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

Proinflammatory cytokine-mediated pancreatic beta-cell dysfunction is a key pathological event in type I diabetes mellitus. Lisofylline (LSF), an anti-inflammatory agent, has been shown to protect pancreatic islets from IL-1 beta-induced inhibitory effects on insulin release. However, the mechanism of LSF action is not known. Increasing evidence suggests that the mitochondria play an important role in regulating the beta-cell insulin release capacity and the control of cellular viability. To examine the direct effects of LSF on beta-cells, insulin-secreting INS-1 cells were exposed to a combination of recombinant IL-1 beta, TNF alpha, and IFN gamma with or without LSF for 18 h. Basal and glucose-stimulated static insulin release were measured using RIA. INS-1 cell viability was determined using in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and LIVE/DEAD dual fluorescence labeling. To evaluate INS-1 mitochondrial function, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolism, change in mitochondrial membrane potential, and intracellular ATP levels were assessed. Cytokine addition reduced basal (7.8 +/- 0.30 vs. 10.0 +/- 0.46 ng/ml.h; P < 0.005), glucose-stimulated insulin secretion (11.6 +/- 0.86 vs. 17.4 +/- 1.86 ng/ml.h; P < 0.005), and MTT metabolism in INS-1 cells. Over 40% of the cytokine-treated beta-cells exhibited nuclear DNA breakage, whereas the control cell death rate remained at 1-2%. Simultaneous application of LSF and cytokines to INS-1 cells restored insulin secretion, MTT metabolism, mitochondrial membrane potential, and cell viability to control levels. LSF increased beta-cell MTT metabolism as well as insulin release and glucose responsiveness. In summary, proinflammatory cytokines lead to a reduction of glucose-induced insulin secretion, mitochondrial activity, and viability in INS-1 cells. LSF at concentrations achievable in vivo protected beta-cells from the cytokine effects. The mechanism of LSF-induced protection may be by promoting mitochondrial metabolism.
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PMID:Lisofylline, a novel antiinflammatory agent, protects pancreatic beta-cells from proinflammatory cytokine damage by promoting mitochondrial metabolism. 1202 Nov 99

Increased levels of IFN-alpha have been found in patients with type 1 diabetes who have detectable levels of coxsackievirus B4 (CVB4) RNA in their blood. The IFN-alpha-inducing activity of CVB4 in vitro is weak but can be enhanced by human IgGs. Therefore, it was investigated in vitro whether a preferential IFN-alpha response of peripheral blood mononuclear cells (PBMCs) to CVB4 exists in patients with type 1 diabetes (n=56) compared with healthy subjects (n=20) and whether antibodies play a role. In patients, the levels of IFN-alpha obtained after stimulation by PBMCs with CVB4 were higher (P=0.008), an individual IFN-alpha response by PBMCs to CVB4 was more frequent (P=0.0004) and increased levels of IFN-alpha were observed in CVB4-infected whole blood cultures. The IFN-alpha-inducing activity of patients plasma and IgGs mixed with CVB4 and then added to PBMCs was high in comparison with healthy subjects (P<0.001) and was inhibited by preincubating the cells with anti-FcgammaRII, anti-FcgammaRIII and anti-CAR (coxsackievirus and adenovirus receptor) antibodies. The strong IFN-alpha responsiveness of PBMCs to CVB4 suggested that IgGs bound to the cell surface might play a role. A short 56 degrees C incubation of PBMCs from patients responsive to CVB4 generated supernatants, which, when added to cells, exhibited IFN-alpha-enhancing activity in combination with CVB4, whereas those of controls did not. Specific antibodies for FcgammaRI, FcgammaRII and CAR inhibited this activity. These studies demonstrate that CVB4, through interactions with circulating and/or cell-bound IgGs, can strongly induce the production of IFN-alpha by PBMCs from patients with type 1 diabetes.
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PMID:Circulating and cell-bound antibodies increase coxsackievirus B4-induced production of IFN-alpha by peripheral blood mononuclear cells from patients with type 1 diabetes. 1218 70

Therapeutic antibodies directed against tumor necrosis factor alpha (TNF-alpha) for the treatment of rheumatoid arthritis, and against the human EGF receptor-2 (HER2) receptor for the treatment of breast cancer have provided significant clinical benefit for the patients. The success of these antibodies has also provided strong support for the possibility that increased activity of cytokines or growth factors is causally implicated in a variety of human diseases. Interferon alpha (IFN-alpha) is induced by viruses (linked by epidemiological studies to autoimmune diseases), has significant direct effects on both epithelial cells and the immune system, and then can be further induced by the autoantibodies and apoptotic cells generated by the actions of IFN-alpha. The direct and deleterious impact on target tissues, the ability to induce an autoimmune response, and the potential for a self-sustaining cycle of induction and damage suggests that IFN-alpha could be a pivotal factor in the development of autoimmune diseases. This review will evaluate the rationale for, possible approaches to, and safety concerns associated with, targeting interferon alpha (IFN-alpha) as a therapeutic strategy for the treatment of autoimmune diseases. While the approach may be applicable to several autoimmune diseases, there will be an emphasis on systemic lupus erythematosus and insulin dependent diabetes mellitus.
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PMID:Neutralizing interferon alpha as a therapeutic approach to autoimmune diseases. 1265 Dec 25

It has been suggested that class I and class II MHC are contributing factors for numerous diseases including autoimmune thyroid diseases, type 1 diabetes, rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis. The class II trans-activator (CIITA), which is a non-DNA-binding regulator of class II MHC transcription, regulates the constitutive and inducible expression of the class I and class II genes. FRTL-5 thyroid cells incubated in the presence of IFN-gamma have a significantly higher level of cell surface rat MHC class II RTI.B. However, the IFN-gamma-induced RT1.B expression was suppressed significantly in cells incubated in the presence of thyrotropin. Thyrotropin (TSH) represses IFN-gamma-induced CIITA expression by inhibiting type IV CIITA promoter activity through the suppression of STAT1 activation and IFN regulatory factor 1 induction. This study found that TSH induces transcriptional activation of the STAT3 gene through the phosphorylation of STAT3 and CREB activation. TSH induces SOCS-1 and SOCS-3, and TSH-mediated SOCS-3 induction was dependent on STAT3. The cell line stably expressing the wild-type STAT3 showed a higher CIITA induction in response to IFN-gamma and also exhibited TSH repression of the IFN-gamma-mediated induction of CIITA. However, TSH repression of the IFN-gamma-induced CIITA expression was not observed in FRTL-5 thyroid cells, which stably expresses the dominant negative forms of STAT3, STAT3-Y705F, and STAT3-S727A. This report suggests that TSH is also engaged in immunomodulation through signal cross-talk with the cytokines in thyroid cells.
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PMID:Thyrotropin-mediated repression of class II trans-activator expression in thyroid cells: involvement of STAT3 and suppressor of cytokine signaling. 1284 26

IL-18 is now identified as a pleiotropic cytokine that acts as a cofactor for both Th1 and Th2 cell development. Type 1 diabetes is considered a Th1-type autoimmune disease, and to date, the suppressive effect of exogenous IL-18 on the development of diabetes has been reported in 10-wk-old nonobese diabetic (NOD) mice. In the present study we administered exogenous IL-18 systemically in 4-wk-old NOD mice using i.m. injection of the IL-18 expression plasmid DNA (pCAGGS-IL-18) with electroporation. Contrary to previous reports, the incidence of diabetes development was significantly increased in NOD mice injected with pCAGGS-IL-18 compared with that in control mice. Systemic and pancreatic cytokine profiles deviated to a Th1-dominant state, and the the frequency of glutamic acid decarboxylase-reactive IFN-gamma-producing CD4(+) cells was also high in the IL-18 group. Moreover, it was suggested that the promoting effect of IL-18 might be associated with increased peripheral IL-12, CD86, and pancreatic IFN-inducible protein-10 mRNA expression levels. In conclusion, we demonstrate here that IL-18 plays a promoting role as an enhancer of Th1-type immune responses in diabetes development early in the spontaneous disease process, which may contribute to elucidating the pathogenesis of type 1 diabetes.
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PMID:Systemic administration of IL-18 promotes diabetes development in young nonobese diabetic mice. 1463 96

Infection of the pancreas with lymphocytic choriomeningitis virus results in rapid and differential expression among CXCR3 chemokines. IFN-gamma-inducible protein of 10 kDa (IP-10), in contrast with monokine induced by IFN-gamma and IFN-inducible T cell-alpha chemoattractant, is strongly expressed within 24 h postinfection. Blocking of IP-10, but not monokine induced by IFN-gamma, aborts severity of Ag-specific injury of pancreatic beta cells and abrogates type 1 diabetes. Mechanistically, IP-10 blockade impedes the expansion of peripheral Ag-specific T cells and hinders their migration into the pancreas. IP-10 expression was restricted to viruses infecting the pancreas and that are capable of causing diabetes. Hence, virus-induced organ-specific autoimmune diseases may be dependent on virus tropism and its ability to alter the local milieu by selectively inducing chemokines that prepare the infected tissue for the subsequent destruction by the adaptive immune response.
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PMID:Among CXCR3 chemokines, IFN-gamma-inducible protein of 10 kDa (CXC chemokine ligand (CXCL) 10) but not monokine induced by IFN-gamma (CXCL9) imprints a pattern for the subsequent development of autoimmune disease. 1466 90

Thymus exerts a prominent role in the establishment os central T-cell tolerance, as well as in the development of self major histocompatibility complex (MHC)-restricted T lymphocytes. Like others autoimmune diseases, type 1 diabetes emergence implies central or peripheric self tolerance breakdown. Environmental factors, especially enterovirus infections, are supposed to be involved in diabetes pathophysiology. Epidemiological studies have highlighted a frequent association between enterovirus Coxsackievirus B4 (CVB4) and type 1 diabetes. The aim of our work was to study whether a thymus infection by CVB4 could induce modifications of thymic function. In primary cultures of thymic epithelial cells (TEC), we detected viral proteins, positive- and negative- strand RNA, and infectious virus in the supernatants, meaning that TEC cultures were susceptible to CVB4 infection and that CVB4 induced a persistent infection in those cells. CVB4 also modulated TEC proliferation and cytokine, such as IL-6, GM-CSF and LIF secretions. Studies using fetal organ thymus culture (FTOC) showed that CVB4 induced a marked and progressive thymocytes depletion, in particular double positive (DP) and CD4+ cells. CVB4 replicated in those subpopulations, indeed positive- and negative-atrand RNA were detected. CVB4 also upregulated MHC class I expression on DP thymocytes. The upregulation of MHC expression required viral infection in DP cells. IL-6 and GM-CSF secretions were also involved in this phenomenom, but IFN-alpha was shown not to be involved. Taken together, our results showed the susceptibility of the human thymus to CVB4 infection, and an important thymic dysfuntion due to this infection. Our work is a novel approach in the understanding of the mechanisms of CVB4-induced type 1 diabetes.
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PMID:[Demonstration and immunologic effect of an infection of the human thymus by the diabetogenic human Coxsackievirus B4]. 1502 68

The incidence of type 1 diabetes has been rapidly rising. Environmental factors such as viruses have been implicated as a possible agent accounting for this rise. Enteroviruses have recently been the focus in many research studies as a potential agent in the pathogenesis of type 1 diabetes. The mechanism of viral infection leading to beta cell destruction not only involves multiple pathways but also the cytokine-interferon alpha (IFN-alpha). Our hypothesis is that activation of toll receptors by double-stranded RNA or poly-IC (viral mimic) through induction of IFN-alpha may activate or accelerate immune-mediated beta cell destruction. Numerous clinical case reports have implicated that IFN-alpha therapy is associated with autoimmune diseases and that elevated serum IFN-alpha levels have been associated with type 1 diabetes. In multiple animal models, given specific genetic susceptibility, poly-IC can induce insulitis or diabetes. Therapeutic agents targeting IFN-alpha may potentially be beneficial in the prevention of type 1 diabetes and autoimmunity.
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PMID:Interferon alpha--a potential link in the pathogenesis of viral-induced type 1 diabetes and autoimmunity. 1518 43

Genetic and environmental factors are decisive in the etiology of type 1 diabetes. Viruses have been proposed as a triggering environmental event and some evidences have been reported: type I IFNs exist in the pancreata of diabetic patients and transgenic mice expressing these cytokines in beta cells develop diabetes. To determine the role of IFNbeta in diabetes, we studied transgenic mice expressing human IFNbeta in the beta cells. Autoimmune features were found: MHC class I islet hyperexpression, T and B cells infiltrating the islets and transfer of the disease by lymphocytes. Moreover, the expression of beta(2)-microglobulin, preproinsulin, and glucagon in the thymus was not altered by IFNbeta, thus suggesting that the disease is caused by a local effect of IFNbeta, strong enough to break the peripheral tolerance to beta cells. This is the first report of the generation of NOD (a model of spontaneous autoimmune diabetes) and nonobese-resistant (its homologous resistant) transgenic mice expressing a type I IFN in the islets: transgenic NOD and nonobese-resistant mice developed accelerated autoimmune diabetes with a high incidence of the disease. These results indicate that the antiviral cytokine IFNbeta breaks peripheral tolerance to beta cells, influences the insulitis progression and contributes to autoimmunity in diabetes and nondiabetes- prone mice.
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PMID:IFN beta accelerates autoimmune type 1 diabetes in nonobese diabetic mice and breaks the tolerance to beta cells in nondiabetes-prone mice. 1555 58

We have shown that neutralization of IFN-inducible protein 10/CXCL10, a chemokine for Th1 cells, breaks Th1 retention in the draining lymph nodes, resulting in exacerbation in Th1-dominant autoimmune disease models induced by immunization with external Ags. However, there have been no studies on the role of CXCL10 neutralization in Th1-dominant disease models induced by constitutive intrinsic self Ags. So, we have examined the effect of CXCL10 neutralization using a type 1 diabetes model initiated by developmentally regulated presentation of beta cell Ags. CXCL10 neutralization suppressed the occurrence of diabetes after administration with cyclophosphamide in NOD mice, although CXCL10 neutralization did not significantly inhibit insulitis and gave no influence on the trafficking of effector T cells into the islets. Because both CXCL10 and CXCR3 were, unexpectedly, coexpressed on insulin-producing cells, CXCL10 was considered to affect mature and premature beta cells in an autocrine and/or paracrine fashion. In fact, CXCL10 neutralization enhanced proliferative response of beta cells and resultantly increased beta cell mass without inhibiting insulitis. Thus, CXCL10 neutralization can be a new therapeutic target for beta cell survival, not only during the early stage of type 1 diabetes, but also after islet transplantation.
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PMID:CXC chemokine ligand 10 neutralization suppresses the occurrence of diabetes in nonobese diabetic mice through enhanced beta cell proliferation without affecting insulitis. 1555 99


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