Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas-mediated cell death may play a role in the autoimmune destruction of pancreatic beta-cells in type 1 diabetes. beta-Cells do not express Fas under physiological conditions, but Fas mRNA and protein are induced in cytokine-exposed mouse and human islets, rendering the beta-cells susceptible to Fas ligand-induced apoptosis. The aim of the present study was to investigate the molecular regulation of Fas by cytokines in rat beta-cells and in insulin-producing RINm5F cells. Fas mRNA expression was increased 15-fold in fluorescence-activated cell sorting-purified rat beta-cells exposed to interleukin (IL)-1beta, whereas gamma-interferon had no effect. Transfection experiments of rat Fas promoter-luciferase reporter constructs into purified rat beta-cells and RINm5F insulinoma cells identified an IL-1beta-responsive region between nucleotides -223 and -54. Inactivation of two adjacent NF-kappaB and C/EBP sites in this region abolished IL-1beta-induced Fas promoter activity in RINm5F cells. Binding of NF-kappaB and C/EBP factors to their respective sites was confirmed by gel shift assays. In cotransfection experiments, NF-kappaB p65 transactivated the Fas promoter. NF-kappaB p50 and C/EBPbeta overexpression had no effect by themselves on the Fas promoter activity, but when cotransfected with p65, each factor inhibited transactivation by p65. These results suggest a critical role for NF-kappaB and C/EBP factors in cytokine-regulation of Fas expression in insulin-producing cells.
 ...
PMID:Cytokine induction of Fas gene expression in insulin-producing cells requires the transcription factors NF-kappaB and C/EBP. 1147 33

Activation of the transcription factor nuclear factor-kappaB (NF-kappaB) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-kappaB in vitro, we observed a long-lasting sustained activation of NF-kappaB in the absence of decreased IkappaBalpha in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-kappaBp65. A comparable increase in NF-kappaBp65 antigen and mRNA was also observed in vascular endothelial cells of diabetic rats. As a mechanism, we propose that binding of ligands such as advanced glycosylation end products (AGEs), members of the S100 family, or amyloid-beta peptide (Abeta) to the transmembrane receptor for AGE (RAGE) results in protein synthesis-dependent sustained activation of NF-kappaB both in vitro and in vivo. Infusion of AGE-albumin into mice bearing a beta-globin reporter transgene under control of NF-kappaB also resulted in prolonged expression of the reporter transgene. In vitro studies showed that RAGE-expressing cells induced sustained translocation of NF-kappaB (p50/p65) from the cytoplasm into the nucleus for >1 week. Sustained NF-kappaB activation by ligands of RAGE was mediated by initial degradation of IkappaB proteins followed by new synthesis of NF-kappaBp65 mRNA and protein in the presence of newly synthesized IkappaBalpha and IkappaBbeta. These data demonstrate that ligands of RAGE can induce sustained activation of NF-kappaB as a result of increased levels of de novo synthesized NF-kappaBp65 overriding endogenous negative feedback mechanisms and thus might contribute to the persistent NF-kappaB activation observed in hyperglycemia and possibly other chronic diseases.
 ...
PMID:Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. 1172 63

Pancreatic beta-cells are selectively destroyed during the course of type 1 diabetes. In the early stages of the disease, inflammatory infiltrates of mononuclear cells, containing predominantly monocytes and T-cells, are present in the islets (insulitis). Chemokines, such as monocyte chemoattractant protein-1 (MCP-1), play a key role in the recruitment and activation of these immunocytes. We have previously described cytokine-induced MCP-1 gene expression in human and rat pancreatic islets. In the present study, the transcriptional regulation by cytokines of the rat MCP-1 gene in fluorescence-activated cell sorting-purified rat beta-cells, insulin-producing INS-1E cells, and RINm5F cells was investigated. Transient transfections with luciferase-reporter constructs identified an interleukin (IL)-1beta-responsive enhancer region between -2,180 bp and -2,478 bp. Mutation of either of the two nuclear factor (NF)-kappaB sites present in this region abrogated IL-1beta-induced MCP-1 promoter activity. Binding of NF-kappaB to the two sites was shown in vitro by gel shift assays, while supershift assays revealed the presence of p65/p50 heterodimers and p65 homodimers. In vivo binding of NF-kappaB was confirmed by chromatin immunoprecipitation assay. Blocking of NF-kappaB activation in cytokine-exposed primary beta-cells by an adenovirus overexpressing a nondegradable form of IkappaBalpha or by pyrrolidine dithiocarbamate decreased IL-1beta-induced MCP-1 mRNA expression. We conclude that NF-kappaB plays an important role for MCP-1 expression in beta-cells. This transcription factor may be an interesting target for ex vivo gene therapy before islet transplantation.
 ...
PMID:Molecular regulation of monocyte chemoattractant protein-1 expression in pancreatic beta-cells. 1254 Jun 7

Recent studies incriminating tumor necrosis factor (TNF)-alpha as the final effector in pancreatic beta-cell death in type 1 diabetes underscore the potential role of TNF-alpha-dependent NF-kappaB activation as an important modulator of pancreatic beta-cell death in autoimmune diabetes. Although nuclear factor (NF)-kappaB activation has been implicated in the protection of target cells against apoptosis by a variety of death effectors, its role in pancreatic islet cell death is not clear. We studied the role of NF-kappaB activation in pancreatic islet cell death by using a gamma-interferon (IFN-gamma)/TNF-alpha synergism model we had previously reported. TNF-alpha induced inhibitor of kappaB (IkappaB) degradation and p65 translocation from cytoplasm to nuclei in MIN6N8 insulinoma cells. The NF-kappaB DNA-binding nuclear complex activated by TNF-alpha contained both the p65 and p50 subunit. IFN-gamma pretreatment did not affect TNF-alpha-induced NF-kappaB activation. Treatment with a proteasome inhibitor blocked p65 translocation and induced susceptibility to TNF-alpha in otherwise resistant insulinoma cells or primary pancreatic islet cells. Specific inhibition of NF-kappaB activation by adenoviral transduction of IkappaB "superrepressor" also sensitized insulinoma cells and primary islet beta-cells to TNF-alpha-induced apoptosis. These results suggest the protective role of NF-kappaB activation against cytokine-mediated pancreatic beta-cell death, contrary to previous reports implicating NF-kappaB as a mediator of pancreatic islet cell death.
 ...
PMID:Nuclear factor kappaB protects pancreatic beta-cells from tumor necrosis factor-alpha-mediated apoptosis. 1271 48

During the development of type 1 diabetes, pancreatic beta-cells are subject to an immune attack, leading to their apoptotic or necrotic cell death. Apoptotic beta-cells are also present during periods of tissue remodeling, such as in early life. Macrophages should clear apoptotic cells silently without production of pro-inflammatory cytokines. The aim of the present study was to investigate the cytokine pattern of NOD macrophages exposed to apoptotic or necrotic cells in vitro. In contrast to the limited response of macrophages from C57BL/6 or NOR mice, NOD macrophages reacted aberrantly to both necrotic and apoptotic cells, with secretion of inappropriately high amounts of IL1beta and TNFalpha. Further exploration of the macrophage behavior showed an excessive response of NOD macrophages when exposed to LPS (high iNOS and IL12p40 levels), accompanied by hyper-activation of NF-kappaB(p65). In contrast, NOD macrophages failed to up-regulate IL1beta and IL12p40 in response to IFNgamma. This failure correlated with low protein levels and a low phosphorylation state of STAT1alpha. We conclude that NOD macrophages have severely aberrant cytokine expression patterns that could contribute to the initiation or continuation of an immune attack towards the pancreatic beta-cells and thus onset and progression of type 1 diabetes.
 ...
PMID:NOD macrophages produce high levels of inflammatory cytokines upon encounter of apoptotic or necrotic cells. 1523 48

Nuclear and mitochondrial genomes combine in ALR/Lt mice to produce systemically elevated defenses against free radical damage, rendering these mice resistant to immune-mediated pancreatic islet destruction. We analyzed the mechanism whereby isolated islets from ALR mice resisted proinflammatory stress mediated by combined cytokines (IL-1beta, TNF-alpha, and IFN-gamma) in vitro. Such damage entails both superoxide and NO radical generation, as well as peroxynitrite, resulting from their combination. In contrast to islets from other mouse strains, ALR islets expressed constitutively higher glutathione reductase, glutathione peroxidase, and higher ratios of reduced to oxidized glutathione. Following incubation with combined cytokines, islets from control strains produced significantly higher levels of hydrogen peroxide and NO than islets from ALR mice. Nitrotyrosine was generated in NOD and C3H/HeJ islets but not by ALR islets. Western blot analysis showed that combined cytokines up-regulated the NF-kappaB inducible NO synthase in NOD-Rag and C3H/HeJ islets but not in ALR islets. This inability of cytokine-treated ALR islets to up-regulate inducible NO synthase and produce NO correlated both with reduced kinetics of IkappaB degradation and with markedly suppressed NF-kappaB p65 nuclear translocation. Hence, ALR/Lt islets resist cytokine-induced diabetogenic stress through enhanced dissipation and/or suppressed formation of reactive oxygen and nitrogen species, impaired IkappaB degradation, and blunted NF-kappaB activation. Nitrotyrosylation of beta cell proteins may generate neoantigens; therefore, resistance of ALR islets to nitrotyrosine formation may, in part, explain why ALR mice are resistant to type 1 diabetes when reconstituted with a NOD immune system.
 ...
PMID:Mechanisms underlying resistance of pancreatic islets from ALR/Lt mice to cytokine-induced destruction. 1600 29

Cytokines, such as IL-1beta and TNF-alpha, contribute to pancreatic beta-cell death in type 1 diabetes mellitus. The transcription factor nuclear factor-kappaB (NF-kappaB) mediates cytokine-induced beta-cell apoptosis. Paradoxically, NF-kappaB has mostly antiapoptotic effects in other cell types. The cellular actions of NF-kappaB depend on the cell type, the nature and duration of the stimulus, the periodicity, and the degree of activity of the particular dimers involved. To clarify the reasons behind the proapoptotic effects of NF-kappaB in pancreatic beta-cells, we compared the pattern of cytokine-induced NF-kappaB activation between rat insulin-producing cells (INS-1E cells) and fibroblasts (208F cells). NF-kappaB activation was induced in INS-1E cells and in 208F cells after exposure to cytokines, but apoptosis was induced only in INS-1E cells, with a more pronounced proapoptotic effect of IL-1beta than of TNF-alpha. NF-kappaB activation in IL-1beta-exposed INS-1E cells was earlier and more marked as compared with TNF-alpha-exposed INS-1E cells or IL-1beta-exposed 208F cells. Both cytokines induced a prolonged (up to 48 h) and stable NF-kappaB activation in INS-1E cells, whereas IL-1beta induced an oscillatory NF-kappaB activation in 208F cells. p65/p65 and p65/p50 were the predominant NF-kappaB dimers in IL-1beta-exposed INS-1E cells and 208F cells, respectively. IL-1beta induced a differential usage of cis-elements in the inducible nitric oxide synthase promoter region in the two cell-lines and an increase in ERK1/2 activity in INS-1E cells but not in 208F cells. Cytokine-induced expression of IkappaB isoforms and other NF-kappaB target genes (Fas, MCP-1, and inducible nitric oxide synthase) was severalfold higher in INS-1E cells than in 208F cells. These results suggest that cytokine-induced NF-kappaB activation in insulin-producing cells is more rapid, marked, and sustained than in fibroblasts, which correlates with a more pronounced activation of downstream genes and a proapoptotic outcome.
 ...
PMID:Cytokine-induced proapoptotic gene expression in insulin-producing cells is related to rapid, sustained, and nonoscillatory nuclear factor-kappaB activation. 1655 31

The aim of this study was to investigate whether high glucose induces aldose reductase (AKR1B1) expression through NFkappaB, which may contribute to the pathogenesis of diabetic nephropathy. 34 Caucasoid patients with type 1 diabetes were recruited; 20 nephropaths and 14 long-term uncomplicated subjects. Peripheral blood mononuclear cells (PBMCs) were cultured under normal or high glucose (25 mmol/l of d-glucose) with or without an aldose reductase inhibitor (ARI). High glucose increased NFkappaB binding activities in the PBMCs from nephropaths compared to the uncomplicated subjects (1.77+/-0.22 vs. 1.16+/-0.04, p=0.02). ARI induced a substantially greater decrease of NFkappaB binding activities in the nephropaths compared to the uncomplicated subjects (0.58+/-0.06 vs. 0.79+/-0.06, p=0.032). AKR1B1 protein levels in the nephropaths were increased under high glucose conditions and decreased in the presence of an ARI, whilst the silencing of the NFkappaB p65 gene in vitro reduced the transcriptional activities of AKR1B1 in luciferase assays. These results show that NFkappaB induces AKR1B1expression under high glucose conditions, and the pattern of expression differs between nephropaths and the uncomplicated subjects.
 ...
PMID:High glucose induction of DNA-binding activity of the transcription factor NFkappaB in patients with diabetic nephropathy. 1832 49

Although Radix clematidis has commonly been used in Chinese medicine for the treatment of arthralgia, the anti-diabetic effects of Radix clematidis have not yet been reported. In the present study, we demonstrated that Radix clematidis extract (RCE) could prevent cytokine-induced beta-cell damage and streptozotocin (STZ)-induced diabetes in mice. Treatment of RINm5F insulinoma cells with interleukin-1beta and interferon-gamma reduced cell viability; however, RCE protected the cells from this cytokine-mediated viability reduction in a concentration-dependent manner. Additionally, incubation with RCE resulted in a significant suppression of cytokine-induced nitric oxide (NO) production, which was correlated with reduced levels of the inducible form of NO synthase (iNOS) mRNA and protein. The molecular mechanism by which RCE inhibited iNOS gene expression appeared to involve inhibition of NF-kappaB activation. Furthermore, RCE abolished the cytokine-induced increases in NF-kappaB binding activity and p65 subunit levels in the nucleus, as well as IkappaBalphadegradation in the cytosol when compared to unstimulated cells. The protective effect of RCE was further demonstrated by the observed suppression of NF-kappaB-dependent iNOS expression and normal insulin secreting responses to glucose in cytokines-treated islets. The anti-diabetic effect of RCE was even more striking in vivo, where nearly complete protection against STZ-induced diabetes was observed. Treatment of mice with STZ resulted in hyperglycemia and hypoinsulinemia, which was further evidenced by immunohistochemical staining; however, pretreatment of mice with RCE blocked the destruction of STZ-induced islets and the development of type 1 diabetes.
 ...
PMID:Radix clematidis extract protects against cytokine- and streptozotocin-induced beta-cell damage by suppressing the NF-kappaB pathway. 1869 94

In type 1 diabetes, dendritic cells (DCs) display defective phenotype and function and possibly play crucial roles in the pathogenesis of this disease. In the present study, we compared transcription profiles of CD11c(+) bone marrow (BM)-derived DCs from NOD mice with those from NON mice, focusing on the NF-kappaB/Rel family members and associated molecules. The BMDCs from NOD mice displayed reduced mRNA expressions of NF-kappaB components, p65, p50, p52, and RelB, compared to NON mice: the proportions of each molecule relative to those of NON DCs were 53.9, 54.1, 54.0, and 37.0%, respectively, which were accompanied with lowered expressions of downstream immunomodulatory molecules, including IL-6, CD80, CD86, 4-1BB, and CD40. The reduction of NF-kappaB components possibly underlies the defective phenotype and function of DCs from NOD mice, and could predispose to autoimmunity.
 ...
PMID:Lowered expressions of the NF-kappaB family members in dendritic cells from NOD mice are associated with a reduced expression of GATA-2. 1912 Feb 68


1 2 3 4 Next >>