Suppression and acceleration of autoimmune diabetes by neutralization of endogenous interleukin-12 in NOD mice.

Fujihira, Kazuhiro; Nagata, Michio; Moriyama, Hiroaki; Yasuda, Hisafumi; Arisawa, K; Nakayama, Maki; Maeda, Sakan; Kasuga, Masato; Okumura, Ko; Yagita, Hideo; Yokono, Koichi

doi:10.2337/diabetes.49.12.1998

Cited by 44 publications

(27 citation statements)

References 59 publications

(61 reference statements)

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“…The unexpected finding that IL-12 (as well as IFN-␥)-deficient NOD mice do not develop diabetes appears to be due to the time of onset of the blockade in the knockout and development of compensatory regulatory pathways that do not function in intact mice (32)(33)(34). Conversely, a lack of IL-12 would be expected to promote Th2 dominance and the B cell hyperactivity characteristic of lupus.…”

Section: Discussionmentioning

confidence: 96%

Distinct Pathways for NF-κB Regulation Are Associated with Aberrant Macrophage IL-12 Production in Lupus- and Diabetes-Prone Mouse Strains

Liu

Beller

2003

The Journal of Immunology

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One characteristic of mice prone to a variety of autoimmune diseases is the aberrant regulation of cytokine production by macrophages (Mφ), noted in cells isolated well before the onset of disease. Strikingly, the pattern of IL-12 dysregulation, in particular, is consistent with the nature of the autoimmune disease that will develop in each strain, i.e., elevated in mice prone to Th1-mediated organ-specific disease (nonobese diabetic (NOD) and SJL mice) and reduced in lupus-prone strains (MRL/+ and NZB/W). Mechanistically, the abnormal regulation of IL-12 in these strains was found to be strictly associated with novel patterns of Rel binding in vitro to the unique NF-κB site in the IL-12 p40 promoter. In this study, we report several new findings related to these Rel-κB interactions. Evaluation of the p40 NF-κB site in vivo, assessed by chromatin immunoprecipitation, revealed Rel usage patterns similar to those found in vitro using EMSA, with preferential association of the p40 κB site with c-Rel in NOD Mφ but with p50 in NZB/W Mφ. Moreover, blocking c-Rel in primary Mφ, using short interfering RNA, selectively blocked IL-12 production and normalized the minimal, residual IL-12 levels. Nuclear extracts from NOD Mφ were characterized by c-Rel hyperphosphorylation, and dephosphorylation of nuclear proteins completely blocked binding to the κB site. In contrast, elevated IκB appears to be a likely mechanism accounting for the reduced nuclear c-Rel levels noted in NZB/W Mφ. Alterations in NF-κB metabolism thus appear to define a pathway regulating intrinsic IL-12 defects in both diabetes- and lupus-prone strains.

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Section: Discussionmentioning

confidence: 96%

Distinct Pathways for NF-κB Regulation Are Associated with Aberrant Macrophage IL-12 Production in Lupus- and Diabetes-Prone Mouse Strains

Liu

Beller

2003

The Journal of Immunology

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“…It is therefore interesting that paradoxical results have been obtained when treating NOD mice with either exogenously administered IL-12 or specific IL-12 inhibitors (monoclonal antibody, the (p40)2 antagonist); the outcome apparently depending on the time of administration during the disease development [27][28][29][30][31][32]. More concording data have recently been obtained by use of transgenic mice whose pancreatic cells constitutively express either biologically active IL-12 or the IL-12 p40 homodimer a naturally occurring antagonist of IL-12 [33,34].…”

Section: Discussionmentioning

confidence: 99%

Essential pathogenic role of endogenous IL‐18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL‐18‐binding protein: Fc construct

Nicoletti¹,

Marco²,

Papaccio³

et al. 2003

Eur J Immunol

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IL-18 is a cytokine structurally and functionally related to IL-1 that, in synergy with IL-12, stimulates the synthesis of IFN-+ from T lymphocytes and natural killer cells. Because IFN-+ plays a key pathogenic role in the development of murine immunoinflammatory diabetes induced by multiple low doses of streptozotocin (STZ) we investigated the effect of negating the actions of endogenous IL-18 in this model by administering recombinant IL-18-binding protein:Fc (IL-18 bp:Fc). C57BL/6 mice were injected once daily with 40 mg/kg STZ for 5 consecutive days, day 0 being the first day of STZ challenge. Relative to control animals treated in parallel with either PBS or human IgG, mice treated from day -3 to day 7 with daily doses of 150 ? g of IL-18 bp:Fc exhibited lower incidence of diabetes and milder insulitis. In contrast, mice that were treated with IL-18 bp:Fc from day 7 to day 14 exhibited clinical and histological signs of STZ-induced diabetes similar to those of control mice treated with IgG. The protective effect of IL-18 bp:Fc was accompanied by modified ex vivo immune responses, in that spleen cells and peritoneal macrophages contained fewer IFN-+ secreting cells and released lower amounts of nitrite (an index of nitric oxide production) and IL-1 g . We conclude that intact IL-18 function is essential for the full diabetogenic effect of low dose STZ in C57BL/6 mice.

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“…Anti-IFN-␥ antibodies reduce the incidence of diabetes in both the MLDS-induced model (Herold et al, 1996) and NOD mouse (Campbell et al, 1991); anti-IL-12 antibodies have proved to be effective at suppressing diabetes in the NOD mouse (Fujihira et al, 2000). Antibodies against IL-1 (Cailleau et al, 1997) and TNF-␣ (Yang et al, 1994) have both been shown to prevent diabetes in the NOD mouse.…”

Section: Discussionmentioning

confidence: 99%

Nicotine Reduces the Incidence of Type I Diabetes in Mice

Mabley

Pacher

Southan

et al. 2002

J Pharmacol Exp Ther

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Nicotine has been previously shown to have immunosuppressive actions. Type I diabetes is an autoimmune disease resulting from the specific destruction of the insulin-producing pancreatic ␤-cells. Thus, we hypothesized that nicotine may exert protective effects against type I diabetes. The multiple lowdose streptozotocin (MLDS)-induced model and spontaneous nonobese diabetic (NOD) mouse model of type I diabetes were used to assess whether nicotine could prevent this autoimmune disease. Blood glucose levels, diabetes incidence, pancreas insulin content, and cytokine levels were measured in both models of diabetes, both to asses the level of protection exerted by nicotine and to further investigate its mechanism of action. Nicotine treatment reduced the hyperglycemia and incidence of disease in both the MLDS and NOD mouse models of diabetes. Nicotine also protected against the diabetes-induced decrease in pancreatic insulin content observed in both animal models. The pancreatic levels of the Th1 cytokines interleukin (IL)-12, IL-1, tumor necrosis factor (TNF)-␣, and interferon (IFN)-␥ were increased in both MLDS-induced and spontaneous NOD diabetes, an effect prevented by nicotine treatment. Nicotine treatment increased the pancreatic levels of the Th2 cytokines IL-4 and IL-10. Nicotine treatment reduces the incidence of type I diabetes in two animal models by changing the profile of pancreatic cytokine expression from Th1 to Th2.Type I diabetes is a disease characterized by the specific destruction of the insulin-producing ␤-cells of the pancreatic islets of Langerhans by the immune system (Bottazzo and Bonifacio, 1991;Noorchashm et al., 1997). The islet is invaded by immune cells, particularly T-cells that are CD4 ϩ and CD8 ϩ (Rabinovitch, 1994), forming a pancreatic inflammation termed insulitis, with the resulting production of immune cell mediators, such as cytokines and free radicals (including nitric oxide and related radicals such as peroxynitrite), inhibiting ␤-cell function and ultimately inducing ␤-cell death (Rabinovitch and Suarez-Pinzon, 1998). The induction of nitric oxide synthase (iNOS) and the subsequent formation of nitric oxide and related free radicals have been implicated in the destruction of the ␤-cells in diabetes.A variety of cytokines have been found expressed in the insulitis lesion of the animal models of diabetes and in the pancreata of humans with type I diabetes. It has been proposed that the insulitis lesion is ␤-cell destructive when Th1 cytokines (IL-12, IFN-␥, IL-1, and TNF-␣), produced by isletinfiltrating T-cells, dominate over Th2 cytokines (Rabinovitch, 1998). Agents that suppress the immune system, including cyclosporine (Baquerizo et al., 1989) and glucocorticoids (Like et al., 1983), have been shown to reduce the disease incidence in animal models of type I diabetes.There are two murine models of autoimmune diabetes: the multiple low-dose streptozotocin (MLDS) model and the spontaneous NOD mouse model. The MLDS model of diabetes is characterized by progressive hy...

show abstract

Suppression and acceleration of autoimmune diabetes by neutralization of endogenous interleukin-12 in NOD mice.

Cited by 44 publications

References 59 publications

Distinct Pathways for NF-κB Regulation Are Associated with Aberrant Macrophage IL-12 Production in Lupus- and Diabetes-Prone Mouse Strains

Distinct Pathways for NF-κB Regulation Are Associated with Aberrant Macrophage IL-12 Production in Lupus- and Diabetes-Prone Mouse Strains

Essential pathogenic role of endogenous IL‐18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL‐18‐binding protein: Fc construct

Nicotine Reduces the Incidence of Type I Diabetes in Mice

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