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

doi:10.1006/jaut.2001.0506

Journal of Autoimmunity

Volume 16, Issue 4, June 2001, Pages 441-447

https://doi.org/10.1006/jaut.2001.0506 Get rights and content

Abstract

The aim of the present study was to examine the effect of a transcriptional inhibitor of tumour necrosis factor-α (TNF-α) on the development of diabetes induced by multiple low doses of streptozotocin (STZ) in mice. MDL 201.449A is a novel transcriptional inhibitor of TNF-α gene expression and protein production and might therefore be potentially interesting in counteracting diabetes. We have studied the effect of MDL 201,449A on the development of hyperglycaemia and pancreatic insulitis in mice treated with multiple low-dose injections of streptozotocin. It was found that one daily sc injection of MDL 201,449A (25 mg/kg body weight) for 14 days prevented the development of hyperglycaemia following the streptozotocin injections. The mice treated with multiple low-dose injections of streptozotocin became gradually hyperglycaemic, and concomitant treatment with MDL 201,449A significantly reduced this elevation in blood glucose levels. In vitro MDL 201,449A reduced TNF-α mRNA levels dose-dependently by 75–80% after ConA stimulation of spleen cells, indicating the efficacy of MDL 201,449A to counteract TNF-α mRNA synthesis. These data suggest that transcriptional inhibition of TNF-α might be an interesting approach in the prevention of type 1 diabetes.

References (28)

J. Ogawa et al.
Troglitazone can prevent development of type 1 diabetes induced by multiple low-dose streptozotocin in mice
Life Sci.
(1999)
P.E. Beales et al.
Troglitazone prevents insulin dependent diabetes in the non-obese diabetic mouse
Eur. J. Pharmacol.
(1998)
A.A. Like et al.
Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus
Science
(1976)
M Bradshaw et al.
Specific transcriptional inhibition of bone marrow-derived macrophage tumor necrosis factor-alpha gene expression and protein production using novel enantiomeric carbocyclic nucleoside analogues
J. Pharmacol. Exp. Ther.
(1995)
I.C.K. Edwards et al.
Inhibition of superantigen-induced proinflammatory cytokine production and inflammatory arthritis in MRL-1pr/Ipr mice by a transcriptional inhibitor of TNF-α
J. Immunol.
(1996)
K.C. Herold et al.
Regulation of cytokine production during development of autoimmune diabetes induced with multiple low-doses of streptozotocin
J. Immunol.
(1996)
A. Rabinovitch
An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus
Diabetes Metab. Rev.
(1998)
Z. Jiang et al.
Cytokine gene expression in the islets of the diabetic Biobreeding/Worcester rat
J. Immunol.
(1991)
C.A. Dinarello et al.
Tumor necrosis factor (cachectin) in an endogenous pyrogen and induces production of interleukin 1
J. Exp. Med.
(1986)
Y. Fong et al.
Antibodies to cachectin/tumor necrosis factor reduce interleukin 1β and interleukin 6 appearance during lethal bacteremia
J. Exp. Med.
(1989)

M.W. Rolfe et al.

Suppression of human alveolar macrophage-derived cytokines by amiloride

Am. J. Resp. Cell Mol. Biol.

(1992)

E. Vannier et al.

Histamine suppresses gene expression and synthesis of tumor necrosis factor alpha via histamine H2 receptors

J. Exp. Med.

(1991)

J.Y. Jeong et al.

Chloroquine inhibits processing of tumor necrosis factor in lipopolysaccharide-stimulated RAW 264.7 macrophages

J. Immunol.

(1997)

A.L. Moreira et al.

Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation

J. Exp. Med.

(1993)

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In susceptible rodents, STZ induces insulinopenic diabetes and is involved in immune destruction as in human Type 1 DM. Multiple low-dose STZ models are widely used to study immunological pathways that lead to insulitis and beta cell death (Herold et al., 1997; Holstad and Sandler, 2001; Mensah-Brown et al., 2002; Müller et al., 2002; Yang et al., 2003; Zuccollo et al., 1999). Legal and ethical restrictions are encountered in studies with experimental animals such as rodents, mammals.
Diabetes Mellitus (DM) is a metabolic disease characterized by hyperglycemia. Chronic hyperglycemia is associated with long-term dysfunction such as retinopathy, nephropathy, neuropathy and cardiovascular diseases. These complications increase rates of death and disability worldwide. Due to the negative effects of DM on the quality of life, the mechanism and treatments of the disease should be investigated in more detail. Most of the research in diabetes is performed in experimental animals. Experimental animal models contributed to the advancement of clinical research, the development of new therapeutic approaches, the discovery of insulin and the purification of insulin. There are many animal models of DM in the literature. But there are a few DM model studies created with chick embryos. In these studies, it was seen that there were differences in STZ doses and STZ administration techniques. The objective of this study was to create a more acceptable and easier DM model. 180 specific pathogen free (SPF) fertilized chicken eggs (White Leghorn chicken) were used in this study. STZ was administered to 160 SPF eggs for an induced DM model. The remaining 20 SPF eggs were separated as a control group. We used two different DM models (Air sack model (ASM) and Chorioallantoic membrane model (CAMM)) and blood sampling technique in our study. 160 SPF eggs were divided into two groups with 80 eggs in each group, according to the model in which STZ was administered. When the relationship between blood glucose and blood insulin levels were examined, it was determined that there was a significantly strong negative correlation in the control group and ASM 1 group; and a significantly very strong negative correlation was found in the ASM 2 group and ASM 3 group. Our data indicate that the optimal STZ dose to create a DM model was 0.45 mg/egg and the best DM model was ASM. The second technique to be the best blood sampling technique for determining blood glucose levels. We believe that ASM can be used in DM studies and anti-DM drug studies in terms of its easebly, applicability, reproducibility and low cost.
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Inflammation is one of the main mechanisms of pancreatic β-cell damage and the development of type 1 diabetes (T1D). Carvedilol, a beta-adrenergic receptor blocker, has been demonstrated to have anti-inflammatory and antioxidant effects. The aim of this study was to investigate the protective effect of carvedilol against pancreatic β-cell damage and the development of T1D in an experimental model. T1D was induced in mice by multiple low-dose streptozotocin (STZ) injections. Diabetic mice were treated with carvedilol (15 and 20 mg/kg/day, orally) for 14 days. Results showed that blood glucose levels, diabetes incidence, body weight loss and insulitis in the pancreatic tissue were significantly reduced in mice treated with carvedilol. Treatment of mice with carvedilol significantly increased the levels of antioxidants glutathione (GSH), superoxide dismutase (SOD), and catalase and decreased the levels of malondialdehyde (MDA), nitric oxide (NO) and myeloperoxidase (MPO) in the pancreatic tissue as compared with those in the STZ-induced diabetic mice. Carvedilol decreased the expression of nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as important modulators of inflammation and β-cell damage in the pancreatic tissue. In addition, carvedilol significantly reduced the levels of proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 IL-12, IL-17, interferon (IFN)-γ and chemokine MCP-1, while increased the anti-inflammatory cytokine IL-10 in the pancreatic tissue. In conclusion, these findings suggest that carvedilol is able to prevent pancreatic β-cell damage and the development of T1D in mice by the inhibition of inflammatory and oxidative mediators.
Withaferin-A attenuates multiple low doses of Streptozotocin (MLD-STZ) induced type 1 diabetes
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It is believed that disturbance of this homeostasis between the pro-and anti-inflammatory cytokines leads to T1DM [57]. It has been reported that inhibitors of TNF-α and IL-1β prevent diabetes in mouse diabetes models [58,59]. To explore the anti-inflammatory activity of WA we quantified the expression of pro-inflammatory cytokines viz; IL-6 and TNF-α in pancreatic tissue.
Type 1 diabetes mellitus (T1DM) is one of the major metabolic disorders with life-long dependence on insulin. The present study was designed to evaluate the antioxidant and anti-diabetic potential of Withaferin A (WA), the active constituent of Withania somnifera in multiple low doses of Streptozotocin (MLD-STZ) induced T1DM. STZ (40 mg/Kg) was administered intraperitoneally (i.p.) for 5 consecutive days to male Swiss albino mice to induce T1DM. Mice were concurrently treated with WA (2 & 10 mg/Kg). Blood glucose levels, intraperitoneal glucose tolerance test, oxidative stress parameters were estimated biochemically (MDA, GSH) and immunohistochemically (Nrf2, NFκB). In addition, inflammatory cytokines, and insulin levels were quantified by ELISA method. Apoptosis was assessed by immunohistochemical staining for cleaved-caspase-3 and TUNEL assay. WA treatment significantly reduced the blood glucose levels and improved glucose clearance. Strikingly, we observed a significant reduction in the incidence of diabetes upon WA treatment and only 2 out of 8 (2/8 = 25%) animals were diabetic. WA ameliorated the MLD-STZ induced oxidative and nitrosative stress. Furthermore, WA exhibited promising anti-inflammatory effect as evident from reduction in the levels of IL-6 (p < 0.05) and TNF-α (p < 0.05) compared to diabetic mice. In addition, insulitis scoring and IHC for Nrf2 and NFκB indicated promising anti-diabetic effect. WA reduced MLD-STZ induced DNA fragmentation and apoptosis, further supporting the observed protective effect. We, to the best of our knowledge, report for the first time that WA can effectively combat MLD-STZ induced T1DM via modulation of Nrf2/NFκB signaling and holds substantial potential for therapy of T1DM.
Dual genetic absence of STAT6 and IL-10 does not abrogate anti-hyperglycemic effects of Schistosoma mansoni in streptozotocin-treated diabetic mice
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Citation Excerpt :
Hp infection also reduced hyperglycemia in DKO mice (Fig. 6b), suggesting that this phenomenon is not restricted to Sm. As Th1/Th17 cytokines (IFN-γ, IL-17 and TNF-α) are reported to have pathogenic roles in T1D (Emamaullee et al., 2009; Holstad and Sandler, 2001; Mensah-Brown et al., 2006; Suk et al., 2001; Vincenz et al., 2011), we measured splenic cytokine production upon stimulation with an anti-CD3 antibody (Fig. 7) to evaluate systemic changes of cytokine environment by the infection. In WT mice, Sm infection enhanced production of IL-4 and IL-10, and simultaneously suppressed production of IFN-γ, IL-17 and TNF-α.
Schistosoma mansoni (Sm) is known to exert protective effects against various allergic and autoimmune disorders. It has been reported that this parasite protects NOD mice from spontaneous type 1 diabetes (T1D) and ameliorates streptozotocin (STZ)-induced T1D in wild-type mice. Here, we tried to clarify the anti-diabetic mechanisms of Sm in the latter model. Sm infection partially prevented the degradation of pancreatic islets and hyperglycemia in multiple low-dose (MLD) STZ-treated mice. Neither Treg cell depletion nor genetic absences of IL-10 and/or STAT6 abrogated the anti-hyperglycemic effects of Sm. Among M2 macrophage markers, Arg-1 and Ym1, but not Retnla, remained up-regulated in the pancreatic lymph nodes and in the spleens of STAT6/IL-10 double deficient (DKO) mice. Collectively, it is suggested that Sm exerts anti-diabetic effects on this experimental T1D model via Treg/IL-4/IL-13/IL-10-independent mechanisms. Augmented expressions of Arg-1 and Ym1 in the lymphoid organs adjacent to pancreas may be relevant to the anti-diabetic effects of Sm.
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Some parasitic helminths are known to protect their hosts from allergic and autoimmune disorders. Here, we tested the effects of a gastrointestinal nematode, Heligmosomoides polygyrus (Hp), on streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice. Hp infection significantly suppressed hyperglycemia induced by multiple low-dose administration of STZ, but did not affect hyperglycemia induced by single high-dose administration of STZ. In the multiple low dose model, Hp infection prevented a decrease in pancreatic islet size. The augmentation of TNF-α and IL-1β expression in the pancreas was abrogated by Hp infection. The genetic absence of IL-10 or STAT6 did not abrogate the anti-hyperglycemic effect of Hp. Hp has a suppressive effect on immune mechanism-mediated experimental T1D via Th2 polarization-independent mechanisms.
Thalidomide attenuates multiple low-dose streptozotocin-induced diabetes in mice by inhibition of proinflammatory cytokines
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Thalidomide is an immunomodulatory and anti-inflammatory agent and is used in autoimmune disorders. It has been shown that thalidomide inhibits proinflammatory cytokines production. The purpose of this study was to investigate the effect of thalidomide on the prevention of autoimmune diabetes in mice. Diabetes was induced by multiple low-dose of streptozotocin (MLDS) injection. Mice were treated with thalidomide (300 mg/kg/day orally) for 21 days. Plasma levels of glucose, insulin and nitrate/nitrite as well as pancreatic cytokine levels were measured. Pathological examinations of the pancreas revealed that thalidomide reduced the islet inflammation (insulitis) and destruction of beta cells. Thalidomide treatment prevented hyperglycemia and preserved pancreatic insulin secretion in the diabetic mice. Thalidomide treatment also significantly decreased plasma levels of nitric oxide and pancreatic proinflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-12, IL-17 and interferon (IFN)-γ)] while increased anti-inflammatory cytokine IL-10. In conclusion, these findings indicate that thalidomide may have a protective effect against the autoimmune destruction of the pancreatic beta-cells during the development of MLDS-induced type 1 diabetes in mice.

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^f1: Correspondence to: Dr Maria Holstad, Department of Medical Cell Biology, Biomedicum, P.O. Box 571, SE-751 23 Uppsala, Sweden. Fax: +46 (0) 18 55 64 01. E-mail:[email protected]

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

Abstract

Life Sci.

Eur. J. Pharmacol.

Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus

Science

Specific transcriptional inhibition of bone marrow-derived macrophage tumor necrosis factor-alpha gene expression and protein production using novel enantiomeric carbocyclic nucleoside analogues

J. Pharmacol. Exp. Ther.

Inhibition of superantigen-induced proinflammatory cytokine production and inflammatory arthritis in MRL-1pr/Ipr mice by a transcriptional inhibitor of TNF-α

J. Immunol.

Regulation of cytokine production during development of autoimmune diabetes induced with multiple low-doses of streptozotocin

J. Immunol.

An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus

Diabetes Metab. Rev.

Cytokine gene expression in the islets of the diabetic Biobreeding/Worcester rat

J. Immunol.

Tumor necrosis factor (cachectin) in an endogenous pyrogen and induces production of interleukin 1

J. Exp. Med.

Antibodies to cachectin/tumor necrosis factor reduce interleukin 1β and interleukin 6 appearance during lethal bacteremia

J. Exp. Med.

Suppression of human alveolar macrophage-derived cytokines by amiloride

Am. J. Resp. Cell Mol. Biol.

Histamine suppresses gene expression and synthesis of tumor necrosis factor alpha via histamine H2 receptors

J. Exp. Med.

Chloroquine inhibits processing of tumor necrosis factor in lipopolysaccharide-stimulated RAW 264.7 macrophages

J. Immunol.

Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation

J. Exp. Med.

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