Interaction of interferon regulatory factor-1 and nuclear factor κB during activation of inducible nitric oxide synthase transcription

Saura, Marta; Zaragoza, Carlos; Bao, Clare; McMillan, Audrey; Lowenstein, Charles J.

doi:10.1006/jmbi.1999.2752

Cited by 152 publications

(136 citation statements)

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“…IFN and LPS act synergistically to enhance iNOS expression and NO production [36,37]. Saura et al [19] demonstrated that IRF-1 and NF-jB synergistically augment iNOS gene transcription and that deletion of the IRF-1 gene greatly decreased the transcriptional activity of NF-jB [19]. Similarly, our studies showed the dependence of iNOS expression on IRF-1 expression.…”

Section: Discussionsupporting

confidence: 55%

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

et al. 2006

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To investigate the role of interferon regulatory factor-1 (IRF-1) in the development of lupus nephritis, IRF-1 -/-genotype mice were bred onto the MRL/lpJfas lpr (MRL/lpr) background. We examined kidney mesangial cell function and disease progression. Endpoints evaluated included inflammatory mediators, autoantibody production, immune complex deposition, renal pathology, T cell subset analysis, and duration of survival. Mesangial cells cultured from IRF-1 -/-mice produced significantly lower levels of nitric oxide and IL-12 but not TNF-a when stimulated with LPS + IFN-c. IRF-1 -/-mice showed less aggravated dermatitis compared to the wild-type mice. Anti-doublestranded DNA production and proteinuria were significantly decreased in IRF-1 -/-mice compared to IRF-1 +/+ mice. IgG and C3 deposition as well as glomerulonephritis were decreased in IRF-1 -/-mice at 26 wk of age compared to the IRF-1 +/+ mice. Splenic CD4 -CD8 -CD44 + T cells were decreased while CD4 + CD25 + T cells were increased in the IRF-1 -/-mice when compared to IRF-1 +/+ mice. Survival rates (ED 50 ) were 22 wk for IRF-1 +/+ mice and 45 wk for IRF-1 -/-mice. These findings suggest an important role of IRF-1 in mediating renal disease in MRL/lpr mice. IntroductionThe etiology of systemic lupus erythematosus remains an enigma although genetic factors influenced by environmental agents appear to trigger the disease. Clearly, B cells, T cells, and macrophages play important roles in the development of lupus pathology [1][2][3].Chronic expression of Th1 cytokines secreted by Th cells is particularly harmful due to their influence on the initiation and promotion of tissue destruction [4,5]. Cytokines, including IFN-c, promote inflammation and provide a positive amplification loop responsible for escalating autoimmune kidney damage [6].MRL/lpr mice develop glomerulonephritis and vasculitis at an early age (4-5 months) [7]. Renal disease is characterized by the early influx of activated T cells and macrophages into the kidney. Activated T cells secrete IFN-c, which induces macrophages to express CSF-1, IL-1b, and TNF-a. Macrophages accumulate in the kidney during inflammation and generate IFN-a, TNF-a, and reactive oxygen species. Locally produced chemokines, particularly monocyte chemoattractant protein (MCP)-1, are also instrumental in attracting and maintaining cellular influx [8] -12 [20]. 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. Results IRF-1 MRL/lpr mouse phenotypeTo determine the role of IRF-1 in autoimmune disease, IRF-1-knockout mice were backcrossed for eight generations to the MRL/lpr mice. After eight backcrosses, the littermates were intercrossed to yield cohorts for these studies....

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Section: Discussionsupporting

confidence: 55%

“…Many studies have shown that the induction of inducible iNOS and subsequent production of NO may induce tissue damage [17,18]. Full expression of iNOS is achieved by direct physical interaction of IRF-1 and NFjB binding sites in the iNOS promoter region [19]. IRF-1 -/-mice have decreased production of iNOS and IL-12 [20].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…We hypothesized that the natural accumulation of TAMs in these hypoxic regions and their expression of iNOS could be exploited to enhance the metabolism of hypoxiaactivated prodrugs with bystander properties to improve their antitumor effects. We selected mouse macrophages because they are able to respond to a combination of IFN-γ and LPS, via an IFN-γ response element and nuclear factor-κB element in the promoter region of the iNOS gene, to readily induce upregulation of the iNOS protein (32). Our data show that cytokine-induced murine macrophages express high levels of iNOS protein as detected by Western blotting.…”

Section: Discussionmentioning

confidence: 81%

Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4N)

Mehibel

Singh

Chinje

et al. 2009

Molecular Cancer Therapeutics

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Tumor-associated macrophages (TAMs) are found in many solid tumors and have often been shown to accumulate in the hypoxic regions surrounding areas of necrosis. TAMs are the major site of expression of nitric oxide synthase (NOS), a heme-containing homodimeric enzyme consisting of oxygenase and reductase domains. The latter has a high degree of sequence homology to cytochrome P450 reductase and a functional consequence of this is the ability of NOS, under hypoxic conditions, to activate the bioreductive drugs tirapazamine and RSU1069. Banoxantrone (AQ4N) is a bioreductive prodrug activated in hypoxia by an oxygen-dependent two-electron reductive process to yield the topoisomerase II inhibitor AQ4. A feature of this process is that the final product could potentially show bystander cell killing. Thus, in this study, we investigated the ability of inducible NOS (iNOS)-expressing TAMs to activate AQ4N and elicit toxicity in cocultured human tumor cells. Murine macrophages were induced to overexpress iNOS by treatment with a combination of cytokines, mixed with HT1080 and HCT116 human tumor cells, and the toxicity of AQ4N was determined under aerobic or hypoxic conditions. The aerobic toxicity of AQ4N toward tumor cells was not affected through coculturing with macrophages. However, under hypoxic conditions, the induction of iNOS activity in the macrophages was associated with an increase in AQ4N metabolism and a substantial increase in tumor cell toxicity, which was dependent on the proportion of macrophages in the culture. This study is the first demonstration of TAM-mediated prodrug activation to result in bystander killing of human tumor cells.

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“…Similarly, 15-deoxy-12, 14-PGJ2 (15d-PGJ2), a ligand for PPAR-γ, attenuates (LPS + IFN-γ)-induced expression of iNOS in rat primary astrocytes independent of the PPAR-γ itself (Giri et al, 2004). Recently, ligands for other NR such as RAR and RXR have been also shown to suppress the expression of iNOS independent of NR in macrophages (Saura et al, 1999).…”

Section: Legend Of Ligands (Of Nuclear Hormone Receptors)mentioning

confidence: 99%

“…While the physical span of the entire event is hard to predict, it has been however, experimentally proved that the iNOS promoter bends physically during iNOS activation by TNF-α and IFN-γ in RAW264.7 cells (Saura et al, 1999). Such a 'loop' formed due to bending of the DNA may help compose a spatially well-organized transcription initiation complex (Model in Fig.…”

Section: In the Nux: Nuclear Eventsmentioning

confidence: 99%

Signals for the induction of nitric oxide synthase in astrocytes

Saha

Pahan

2006

Neurochemistry International

101

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Nitric oxide (NO), being a double-edged sword depending on its concentration in the microenvironment, is involved in both physiological and pathological processes of many organ systems including brain and spinal cord. It is now well-documented that once inducible nitric oxide synthase (iNOS) is expressed in CNS in a signal-dependent fashion, NO in excess of physiological thresholds is produced and this excess NO then plays a role in the pathogenesis of stroke, demyelination and other neurodegenerative diseases. Therefore, a keen interest has been generated in recent years in comprehending the regulation of this enzyme in brain cells. The present review summarizes our current understanding of signaling mechanisms leading to transcription of the iNOS gene in activated astrocytes. We attempt this comprehension with a hope to identify potential targets to intervene NO-mediated CNS disorders.

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Interaction of interferon regulatory factor-1 and nuclear factor κB during activation of inducible nitric oxide synthase transcription

Cited by 152 publications

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

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

Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4N)

Signals for the induction of nitric oxide synthase in astrocytes

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