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M-C Many, S Maniratunga, I Varis, M Dardenne, H A Drexhage, and J-F Denef

Abstract

The administration of a high iodide dose (HID; 10 μg/day) to goitrous mice is known to induce thyroid cell necrosis and inflammation, which, in most strains, is transient. In this study, we analyzed the effects of iodide in autoimmune prone non-obese diabetic (NOD) mice.

Control NOD mice fed a standard diet (MID; 1 μg I/day) or HID did not spontaneously develop thyroiditis. In NOD mice previously made goitrous, HID provoked thyroid cell necrosis and diffuse inflammation within 4 days. Inflammatory cells consisted of MHC-class II+ antigen-presenting cells, CD4+ T helper cells and CD8+ T suppressor/cytotoxic cells. After 96 days of treatment with HID, thyroiditis similar to Hashimoto's disease was obtained in 100% of the animals, with destruction of thyroid follicles, large clusters of T and B cells, and antithyroid antibodies in the plasma. When treating goitrous mice with MID, no cell necrosis was observed and no autoimmune thyroiditis was obtained. The early iodide-induced cell necrosis and inflammation may thus be considered as an important factor in the induction and persistence of autoimmune thyroiditis in individuals carrying a genetic susceptibility to autoimmune disease.

Journal of Endocrinology (1995) 147, 311–320

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J Sternesjo and S Sandler

Administration of the T-helper 1 (Th 1) cell promoting cytokine interleukin-12 (IL-12) accelerates the development of autoimmune diabetes in non-obese diabetic (NOD) mice. In this study we examined the effects of IL-12 on isolated islets from NMRI (Naval Medical Research Institute-established) mice, Sprague-Dawley (S-D) rats and NOD mice. NMRI and S-D islets were cultured in medium RPMI 1640 + 10% fetal calf serum and exposed for 48 h to recombinant mouse IL-12 (0, 0.1, 1 and 10 ng/ml). Islet glucose metabolism, as measured by glucose oxidation rate, was suppressed by about 25% in NMRI islets exposed to 10 ng/ml IL-12. In rat islets 0.1 ng/ml IL-12 induced a 20% decrease in glucose oxidation rate. Islets cultured with 10 ng/ml IL-12 showed a decrease in medium insulin accumulation both in mouse and rat. Glucose-stimulated insulin release was lowered in rat islets exposed to 10 ng/ml IL-12, but not affected in NMRI islets. In NMRI islets IL-12 did not influence nitric oxide production as measured by nitrite formation. In rat islets IL-12 induced a decrease in nitrite formation compared with control islets. Islets were isolated from female NOD mice (age 5, 12, 20 and 26 weeks) and examined either immediately or cultured for 7 days with 10 ng/ml IL-12 alone or in combination with 4 ng/ml of the T-cell stimulating cytokine interleukin-2 (IL-2). In the age groups > 5 weeks of age the glucose-stimulated insulin release was lower in freshly isolated compared with cultured control islets. IL-2 + IL-12 addition induced a small decrease in glucose-stimulated insulin release in islets from 12-week-old animals. With increasing age the DNA content in freshly isolated islets increased due to immune cell infiltration. The DNA content in cultured islets was decreased by 40-60% compared with freshly isolated islets in the age groups over 5 weeks. Islet insulin content was similar in both freshly isolated and cultured islets. None of the cytokines, either alone or in combination, affected islet DNA or insulin content. We conclude that IL-12 has minor suppressive effects in vitro on normal rodent islets. It is likely that the reported accelerated diabetes development of IL-12 administration to NOD mice in vivo is not mediated by a direct toxic effect to the islets. The suppressed insulin release in NOD mouse islets treated with IL-2 + IL-12 suggests, however, that the accelerating effect might partly be attributed to stimulation of immune cells present in the insulitic lesion.

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G Liu, SV Pakala, D Gu, T Krahl, L Mocnik, and N Sarvetnick

In developmental terms, the endocrine system of neither the gut nor the pancreatic islets has been characterized fully. Little is known about the involvement of cholecystokinin (CCK), a gut hormone, involved in regulating the secretion of pancreatic hormones, and pancreatic growth. Here, we tracked CCK-expressing cells in the intestines and pancreata of normal mice (BALB/c), Non Obese Diabetic (NOD) mice and interferon (IFN)-gamma transgenic mice, which exhibit pancreatic regeneration, during embryonic development, the postnatal period and adulthood. We also questioned whether IFN-gamma influences the expression of CCK. The results from embryonic day 16 showed that all three strains had CCK in the acinar region of pancreata, and specifically in alpha cells that also expressed glucagon. However, in adulthood only BALB/c and NOD mice continued this pattern. By contrast, in IFN-gamma transgenic mice, CCK expression was suppressed from birth to 3 months of age in the pancreata but not intestines. However, by 5 months of age, CCK expression appeared in the regenerating pancreatic ductal region of IFN-gamma transgenic mice. In the intestine, CCK expression persisted from fetus to adulthood and was not influenced by IFN-gamma. Intestinal cells expressing CCK did not co-express glucagon, suggesting that these cells are phenotypically distinct from CCK-expressing cells in the pancreatic islets, and the effect of IFN-gamma on CCK varies depending upon the cytokine's specific microenvironment.

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G Papaccio, E Ammendola, and FA Pisanti

Pancreases of untreated and nicotinamide (NIC)-treated pre-diabetic (10-week-old) and overtly diabetic (25-week-old) female NOD (non-obese diabetic) mice and of NON (non-obese non-diabetic) control mice were studied, with the following results. (1) Islets and ducts of overtly diabetic untreated NOD mice (25-week-old) were found to express low levels of MHC class I and II molecules, like NON controls, and high levels of adhesive molecules. (2) NIC was able to slightly affect glycaemia and insulitis, slowing down diabetes progression. Moreover it significantly decreased MHC class II expression (but not class I) in vivo by week 10, and significantly enhanced intercellular adhesion molecule-1 (ICAM-1) expression, mainly by week 25, within the pancreas, where 5-bromo-2'-deoxyuridine positive nuclei and insulin positive cells were present, demonstrating that a stimulation of endocrine cell proliferation occurs. (3) In addition, NIC partly counteracted the fall of superoxide dismutase levels, observed in untreated diabetic NOD animals. (4) In vitro studies demonstrated that NIC: (i) was able to significantly reduce nitrite accumulation and to increase NAD+NADH content significantly, and (ii) was able to increase the levels of interleukin-4, a T helper 2 lymphocyte (Th2) protective cytokine, and of interferon-alpha (IFN-alpha), which is known to be able to induce MHC class I and ICAM-1 but not MHC class II expression, as well as IFN-gamma, which is also known to be able to induce MHC class I and ICAM-1 expression. The latter, although known to be a proinflammatory Th1 cytokine, has also recently been found to exert an anti-diabetogenic role. This study therefore clearly shows that adhesive mechanisms are ongoing during the later periods of diabetes in pancreatic ducts of NOD mice, and suggests they may be involved in a persistence of the immune mechanisms of recognition, adhesion and cytolysis and/or endocrine regeneration or differentiation processes, as both NIC-increased ICAM-1 expression and 5-bromo-2'-deoxyuridine positivity imply. The effects of NIC on MHC class II (i.e. a reduction) but not class I, and, mainly, on ICAM-1 expression (i.e. an increase), together with the increase in Th2 protective cytokine levels are very interesting, and could help to explain its mechanism of action and the reasons for alternate success or failure in protecting against type 1 diabetes development.

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DJ Hill, J Petrik, E Arany, TJ McDonald, and TL Delovitch

Interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) contribute to the initial stages of the autoimmune destruction of pancreatic beta cells. IL-1beta is released by activated macrophages resident within islets, and its cytotoxic actions include a stimulation of nitric oxide (NO) production and the initiation of apoptosis. Insulin-like growth factors (IGFs)-I and -II prevent apoptosis in non-islet tissues. This study investigated whether IGFs are cytoprotective for isolated islets of Langerhans from non-obese diabetic mice (NOD) mice exposed to cytokines. Pancreatic islets isolated from 5-6-week-old, pre-diabetic female NOD mice were cultured for 48 h before exposure to IL-1beta (1 ng/ml), TNF-alpha (5 ng/ml), IFN-gamma (5 ng/ml) or IGF-I or -II (100 ng/ml) for a further 48 h. The incidence of islet cell apoptosis was increased in the presence of each cytokine, but this was significantly reversed in the presence of IGF-I or -II (IL-1beta control 3.5+/-1.6%, IL-1beta 1 ng/ml 27.1+/-5.8%, IL-1beta+IGF-I 100 ng/ml 4.4+/-2.3%, P<0.05). The majority of apoptotic cells demonstrated immunoreactive glucose transporter 2 (GLUT-2), suggesting that they were beta cells. Islet cell viability was also assessed by trypan blue exclusion. Results suggested that apoptosis was the predominant cause of cell death following exposure to each of the cytokines. Co-incubation with either IGF-I or -II was protective against the cytotoxic effects of IL-1beta and TNF-alpha, but less so against the effect of IFN-gamma. Exposure to cytokines also reduced insulin release, and this was not reversed by incubation with IGFs. Immunohistochemistry showed that IGF-I was present in vivo in islets from pre-diabetic NOD mice which did not demonstrate insulitis, but not in islets with extensive immune infiltration. Similar results were seen for IGF-binding proteins (IGFBPs). These results suggest that IGFs protect pre-diabetic NOD mouse islets from the cytotoxic actions of IL-1beta, TNF-alpha and IFN-gamma by mechanisms which include a reduction in apoptosis.

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E Strandell and S Sandler

Abstract

The aim of the present study was to examine if the islet donor gender influences the β-cell sensitivity to possible mediators of β-cell destruction in insulin-dependent diabetes mellitus (IDDM). We have currently addressed this issue by comparing the action of the cytokine interleukin-1β (IL-1β) and the alkylating agent streptozotocin (STZ), on isolated pancreatic islets derived from prediabetic female and male nonobese diabetic (NOD) mice. In this mouse strain the females have a much higher incidence of spontaneous IDDM than the males. Pancreatic islets were isolated from female and male mice of the same litter, cultured for 6 days and thereafter either 5–50 U/ml IL-1β were added for 48 h or 1·8 mm STZ for 30 min. The cytokine exposure caused a strong increase in the medium insulin accumulation in the cultures of islets obtained from both males and females. The insulin and DNA contents were similar when comparing female and male islets before and after cytokine exposure. The male pancreatic islets exhibited a higher rate of islet glucose oxidation than islets obtained from females after IL-1β addition. Non-cytokine treated islets from males showed a higher insulin content compared with corresponding female islets. After IL-1β addition male and female islets had a similar inhibition of insulin secretion following stimulation by glucose. On the other hand, islets of both genders were equally sensitive to the inhibitory action of STZ, when studied 6 days after STZ incubation, as assessed by glucose oxidation and insulin release experiments. In conclusion the data of the present study did not demonstrate a clear gender difference in the islet β-cell sensitivity to immune mediated suppression by IL-1β or alkylation damage in IDDM-prone NOD mice. However, it cannot be excluded that in vivo, under the influence of sex hormones, a decisive alteration in β-cell sensitivity to damage might develop.

Journal of Endocrinology (1997) 153, 81–86

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Eliane Correa-de-Santana, Bianca Fröhlich, Marta Labeur, Marcelo Páez-Pereda, Marily Theodoropoulou, Jose Luis Monteserin, Ulrich Renner, and Günter K Stalla

transductions of signals of MDP but also for the response to LPS. Nevertheless, Kobayashi et al . (2005) showed in a study of macrophages from NOD-deficient mouse that responses to LPS were generally equivalent in wild-type and NOD2 knockout mice. Therefore

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Martha Lappas

upon adipocyte conversion. Moreover, Nod1 mRNA is markedly increased only in the fat tissues of diet-induced obese mice ( Zhao et al . 2011 ). The Nod1/2 knockout mice are protected from high-fat-diet-induced inflammation, lipid accumulation and

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Chun Zeng, Xin Yi, Danny Zipris, Hongli Liu, Lin Zhang, Qiaoyun Zheng, Krishnamurthy Malathi, Ge Jin, and Aimin Zhou

autoimmune responses ( Anderson & Bluestone 2005 ). NOD mice are an ideal model of spontaneous type 1 diabetes, a T-cell-mediated autoimmune disease. Results from histological studies have indicated that infiltration of immune cells, including macrophages and

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A G Kayali, A Stotland, K V Gunst, M Kritzik, G Liu, S Dabernat, Y-Q Zhang, W Wu, and N Sarvetnick

were maintained on the non-obese-diabetic (NOD) background. The NOD background mice were used as controls. The presence of the transgene was confirmed by PCR. Eight- to ten-week-old non-transgenic NOD and littermate transgenic mice, which display