Complete Suppression of Insulitis and Diabetes in NOD mice Lacking Interferon Regulatory Factor-1

Nakazawa, Tomoyuki; Satoh, Jo; Takahashi, Kazuma; Sakata, Yoshiyuki; Ikehata, F.; Takizawa, Yui; Bando, Shin Ichiro; Housai, Toshimune; Li, Yan; Chen, Chen; Matsumoto, Takayuki; Kure, Shigeo; Kato, Ichiro; Takasawa, Shin; Taniguchi, Tadatsugu; Okamoto, Hiroshi; Toyota, Takayoshi

doi:10.1006/jaut.2001.0531

Cited by 58 publications

(45 citation statements)

References 26 publications

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“…We therefore hypothesise that while Irf-1 −/− islets as such are partially protected against cytokine-induced cell death, this is of little relevance in vivo, since exposure of these islets to inflammatory cytokines leads to enhanced functional impairment (via IL-1β and nitric oxide) and induces secretion by the beta cells themselves of chemokines that accelerate the influx of inflammatory and immune cells into the grafts, in turn leading to destruction of the beta cells via different pathways. Finally, these data are in contrast to the lower insulitis and diabetes prevalence in Irf-1 −/− NOD mice [37]. A major criticism of this model is that Irf-1 is knocked-out in the whole mouse, including the immune system, where it is crucial for IFN-γ signalling.…”

Section: Discussionmentioning

confidence: 88%

“…This increase in primary non-function of Irf-1 −/− islets was surprising given that (1) Irf-1 −/− islets are partly protected against cytokine-induced cell death in vitro [36]; (2) Irf-1 −/− NOD mice have decreased prevalence of insulitis and diabetes [37]; and (3) elimination of STAT-1, the transcription factor upstream of IRF-1 in the IFN-γ signalling cascade, results in complete protection against islet primary non-function in vivo [35]. To date, the pathophysiology of islet primary non-function is incompletely understood, but we have previously shown that it is of great importance in autoimmune hosts (spontaneously diabetic NOD mice) and seems to be associated with nonspecific inflammation at the implantation site, with a major role being played by IL-1β and free radicals (nitric oxide) [23,34].…”

Section: Discussionmentioning

confidence: 99%

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Interferon regulatory factor-1 is a key transcription factor in murine beta cells under immune attack

Gysemans¹,

Callewaert²,

Moore

et al. 2009

Diabetologia

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Aims/hypothesis IFN-γ, together with other inflammatory cytokines such as IL-1β and TNF-α, contributes to beta cell death in type 1 diabetes. We analysed the role of the transcription factor interferon regulatory factor (IRF)-1, a downstream target of IFN-γ/signal transducer and activator of transcription (STAT)-1, in immune-mediated beta cell destruction. Methods Islets from mice lacking Irf-1 (Irf-1 −/− ) and control C57BL/6 mice were transplanted in overtly diabetic NOD mice. Viability and functionality of islets were evaluated in vitro. Chemokine expression by Irf-1 −/− islets and INS-1E cells transfected with Irf-1 short interfering RNA (siRNA) was measured by real-time PCR as well as in functional assays in vitro. Results IRF-1 deletion in islets was associated with higher prevalence of primary non-function (63% vs 25%, p≤0.05) and shorter functioning graft survival (6.0±2.6 vs 10.4± 4.8 days, p≤0.05) in contrast to similar skin graft survival. Although Irf-1 −/− islets were resistant to cytokine-induced cell death, insulin secretion by them was lower than that of control C57BL/6 islets under medium and cytokine conditions. IL-1 receptor antagonist partly restored the cytokine-induced secretory defect in vitro and completely prevented primary non-function in vivo. Cytokine-exposed Irf-1 −/− islets and INS-1E cells transfected with Irf-1 siRNA showed increased expression of Mcp-1 (also known as Ccl2), Ip-10 (also known as Cxcl10), Mip-3α (also known as Ccl20) and Inos (also known as Nos2) mRNA and elevated production of monocyte chemoattractant protein-1 (MCP-1) and nitrite compared with controls. In vivo, Irf-1 −/− islets displayed a higher potential to attract immune cells, reflected by more aggressive immune infiltration in the grafted islets. Conclusions/interpretation These data indicate a key regulatory role for IRF-1 in insulin and chemokine secretion by pancreatic islets under inflammatory attack.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Interferon regulatory factor-1 is a key transcription factor in murine beta cells under immune attack

Gysemans¹,

Callewaert²,

Moore

et al. 2009

Diabetologia

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“…Furthermore, IRF-1 -/-mice displayed less organ injury, reduced necrosis, and survived longer than wild-type mice when injected with lethal doses of a murine malaria strain, Plasmodium berghei [43]. Further evidence in support of targeting IRF-1 in autoimmune diseases includes studies by Nakazawa et al [21], which showed a complete suppression of insulitis and diabetes in the NOD mice lacking IRF-1.…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

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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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“…Taken together, IRF-1 may play a role in the pathogenesis of AITD. We have recently consistently demonstrated that IRF-1-deficient non-obese diabetic (NOD) mice did not develop insulitis and diabetes (21). However, it remains unknown as to whether IRF-1 is involved in the development of AITD.…”

Section: Introductionmentioning

confidence: 99%

Prevention of lymphocytic thyroiditis in iodide-treated non-obese diabetic mice lacking interferon regulatory factor-1

Tani

Mori

Hoshikawa³

et al. 2002

European Journal of Endocrinology

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Objective: Interferon regulatory factor-1 (IRF-1) is a critical regulator of interferon-g (IFNg)-mediated immune responses. To determine whether IRF-1 is involved in the pathogenesis of thyroiditis in animal models, we evaluated the incidence of iodide-induced lymphocytic thyroiditis (LT) in nonobese diabetic (NOD) mice lacking IRF-1 as well as IRF-1 þ/þ and þ /2 mice. Design: IRF-1 þ /þ , þ/2 and 2 /2 NOD mice at 6 weeks of age were fed water (group 1) or iodide water (group 2) for 8 weeks. Methods: Thyroids were examined histopathologically and intrathyroidal lymphocytic infiltration was arbitrarily graded. Serum thyroxine (T 4 ) and anti-mouse thyroglobulin antibody (anti-mTgAb) levels were measured. Spleen cell population was analyzed by flow cytometry, and IFNg and interleukin-10 produced by splenocytes were measured by enzyme-linked immunosorbent assay. Results: In group 1, only 4.3% of NOD mice developed LT. In contrast, 67.6% of mice in group 2 developed the disease. Iodide treatment induced LT in more than 80% of IRF-1 þ/þ and þ/2 mice. However, no IRF-1 2 /2 mice in group 2 developed LT. There was no difference in both serum antimTgAb and T 4 levels among the three IRF-1 genotypes of NOD mice. Numbers of splenic CD8 þ T cells and IFNg production by Concanavalin A-stimulated splenocytes were markedly decreased in IRF-1-deficient NOD mice. Conclusions: IRF-1 is involved in the development of iodide-induced LT in NOD mice.

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Complete Suppression of Insulitis and Diabetes in NOD mice Lacking Interferon Regulatory Factor-1

Cited by 58 publications

References 26 publications

Interferon regulatory factor-1 is a key transcription factor in murine beta cells under immune attack

Interferon regulatory factor-1 is a key transcription factor in murine beta cells under immune attack

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

Prevention of lymphocytic thyroiditis in iodide-treated non-obese diabetic mice lacking interferon regulatory factor-1

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