In situ islet cytokine gene expression during development of type I diabetes in the non-obese diabetic mouse

Toyoda, Hiroo; Formby, Bent; Magalong, D.; Redford, Andreea; Chan, Erwin; Takei, Shinichiro; Charles, M. Arthur

doi:10.1016/0165-2478(94)90170-8

Cited by 31 publications

(23 citation statements)

References 24 publications

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“…Proinflammatory cytokines can induce or accelerate the recurrence of autoimmune process (16,34,35), whereas the inhibition of inflammatory pathways suppresses cytokine secretion and improves islet graft function (36). The relevance of our in vitro studies to the clinical islet transplant setting is supported by studies from Piemonti et al (18) showing an inverse correlation between MCP-1 protein expression in isolated human islets and clinical outcomes.…”

Section: Discussionsupporting

confidence: 62%

CD40–CD40 Ligand Interaction Activates Proinflammatory Pathways in Pancreatic Islets

et al. 2006

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Pancreatic islet transplantation is becoming an alternative to insulin therapy in patients suffering from brittle type 1 diabetes. A major obstacle to the procedure is the early graft loss caused by nonspecific inflammation at the site of implantation. We recently discovered that CD40, a member of tumor necrosis factor (TNF) receptor family, is expressed in pancreatic ␤-cells. CD40 expression in nonhematopoietic cells is generally associated with inflammation. Therefore, we investigated the potential proinflammatory role of CD40 in human and nonhuman primate islets.

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Section: Discussionsupporting

confidence: 62%

CD40–CD40 Ligand Interaction Activates Proinflammatory Pathways in Pancreatic Islets

et al. 2006

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“…In the early stages of insulitis, at 2 and 4 weeks of age, the mild IFN-g mRNA expression in islets and spleen coincides with the low number of activated T cells in pancreatic islets (24,26,34). However, with the increase of infiltrating T cells in islets the level of IFN-g expression increases in older mice after 14 weeks of age, associated with destructive insulitis (21,24,32).…”

Section: Discussionmentioning

confidence: 99%

Kinetics of TNF-alpha and IFN-gamma mRNA expression in islets and spleen of NOD mice

Ventura-Oliveira

Vilella

Zanin

et al. 2002

Braz J Med Biol Res

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Insulin-dependent diabetes mellitus is caused by autoimmune destruction of pancreatic ß cells. Non-obese diabetic (NOD) mice spontaneously develop diabetes similar to the human disease. Cytokines produced by islet-infiltrating mononuclear cells may be directly cytotoxic and can be involved in islet destruction coordinated by CD4+ and CD8+ cells. We utilized a semiquantitative RT-PCR assay to analyze in vitro the mRNA expression of TNF-a and IFN-g cytokine genes in isolated islets (N = 100) and spleen cells (5 x 10 5 cells) from female NOD mice during the development of diabetes and from female CBA-j mice as a related control strain that does not develop diabetes. Cytokine mRNAs were measured at 2, 4, 8, 14 and 28 weeks of age from the onset of insulitis to the development of overt diabetes. An increase in IFN-g expression in islets was observed for females aged 28 weeks (149 ± 29 arbitrary units (AU), P<0.05, Student t-test) with advanced destructive insulitis when compared with CBA-j mice, while TNF-a was expressed in both NOD and CBA-j female islets at the same level at all ages studied. In contrast, TNF-a in spleen was expressed at higher levels in NOD females at 14 weeks (99 ± 8 AU, P<0.05) and 28 weeks (144 ± 17 AU, P<0.05) of age when compared to CBA-j mice. The data suggest that IFN-g and TNF-a expression in pancreatic islets of female NOD mice is associated with ß cell destruction and overt diabetes.

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“…CD40 expression is upregulated by proinflammatory cytokines We treated human islets with a combination of proinflammatory cytokines that are reportedly associated with beta cell damage in autoimmune diabetes [37,38]. Overnight incubation with a combination of IL-1β (5×10 4 U/l), IFN-γ (10 6 U/l) and TNF-α (10 6 U/l) upregulated CD40 expression in human beta cells (7-AADnegative/NG-bright positive) as shown by an increase in the median fluorescence intensity from 37.5±2.9 in control cells to 67.3±6.8 in the cytokine-treated cells (p=0.02) (Fig.…”

Section: Cd40 Receptor Is Expressed On the Surface Of Mouse Islet Cellsmentioning

confidence: 99%

A functional CD40 receptor is expressed in pancreatic beta cells

et al. 2005

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Aims/hypothesis: Despite differences in function and embryonic origin, pancreatic islet cells and neurons express proteins belonging to the tumour necrosis factor receptor superfamily. While neurons express the CD40 receptor, it is unknown whether islet cells also express it. We investigated CD40 expression in human and mouse pancreatic islets as well as in NIT-1 insulinoma cells. Methods: CD40 expression was studied by reverse transcriptase polymerase chain reaction, flow cytometry, immunohistochemistry and western blot. Responses mediated by CD40 were assessed by a luciferase gene reporter assay following stimulation with a CD40 agonist antibody. Results: We found that CD40 is expressed in mouse and human pancreatic islet cells. CD40 is expressed by beta cells, and its expression is upregulated by proinflammatory cytokines (IL-1β, IFN-γ and TNF-α). CD40 signalling in NIT-1 insulinoma cells activates nuclear factor kappa-B, demonstrating that CD40 is functional. Conclusions/ interpretation: We present evidence that, in addition to immune cell types, mouse and human pancreatic beta cells express CD40. Its expression is upregulated by proinflammatory stimuli, and signalling through this receptor activates NF-κB. We suggest that the effects of inflammatory stimuli that affect beta cell function and survival may be also mediated by signalling through the CD40 receptor. Thus, CD40 may have a role in processes associated with islet autoimmunity and transplantation.

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In situ islet cytokine gene expression during development of type I diabetes in the non-obese diabetic mouse

Cited by 31 publications

References 24 publications

CD40–CD40 Ligand Interaction Activates Proinflammatory Pathways in Pancreatic Islets

CD40–CD40 Ligand Interaction Activates Proinflammatory Pathways in Pancreatic Islets

Kinetics of TNF-alpha and IFN-gamma mRNA expression in islets and spleen of NOD mice

A functional CD40 receptor is expressed in pancreatic beta cells

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