes of p53,B cell lymphoma/leukemia-2 associated X protein (bax) and p21,were detected by real-time reverse transcriptase-polymerase chain reaction (RT-qPCR).Results Western blotting showed that the expression of IRF-1 has been improved significantly when p53 +/+ U2OS and p53-/-SaOS-2 were treated with adriamycin for 24 h.The significant increase in the death rate of cells has been detected by the release of lactate dehydrogenase (LDH) Activity (P ＜ 0.05).When IRF-1 gene were overexpressed with transient transfection,adriamycin-induced apoptosis effect were increased significantly (P ＜ 0.05),while the knockdown of IRF-1 gene by small interfering RNA (siRNA) transfection were decreased significantly (P ＜ 0.05).RT-qPCR were used to further detected the expression of downstream target genes bax and p21,which do great favor to p53-dependent apoptosis.The results showed that bax and p21 were both upregulated significantly in p53-/-osteosarcoma cells (P ＜ 0.05),but not observed in p53 +/+ osteosarcoma cells (P ＞ 0.05).Conclusion IRF-1 plays a crucial role in adrymycin induced apoptosis by modulating p53 target genes,especially to the cancer cells with p53 gene deficient. Key words: Interferon regulatory factor-1 ; Osteosarcoma cells ; p53 ; Apoptosis

Central Nervous System Expression of Interferon Regulatory Factor 1 Regulates Experimental Autoimmune Encephalomyelitis

Interferon regulatory factor 1 (IRF-1) is a transcription factor that has been implicated in the disease mechanisms of experimental autoimmune encephalomyelitis (EAE). In this study, we examined the role of central nervous system (CNS) expression of IRF-1 in the natural course of EAE. In an effort to dissect the CNS effects from the peripheral immune effects of IRF-1, we generated bone marrow chimera mice that differentially expressed IRF-1 in the CNS and in the immune system. We found that mice lacking IRF-1 in the CNS developed significantly milder clinical symptoms and shorter disease duration compared to those with wild-type background. Based on these results, we concluded that the CNS expression of IRF-1 regulates the disease process in EAE. Our findings are relevant to the inflammatory mechanisms involved in multiple sclerosis and may provide a basis for development of novel therapeutic targets of the disease.

Interferon regulatory factor-1 (IRF-1) exhibits tumor suppressor activities in breast cancer associated with caspase activation and induction of apoptosis

We have directly assessed the ability of interferon regulatory factor-1 (IRF-1) to act as a tumor suppressor gene in human breast cancer cells and explored whether this suppressor function is mechanistically conferred by affecting cell cycle transition, apoptosis and/or caspase activation. We have used a dual approach, measuring whether overexpression of wild-type IRF-1 or a dominant negative IRF-1 (dnIRF-1) produce opposing effects on breast cancer cell proliferation in vitro or tumorigenicity in athymic nude mice. Mechanistic studies determined the effects of blocking endogenous IRF-1 expression on cell cycle transition by flow cytometry, on apoptosis by Annexin V staining, and on caspase activation by fluorescent substrate cleavage. IRF-1 mRNA (P < or = 0.001) and protein (P < or = 0.001) are highly expressed in non-tumorigenic, normal, mammary epithelial cells, with intermediate expression in tumorigenic, but non-metastatic, cells and very low expression in metastatic cell lines. In MCF-7 cells transfected with a wild-type IRF-1 (MCF-7/IRF-1), IRF-1 mRNA expression inversely correlates with the rate of cell proliferation (r = -0.91; P = 0.002). Conversely, expression of dnIRF-1 in both MCF-7 (MCF-7/dnIRF-1; p53 wild-type) and T47D cells (T47D/dnIRF-1; p53 mutant) increases cell proliferation (P < or = 0.001). In athymic nude mice, the incidence of MCF-7/IRF-1 xenografts is reduced (P = 0.045), whereas MCF-7/dnIRF-1 xenografts exhibit a significantly higher tumor incidence (P < or = 0.001). Effects of IRF-1/dnIRF-1 are mediated through changes in the rates of apoptosis and not through cell cycle regulation. MCF-7/dnIRF-1 cells exhibit a 50% decrease in basal apoptosis (P = 0.007) and a significant reduction in caspase 8 activity (P = 0.03); similar effects occur in T47D/dnIRF-1 cells, where the effects on apoptosis appear to be mediated through inhibition of caspases 3/7 (P < 0.001) and caspase 8 (P = 0.03). These data establish a functional role for IRF-1 in the growth suppression of breast cancer cells and strongly implicate IRF-1 as a tumor suppressor gene in breast cancer that acts, independent of p53, to control apoptosis.

Expression of Interferon Regulatory Factor 1 and 2 in Hematopoietic Cells of Children with Juvenile Myelomonocytic Leukemia

Interferon regulatory factor 1 (IRF-1) is a transcriptional activator in the interferon system and acts as a tumor suppressor. The structurally related IRF-2 represses the effects of IRF-1 by competitive binding to the same DNA sequence elements. Changes in the relative balance between IRF-1 and IRF-2 lead to dysregulation of cell growth and may play a role in the development of neoplasias. The loss of functional IRF-1 has been observed in a number of patients with myelodysplastic syndrome (MDS) and leukemia, suggesting a potentially critical role of IRF-1 in leukemogenesis. We studied the expression of both transcription factors in peripheral blood (PB) and bone marrow (BM) cells of children with juvenile myelomonocytic leukemia (JMML) using RT-PCR and Southern blot hybridization. No significant difference between the expression levels of IRF-1 and IRF-2 could be detected in PB and BM of patients with JMML and normal donors. Although our results are preliminary they suggest that neither the tumor suppressor gene IRF-1 nor the oncogene IRF-2 is involved in the pathogenesis of JMML.

The activation of major histocompatibility complex class I genes by interferon regulatory factor-1 (IRF-1).

We have investigated the role of interferon regulatory factor-1 (IRF-1), an interferon-gamma (IFN-gamma) inducible transcriptional activator, on major histocompatibility complex (MHC) class I gene transcription. IRF-1 alone is sufficient to trans-activate both transfected and endogenous class I genes and the effect of IRF-1 appears to be direct and sequence-specific. These data suggest that IRF-1 is involved in the IFN-gamma mediated induction of MHC class I expression.