A Transcriptional Inhibitor of TNF-α Prevents Diabetes Induced by Multiple Low-Dose Streptozotocin Injections in Mice

Holstad, Maria; Sandler, Stellan

doi:10.1006/jaut.2001.0506

Cited by 34 publications

(22 citation statements)

References 25 publications

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“…Reportedly, a transcriptional TNF-α inhibitor prevents diabetes development in the streptozotocin-induced diabetes model (Holstad and Sandler, 2001). IL-1β has been implicated in early events in β-cell destruction.…”

Section: Discussionmentioning

confidence: 99%

Sulfuretin protects against cytokine-induced β-cell damage and prevents streptozotocin-induced diabetes

et al. 2010

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NF-κB activation has been implicated as a key signaling mechanism for pancreatic β-cell damage. Sulfuretin is one of the main flavonoids produced by Rhus verniciflua, which is reported to inhibit the inflammatory response by suppressing the NF-κB pathway. Therefore, we isolated sulfuretin from Rhus verniciflua and evaluated if sulfuretin could inhibit cytokine-or streptozotocin-induced β-cell damage. Rat insulinoma RINm5F cells and isolated rat islets were treated with IL-1β and IFN-γ to induce cytotoxicity. Incubation of cells and islets with sulfuretin resulted in a significant reduction of cytokine-induced NF-κB activation and its downstream events, iNOS expression, and nitric oxide production. The cytotoxic effects of cytokines were completely abolished when cells or islets were pretreated with sulfuretin. The protective effect of sulfuretin was further demonstrated by normal insulin secretion of cytokine-treated islets in response to glucose. Treatment of mice with streptozotocin resulted in hyperglycemia and hypoinsulinemia, which was further evidenced by immunohistochemical staining of islets. However, the diabetogenic effects of streptozotocin were completely prevented when mice were pretreated with sulfuretin. The anti-diabetogenic effects of sulfuretin were also mediated by suppression of NF-κB activation. Collectively, these results indicate that sulfuretin may have therapeutic value in preventing β-cell damage.

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Section: Discussionmentioning

confidence: 99%

Sulfuretin protects against cytokine-induced β-cell damage and prevents streptozotocin-induced diabetes

et al. 2010

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“…One way to preserve β cell mass is to reduce apoptosis (25,39). Streptozotocin in multiple low doses induces β cell apoptosis and diabetes in mice and other mammals, at least in part by promoting T cell infiltration that promotes the production of TNF-α and IFN-γ in the pancreas (40,41). Upregulation of Irs2 in mouse β cells does not reduce T cell infiltration during streptozotocin treatment; however, it reduces apoptosis of β cells by 50%, and prevents the onset of diabetes for at least 15 days.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes

et al. 2003

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“…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. Inhibitors of TNF-␣ transcription, such as MDL 201,449A (Holstad and Sandler, 2001), or secretion, such as troglitazone (Beales et al, 1998), have both prevented diabetes in the MLDS and NOD mouse models of diabetes, respectively.…”

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...

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A Transcriptional Inhibitor of TNF-α Prevents Diabetes Induced by Multiple Low-Dose Streptozotocin Injections in Mice

Cited by 34 publications

References 25 publications

Sulfuretin protects against cytokine-induced β-cell damage and prevents streptozotocin-induced diabetes

Sulfuretin protects against cytokine-induced β-cell damage and prevents streptozotocin-induced diabetes

Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes

Nicotine Reduces the Incidence of Type I Diabetes in Mice

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