IL-1 Receptor Deficiency Slows Progression to Diabetes in the NOD Mouse

Thomas, Helen E.; Irawaty, Windy; Darwiche, Rima; Brodnicki, Thomas C.; Santamaría, Pere; Allison, Janette; Kay, Thomas

doi:10.2337/diabetes.53.1.113

Cited by 119 publications

(103 citation statements)

References 55 publications

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“…In addition, IL-1b dramatically decreased the production of the insulinsensitizing adipokine adiponectin in 3T3-L1 adipocytes and in human primary fat cells (Lagathu et al 2006). Consistent with these findings, Thomas and co-workers have shown that IL-1 receptor-deficient non-obese diabetic mice were partially protected from the development of T2DM (Thomas et al 2004). Furthermore, blockage of IL-1 signaling with anakinra, a recombinant human IL-1 receptor antagonist, improved glycemic control in patients with T2DM most likely through improved secretory function of b-cells (Larsen et al 2007).…”

Section: Introductionsupporting

confidence: 71%

Tissue inhibitor of metalloproteinase-1 mRNA production and protein secretion are induced by interleukin-1β in 3T3-L1 adipocytes

Weise

Kralisch²,

Sommer³

et al. 2008

Journal of Endocrinology

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The adipokine tissue inhibitor of metalloproteinase (TIMP)-1 is upregulated when weight is gained and promotes adipose tissue development. In the present study, the effect of insulin resistance-inducing and proinflammatory interleukin (IL)-1b on TIMP-1 gene expression and secretion was investigated in 3T3-L1 adipocytes. Interestingly, protein secretion and mRNA production of TIMP-1 were significantly stimulated by IL-1b. Thus, IL-1b induced TIMP-1 secretion in a dosedependent manner with maximal 3 . 5-fold upregulation seen at 0 . 67 ng/ml IL-1b relative to untreated cells. Furthermore, TIMP-1 mRNA synthesis was significantly stimulated by IL-1b in a dose-dependent fashion with 2 . 5-fold induction seen at IL-1b concentrations as low as 0 . 02 ng/ml and maximal 8 . 1-fold upregulation found at 20 ng/ml effector.Induction of TIMP-1 mRNA was also time dependent with maximal 9 . 6-fold upregulation detectable after 8 h of IL-1b treatment. Signaling studies suggested that janus kinase 2 is involved in IL-1b-induced TIMP-1 mRNA expression. Taken together, our results demonstrate that the TIMP-1 expression is selectively upregulated by proinflammatory IL-1b, supporting a direct association between insulin resistance, inflammation, and adipose tissue development in obesity.

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Section: Introductionsupporting

confidence: 71%

Tissue inhibitor of metalloproteinase-1 mRNA production and protein secretion are induced by interleukin-1β in 3T3-L1 adipocytes

Weise

Kralisch²,

Sommer³

et al. 2008

Journal of Endocrinology

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“…These results are important given the role of IL-1␤ and NO in ␤-cell death and type 1 diabetes (15,20,32). For instance, IL-1␤ receptor deficiency slows the development of diabetes in NOD mice (33), whereas use of an IL-1␤ trap suppressed toxic effects of cytokine-mediated cytotoxicity (34). In addition, transgenic mice overexpressing iNOS specifically in ␤-cells develop spontaneous insulin-dependent diabetes (35), whereas iNOS-KO mice are resistant to MLDS-induced diabetes (36).…”

Section: Discussionmentioning

confidence: 99%

Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes

Emre

Hurtaud

Karaca

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Infiltration of inflammatory cells into pancreatic islets of Langerhans and selective destruction of insulin-secreting ␤-cells are characteristics of type 1 diabetes. Uncoupling protein 2 (UCP2) is a mitochondrial protein expressed in immune cells. UCP2 controls macrophage activation by modulating the production of mitochondrial reactive oxygen species (ROS) and MAPK signaling. We investigated the role of UCP2 on immune cell activity in type 1 diabetes in Ucp2-deficient mice. Using the model of multiple low-dose streptozotocin (STZ)-induced diabetes, we found that autoimmune diabetes was strongly accelerated in Ucp2-KO mice, compared with Ucp2-WT mice with increased intraislet lymphocytic infiltration. Macrophages from STZ-treated Ucp2-KO mice had increased IL-1␤ and nitric oxide (NO) production, compared with WT macrophages. Moreover, more macrophages were recruited in islets of STZ-treated Ucp2-KO mice, compared with Ucp2-WT mice. This finding also was accompanied by increased NO/ROS-induced damage. Altogether, our data show that inflammation is stronger in Ucp2-KO mice and islets, leading to the exacerbated disease in these mice. Our results highlight the mitochondrial protein UCP2 as a new player in autoimmune diabetes.inflammation ͉ nitric oxide M itochondria are important organelles for cellular functions, including ATP synthesis. Oxidative glucose metabolism in pancreatic ␤-cells increases the ATP/ADP ratio, leading to insulin release. Uncoupling protein 2 (UCP2) is a mitochondrial carrier protein expressed in pancreatic ␤-cells (1, 2) and immune cells (3,4).In pancreatic ␤-cells, UCP2 was reported to alter the yield of ATP synthesis from glucose, and it has been proposed as a negative regulator of glucose-stimulated insulin secretion (2). In other respects, there is much evidence for the influence of UCP2 on immune responses. First, Ucp2-KO mice exhibit increased resistance to a Toxoplasma gondii or Listeria monocytogenes infection (4, 5). Second, in an LDL receptor-null background, Ucp2-KO mice develop greater and more unstable atherosclerotic plaques than WT mice (6). Third, in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis, Ucp2-KO mice develop higher disease scores than Ucp2-WT mice (7). We showed that UCP2 regulates LPS-induced reactive oxygen species (ROS) signaling in macrophages (8). MAPK activation in Ucp2-KO macrophages is quicker and stronger than in WT macrophages (8), leading to increased nitric oxide (NO), cytokine production, and migration ability (8, 9). Consistent with these findings, overexpression of UCP2 in macrophages is associated with diminished NO production (10) and decreased migration capacity (11).Given the evidence for a role of UCP2 in the immune system, in macrophages, and in ␤-cell function, we investigated whether UCP2 affects the development of autoimmune diabetes by using the model of multiple low-dose of streptozotocin (STZ). In this report, we show that the absence of UCP2 renders animals more sensitive to the onset of diabetes in mice....

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“…Evidence for the role of IL-1β in in vivo beta-cell killing was provided in IL-1R deficient NOD mice, which present a delayed onset of diabetes (34). Moreover, blocking IL-1 signaling with an IL-1 receptor antagonist delays the onset of diabetes in NOD mice, prevents the induction of diabetes by multiple low doses of streptozotocin, prolongs mouse islet allograft survival and prevents the recurrence of hyperglycemia in diabetic NOD mice following islet transplantation (27).…”

Section: Beta-cell Death In T1dmentioning

confidence: 97%

Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes

Pirot

Cardozo

Eizirik

2008

Arq Bras Endocrinol Metab

136

113

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type 1 diabetes mellitus (t1d) is characterized by severe insulin deficiency resulting from chronic and progressive destruction of pancreatic beta-cells by the immune system. the triggering of autoimmunity against the beta-cells is probably caused by environmental agent(s) acting in the context of a predisposing genetic background. once activated, the immune cells invade the islets and mediate their deleterious effects on beta-cells via mechanisms such as Fas/Fasl, perforin/granzyme, reactive oxygen and nitrogen species and pro-inflammatory cytokines. Binding of cytokines to their receptors on the beta-cells activates MAP-kinases and the transcription factors stAt-1 and nFκ-B, provoking functional impairment, endoplasmic reticulum stress and ultimately apoptosis. this review discusses the potential mediators and mechanisms leading to beta-cell destruction in t1d. Keywords: Pancreatic beta-cell; diabetes mellitus; Apoptosis; cytokines; endoplasmic reticulum; er stress RESuMOMecanismos de Destruição e Morte da Célula-beta Pancreática no Diabetes. o diabetes melito tipo 1 (dM1) tem como característica uma grave deficiência de insulina que resulta da destruição da célula-beta, crônica e progressiva, pelo sistema imune. o desencadeamento da autoimunidade contra a célula-beta é causado, provavelmente, por agentes ambientais que atuam quando existe predisposição genética. uma vez ativadas, células imunes invadem as ilhotas, e os efeitos deletérios sobre as células-beta são mediados por mecanismos relacionados a Fas/Fasl, perforina/granzima, espécies reativas de oxigênio e nitrogênio, e a citocinas pró-inflamatórias. A ligação de citocinas a seus receptores na célula-beta ativa MAP-quinase e fatores de transcrição stAt-1 e nFkB, provocando prejuízo funcional, estresse de retículo endoplasmático e, por fim, apoptose. esta revisão discute os mecanismos e os mediadores potenciais que levam à destruição da célula-beta no dM1. Descritores: célula-beta pancreática; diabetes melito; Apoptose; citocinas; estresse do retículo endoplasmático thE GENEtic BAcKGROuND Of typE 1 DiABEtES MEllituS (t1D)

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IL-1 Receptor Deficiency Slows Progression to Diabetes in the NOD Mouse

Cited by 119 publications

References 55 publications

Tissue inhibitor of metalloproteinase-1 mRNA production and protein secretion are induced by interleukin-1β in 3T3-L1 adipocytes

Tissue inhibitor of metalloproteinase-1 mRNA production and protein secretion are induced by interleukin-1β in 3T3-L1 adipocytes

Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes

Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes

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