Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development

Matsuyama, Tomohiro; Kimura, Tohru; Kitagawa, Motoo; Pfeffer, Klaus; Kawakami, Toshifumi; Watanabe, Nobumasa; Kündig, Thomas M.; Amakawa, Ryuichi; Kishihara, Kenji; Wakeham, Andrew; Potter, Julia M.; Furlonger, Caren; Narendran, A.; Suzuki, Haruhiko; Ohashi, Pamela S.; Paige, Christopher J.; Taniguchi, Tadatsugu; Mak, Tak W.

doi:10.1016/s0092-8674(05)80086-8

Cited by 577 publications

(390 citation statements)

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“…Several studies have demonstrated the role of IRF-1 and IRF-2 factors in the regulation of IFN type I genes (Matsuyama et al, 1993;Kamijo et al, 1994;Kimura et al, 1994); less clear is the direct role of IRFs in the regulation of cell growth. We analysed in particular the regulation of two genes potential target of the IFN-g induced growth inhibition mediated by IRFs: the 2-5A synthetase directly involved in the IFNmediated growth inhibition and the cell-cycle inhibitor p21 (WAF/CP1).…”

Section: Discussionmentioning

confidence: 99%

Activation and repression of the 2-5A synthetase and p21 gene promoters by IRF-1 and IRF-2

et al. 1999

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Section: Discussionmentioning

confidence: 99%

Activation and repression of the 2-5A synthetase and p21 gene promoters by IRF-1 and IRF-2

et al. 1999

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“…The gene for IRF-1 is located on chromosome 11 and IRF-1 -/-mice were originally derived in the laboratory of T. Mak as previously described [62]. Briefly, the construct used to disrupt the IRF-1 gene (pMIRF1neoB) contained 4.9-kb homologous IRF-1 genomic DNA and a deletion of 1.2 kb into which the neomycin (neo r ) gene was introduced in the same transcriptional orientation as IRF-1.…”

Section: Micementioning

confidence: 99%

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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“…The IFNAR1 -/-, Stat1 -/-, p48 -/-and IRF-1 -/-mice used in this study have been previously described (Matsuyama et al 1993;Müller et al 1994;Kimura et al 1996;Meraz et al 1996). Mouse primary embryonic fibroblast (EF) cells were isolated from wildtype and mutant mice embryos at 12ϳ14 days gestation.…”

Section: Cell Culturementioning

confidence: 99%

Type I interferons are essential mediators of apoptotic death in virally infected cells

et al. 1998

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Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development

Cited by 577 publications

References 67 publications

Activation and repression of the 2-5A synthetase and p21 gene promoters by IRF-1 and IRF-2

Activation and repression of the 2-5A synthetase and p21 gene promoters by IRF-1 and IRF-2

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

Type I interferons are essential mediators of apoptotic death in virally infected cells

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