Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the regulatory effects of decoy receptor 3 (DcR3) on the differentiation and function of dendritic cells (DCs), bone marrow-derived DCs (BM-DCs) from nonobese diabetic (NOD) mice were cultured with recombinant DcR3.Fc protein. Their differentiating phenotypes and T cell-stimulating functions were then evaluated. Expression of CD11c, CD40, CD54, and major histocompatibility complex I-A(g7) was reduced in cells cultured with additional DcR3.Fc, compared with DCs incubated with granulocyte macrophage-colony stimulating factor and interleukin (IL)-4, indicating that DcR3 interferes with the differentiation and maturation of BM-DCs. One of the most striking effects of DcR3.Fc on the differentiation of DCs was the up-regulation of CD86 and down-regulation of CD80, suggesting a modulatory potential to skew the T cell response toward the T helper cell type 2 (Th2) phenotype. Consistent with this, the proliferation of CD4(+) T cells cocultured with DcR3.Fc-treated DCs was significantly reduced compared with that of T cells stimulated by normal DCs. Moreover, the secretion of interferon-gamma from T cells cocultured with DcR3.Fc-treated DCs was profoundly suppressed, indicating that DcR3 exerts a Th1-suppressing effect on differentiating DCs. Furthermore, adoptive transfer experiments revealed that NOD/severe combined immunodeficiency mice received DcR3.Fc-treated DCs, and subsequently, autoreactive T cells showed delayed onset of diabetes and a decrease in diabetic severity compared with mice that received normal DCs and T cells, suggesting a future therapeutic potential in autoimmune diabetes. Data from two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight analysis show an up-regulation of some proteins-such as mitogen-activated protein kinase p38 beta, cyclin-dependent kinase 6, and signal-induced proliferation-associated gene 1-and a down-regulation of the IL-17 precursor; tumor necrosis factor-related apoptosis-inducing ligand family member-associated nuclear factor-kappaB activator-binding kinase 1; and Golgi S-nitroso-N-acetylpenicillamine in cells treated with DcR3, further demonstrating its effect on DC differentiation and function.
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PMID:Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication. 1463 66

The influence of the proinflammatory cytokine interleukin (IL)-17 on inducible nitric oxide (NO) synthase (iNOS)-mediated NO release was investigated in the mouse insulinoma cell line MIN6 and mouse pancreatic islets. IL-17 markedly augmented iNOS mRNA/protein expression and subsequent NO production induced in MIN6 cells or pancreatic islets by different combinations of interferon-gamma, tumor necrosis factor-alpha, and IL-1beta. The induction of iNOS by IL-17 was preceded by phosphorylation of p38 mitogen-activated protein kinase (MAPK), and inhibition of p38 MAPK activation completely abolished IL-17-stimulated NO release. IL-17 enhanced the NO-dependent toxicity of proinflammatory cytokines toward MIN6 cells, while IL-17-specific neutralizing antibody partially reduced the NO production and rescued insulinoma cells and pancreatic islets from NO-dependent damage induced by activated T cells. Finally, a significant increase in blood IL-17 levels was observed in a multiple low-dose streptozotocin model of diabetes, suggesting that T cell-derived IL-17 might be involved in NO-dependent damage of beta cells in this disease.
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PMID:Interleukin-17 stimulates inducible nitric oxide synthase-dependent toxicity in mouse beta cells. 1626 Dec 64

IL-23, a proximal regulator of IL-17, may be a major driving force in the induction of autoimmune inflammation. We have used a model of subdiabetogenic treatment with multiple low doses of streptozotocin (MLD-STZ; 4 x 40 mg/kg body weight) in male C57BL/6 mice to study the effect of IL-23 on immune-mediated beta cell damage and the development of diabetes, as evaluated by blood glucose, quantitative histology, immunohistochemistry and expression of relevant cytokines in the islets. Ten daily injections of 400 ng IL-23, starting on the first day of MLD-STZ administration led to significant and sustained hyperglycemia along with weight loss compared with controls (no IL-23), and a significant increase in the number of infiltrating cells, a lower insulin content, enhanced apoptosis, expression of IFN-gamma and IL-17 (not seen in the controls) and a significant increase in the expression of TNF-alpha and IL-18 in the pancreatic islets. IL-23 treatment started 5 days prior to MLD-STZ administration had no effect on diabetogenesis or cytokines expression in the pancreatic islets. We provide the first evidence in an animal model that IL-23 is involved in the development of type-1 diabetes, by inducing IL-17 and possibly IFN-gamma production in the target tissue.
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PMID:IL-23 leads to diabetes induction after subdiabetogenic treatment with multiple low doses of streptozotocin. 1635 60

Recently, mouse models for latent (LTB) and slowly progressive primary tuberculosis (SPTB) have been established. However, cytokine profiles during the two models are not well established. Using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) we studied the expression levels of interleukin (IL)-2, IL-4, IL-10, IL-12, IL-15, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha during the course of LTB and SPTB in the lungs and spleens of B6D2F1Bom mice infected with the H37Rv strain of Mycobacterium tuberculosis (Mtb). The results show that, except for IL-4, cytokine expression levels were significantly higher during SPTB than LTB in both the lungs and spleens. During LTB, all the cytokines (except IL-2 in the lungs) had higher expression levels during the initial period of infection both in the lungs and spleens. During SPTB, the expression levels of IL-15 increased significantly from phases 1 to 3 in the lungs. The expression levels of IL-10, IL-12 and IFN-gamma increased significantly from 2 to 3 in the lungs. IL-10 and IL-15 increased significantly from phases 2 to 3, whereas that of TNF-alpha decreased significantly and progressively from phases 1 to 3 in the spleens. Over-expression of proinflammatory cytokines during active disease has been well documented, but factor(s) underlying such over-expression is not known. In the present study, there was a progressive and significant increase in the expression levels of IL-15, together with Th1 cytokines (IL-12 and IFN-gamma) during SPTB but a significant decrease during LTB. IL-15 is known to up-regulate the production of proinflammatory cytokines, IL-1beta, IL-8, IL-12, IL-17, IFN-gamma and TNF-alpha and has an inhibitory effect on activation-induced cell death. IL-15 is known to be involved in many proinflammatory disease states such as rheumatoid arthritis, sarcoidosis, inflammatory bowel diseases, autoimmune diabetes, etc. Our results, together with the above observations, suggest that IL-15 may play an important role in mediating active disease during Mtb infection.
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PMID:Cytokine profile during latent and slowly progressive primary tuberculosis: a possible role for interleukin-15 in mediating clinical disease. 1636 49

Chronic diseases, such as periodontal disease (PD) and rheumatoid arthritis (RA), are characterized by a robust immune response resulting in unresolved inflammation. Inflammation is mediated by proinflammatory cytokines; recently, a novel subset of T-helper (Th) cells was identified that plays a crucial role in inflammation and autoimmune disease. This population secretes several proinflammatory cytokines, including the novel cytokine interleukin (IL)-17, and, hence, has been termed "Th17." Inflammatory cytokines are implicated in the progression of localized chronic infections, such as PD, and in serious systemic pathologies, such as diabetes, chronic obstructive pulmonary disease, and cardiovascular disease. IL-17 mediates inflammation through a receptor (IL-17R) composed of two subunits, IL-17RA and IL-17RC. Drugs that antagonize inflammatory cytokines are used therapeutically to downregulate immune-mediated pathology in conditions such as RA, although not all patients respond well to this approach. Therefore, identification of potential novel therapeutic targets, such as the IL-17 signaling complex, may be clinically relevant for mitigating inflammatory pathology. However, the manner in which such a therapeutic may influence the onset and progression of PD is poorly understood. Therapeutics that antagonize inflammatory cytokines ameliorate inflammation and bone loss and may have broader implications for individuals with systemic diseases in which inflammation and autoimmunity predominate.
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PMID:Interleukin-17: a new paradigm in inflammation, autoimmunity, and therapy. 1753 23

A human T-cell receptor (TcR) derived from an autoreactive T-cell specific for GAD65, from a subject at high risk for autoimmune diabetes, was introduced into HLA-DR4 transgenic mice. The source of TcR was a CD4(+) T(H)1(+) T-cell clone which responded to an immunodominant epitope of the human islet protein GAD65, an epitope shared with both GAD65 and GAD67 in the mouse. The resulting HLA-DR4/GAD-TcR transgenic mice on a Rag2(o/o)/I-Ab(o/o)/B6 background exhibited a CD4(+) infiltrate into pancreatic islets that correlated with a loss of insulin in infiltrated islets. These mice also exhibited a subclinical impaired tolerance to exogenously fed glucose as assayed by an intraperitoneal glucose tolerance test. T cells containing the GAD65/67 (555-567) responsive TcR undergo strong negative selection as evidenced by a 10-fold lower thymocyte cellularity compared to non-TcR transgenic mice, and clonotype peripheral T cells represented approximately 1% of CD4(+) T cells in Rag2 sufficient mice. Upon in vitro stimulation, GAD65/67 555-567 responsive T cells secrete interferon-gamma, minimal interleukin (IL)-2 and tumor necrosis factor-alpha, and no IL-4, IL-5, IL-10, or IL-17, consistent with a T(H)1 profile. These data demonstrate that CD4(+) T cells specific for a naturally processed epitope within GAD can specifically home to pancreatic islets and lead to impaired islet beta-cell function in diabetes-associated HLA-DR4 transgenic mice on the relatively non-autoimmune C57BL/6 background. The relatively slow progression and patchy insulitis are reminiscent of the chronic pre-clinical phase similar to a majority of human at-risk subjects, and models these indolent features of human T1D.
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PMID:Autoreactive human T-cell receptor initiates insulitis and impaired glucose tolerance in HLA DR4 transgenic mice. 1794 47

The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206-220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon gamma (IFNgamma) protect against passive TID. Because IFNgamma is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and beta-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNgamma that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNgamma led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNgamma induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17-producing cells.
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PMID:Innocuous IFNgamma induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production. 1819 74

Perivascular adipose tissue AT is a critical regulator of vascular function, which until recently has been greatly overlooked. Virtually all arteries are surrounded by a significant amount of perivascular adipose tissue, which has long been considered to serve primarily a supportive, mechanical purpose. Recent studies show that both visceral and perivascular fat is a very active endocrine and paracrine source of inflammatory cytokines and adipokines. The latter include beneficial adipocytokines such as adiponectin or so far unidentified adipocyte derived relaxing factor (ADRF) as the presence of perivascular AT may decrease contractile responses to vasoconstrictive agents. However, in pathological states such as obesity, hypertension, diabetes metabolic syndrome and other cardiovascular disorders perivascular tissue becomes dysfunctional and production of protective factors diminishes while detrimental adipocytokines such as leptin, resistin, IL-6, TNF-alpha or IL-17 increases. Moreover the dysfunction of perivascular fat can lead to imbalance between vascular nitric oxide (NO) and superoxide production. Adipokines also regulate immune system as chemokines (such as MIP-1 or RANTES) and induce inflammation with infiltration of T cells and macrophages to the vessel wall. Interestingly central nervous system can affect vascular function through mediation of perivascular adipose tissue dysfunction. In particular sympathetic nervous system endings are present in both visceral and perivascular AT. This powerful relationship between the brain and the vessel can be termed "brain-vessel axis" in which--we propose in the Review--perivascular adipose tissue may take center stage. The role of perivascular fat in the regulation of blood vessels depends on metabolic state, inflammation and clinical risk factors. In health protective and vasorelaxant properties of perivascular AT dominate while in pathology pathogenetic influences including neural stimulation of sympathetic nerve endings or humoral effects of certain hormones and adipocytokines dominates. We propose to term this state "perivascular adipose tissue dysfunction" in similarity to endothelial dysfunction.
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PMID:Perivascular adipose tissue as a messenger of the brain-vessel axis: role in vascular inflammation and dysfunction. 1819 75

The impressive correlation between cardiovascular disease and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes may share common antecedents. Inflammation is emerging as a conceivable etiologic mechanism for both. Interleukins are regulatory proteins with ability to accelerate or inhibit inflammatory processes, and matrixins are prepro enzymes responsible for the timely breakdown of extracellular matrix. Interleukins (ILs) are classified based on their role in diabetes and atherosclerosis, hypothesizing that each interleukin acts on both diseases in the same direction - regardless if harmful, favorable or neutral. They are clustered into three groups: noxious (the 'bad', 8 members), comprising IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-17 and IL-18; protective (the 'good', 5 members), comprising IL-4, IL-10, IL-11, IL-12 and IL-13; and 'aloof' , comprising IL-5, IL-9, IL-14, IL-16 and IL-19 through IL-29 (15 members). Each group presented converging effects on both diseases. IL-3 was reluctant to clustering and IL-30 through 33 were not included due to the scarce available data. It may be seen that (1) favorable effects of a given interleukin on either diabetes or atherosclerosis predicts similar effects on the other; (2) equally, harmful interleukin effects on one disease can be extrapolated to the other, and (3) absence of influence of a given interleukin on one of these diseases forecasts lack of effects on the other. Matrixins seem to present a similar pathophysiological pattern. These facts further support the unifying etiologic theory of diabetes and heart disease, emphasizing the importance of a cardiovascular diabetologic approach to these cytokines for future research. A pharmacologic simultaneous targeting of interleukins and matrixins might provide an effective means to concurrently control both atherosclerosis and diabetes.
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PMID:Biomarkers in cardiovascular diabetology: interleukins and matrixins. 1823 Sep 55

Burkholderia pseudomallei is the causative agent of melioidosis. One of the main risk factors for B. pseudomallei infection in endemic areas is diabetes mellitus. The present study investigated IL-17 mRNA and protein expression by peripheral blood mononuclear cells in response to B. pseudomallei infection in 10 diabetic patients in comparison to 10 healthy blood donors. The IL-17 expression in diabetic patients was significantly lower (p < 0.05) than in the controls. However, IL-23 mRNA expression of the 2 groups was comparable. The present findings suggest that melioidosis affects T cell IL-17 production and that patients with diabetes mellitus have a defective IL-17 production in response to this type of infection.
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PMID:Reduced interleukin-17 expression of Burkholderia pseudomallei-infected peripheral blood mononuclear cells of diabetic patients. 1859 31


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