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)

Interleukin-1 (IL-1) is a 17-kDa pro-inflammatory cytokine synthesized from a variety of cell types primarily in association with disease states or during host perturbation such as immune responses. At pM or even fM concentrations, IL-1 triggers various responses in nearly all cells. It appears that there is little or no major role for IL-1 in homoeostatic mechanisms. There are two IL-1's (alpha and beta) each with its distinct sequence; there are two IL-1 receptors. Disease states such as local and systemic infection, septic shock, degenerative arthritis and autoimmune diseases such as nephritis, vasculitis and inflammatory bowel disease appear to be mediated, in part, by IL-1. Organ failure, capillary leak and death occur in animals after a combination of tumour necrosis factor (TNF) and IL-1 which is more effective in inducing these changes than either cytokine alone. IL-1 is also a potent inducer of endothelial cell adhesion molecules, IL-6, and IL-8, a neutrophil chemotactic and activating factor. Strategies for reducing the effects of IL-1 have been based on suppression of transcription, translation, or secretion; more recently, receptor blockade has been a new approach. A naturally occurring IL-1-specific receptor antagonist (IL-1ra), which shares 40% conserved amino-acid homology with IL-1 beta, binds to IL-1 surface receptors with the same affinity as IL-1 but does not possess agonist activity and acts as a competitive inhibitor of IL-1. Studies using the IL-1ra to block endogenous IL-1 in a variety of animal disease models suggest that IL-1 plays a key role in triggering the cascade of inflammatory responses. In addition, the IL-1ra reduces the spontaneous production of growth factors and proliferation of leukaemic cells. The IL-1ra may be an advantageous therapy in patients with sepsis, diabetes, inflammatory bowel, arthritis and cancer.
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PMID:Reduction of inflammation by decreasing production of interleukin-1 or by specific receptor antagonism. 139 23

Most autoimmune diseases are HLA-associated which supports the notion that they are dependent upon specific immune activation of a limited set of T cell clones. Findings which imply that induction of autoimmune reactivity probably does not differ from normal immune responses are discussed. The possibility of transferring autoimmune disease using T cell clones indicates that target structures for auto-immune attack are also present in healthy individuals. In the present article, it is argued that autoimmune reactions and immunity against nominal conventional antigens in principle are effected and regulated by similar mechanisms. It is assumed that persistent tissue damage occurs if immune attack is directed against tissues that cannot be regenerated, such as in diabetes, or are only slowly reconstituted, such as in rheumatoid arthritis. Normal immune responses are regulated by various inflammatory mediators and cytokines/interleukins. The joint of patients with rheumatoid arthritis is discussed as a model for propagation of immune reactions and tissue destruction in autoimmune disease. Of the different cytokines which are present in the synovial fluid or produced by cells in the synovial tissue, most are presumed to have originated in macrophages/monocytes such as IL-1, IL-6, IL-8, TNF-alpha and TGF-beta. Even so, T cells are believed to have an important role for the continued reactivity associated with autoimmune disease. This discrepancy can be explained in different ways. T cell products might escape detection because they are short-lived, they are immediately consumed or they are produced only during short time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specific and non-specific autoreactive immunity. 150 34

Thyroid-associated orbitopathy (TAO) involves a remodelling of the connective tissue in the orbit, accumulation of the non-sulfated glycosaminoglycan, hyaluronan, and often intense inflammation. Orbital fibroblasts exhibit a remarkable susceptibility to various actions of pro-inflammatory cytokines and these molecular interactions we hypothesize are the basis for the peculiar tissue changes seen in ophthalmopathy, including the accumulation of hyaluronan. We have found that several pro-inflammatory cytokines can dramatically induce prostaglandin endoperoxide H synthase-2 (PGHS-2), the inflammatory cyclooxygenase, and that this induction results in a substantial increase in PGE2 production. The increase in cyclooxygenase expression and PGE2 synthesis can be blocked with glucocorticoids. The magnitude of the up-regulation of the prostanoid biosynthetic machinery in orbital fibroblasts from patients with ophthalmopathy was considerably greater than that found in dermal cultures or in orbital fibroblasts from normal tissue. Orbital fibroblasts, unlike most fibroblasts, express CD40 and when that surface receptor is cross-linked with CD154, its natural ligand, a number of inflammation-related genes are activated. These include IL-1alpha, IL-6, IL-8 and PGHS-2. It would appear that orbital fibroblasts, especially those from patients with ophthalmopathy, exhibit several exaggerated responses to pro-inflammatory signals and that those cellular actions could provide the molecular basis for orbital tissue remodelling.
Exp Clin Endocrinol Diabetes 1999
PMID:The putative role of prostaglandin endoperoxide H synthase-2 in the pathogenesis of thyroid-associated orbitopathy. 1061 12

The vascular endothelium influences not only the three classically interacting components of hemostasis: the vessel, the blood platelets and the clotting and fibrinolytic systems of plasma, but also the natural sequelae: inflammation and tissue repair. Two principal modes of endothelial behaviour may be differentiated, best defined as an anti- and a prothrombotic state. Under physiological conditions endothelium mediates vascular dilatation (formation of NO, PGI2, adenosine, hyperpolarizing factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI2, removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activation of protein C via thrombomodulin, activation of antithrombin III) and mitigates fibrin deposition (t- and scuplasminogen activator production). Adhesion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, glutathione, SOD). When the endothelium is physically disrupted or functionally perturbed by postischemic reperfusion, acute and chronic inflammation, atherosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is characterised by vaso-constriction, platelet and leukocyte activation and adhesion (externalization, expression and upregulation of von Willebrand factor, platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, etc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine, etc.) and, in platelet-leukocyte coaggregates, additional inflammatory interactions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial responses cannot be the goal of clinical interventions aimed at limiting procoagulatory, prothrombotic actions of a dysfunctional vascular endothelium.
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PMID:Endothelial function and hemostasis. 1079 71

To determine whether inflammatory cytokines are increased in proliferative diabetic retinopathy. We measured concentrations of interleukin-6, 8 (IL-6, 8) and tumor necrosis factor (TNF)-alpha by enzyme-linked immunosorbent assay (ELISA) in vitreous and serum from 47 patients with proliferative diabetic retinopathy and 21 patients with vitreous noninflammatory retinopathies. Vitreous concentration of IL-6 were 64.7+/-12.8 pg/ml in proliferative diabetic retinopathy, much greater (P<.005) than in noninflammatory retinopathy (2.8+/-4.5 pg/ml). Amounts of IL-8 in vitreous fluid also were greater in proliferative retinopathy than in noninflammatory retinopathy (34.0+/-11.5 vs. 6.1+/-2.0 pg/ml, P<.005). Concentrations of TNF-alpha in vitreous fluid were not statistically different in proliferative retinopathy from those in noninflammatory retinopathy. In sera, concentrations of IL-6 and IL-8 were not different between proliferative and noninflammatory retinopathy. However, serum TNF-alpha was much greater in proliferative retinopathy than in noninflammatory retinopathy (0.81+/-0.72 vs. 0.09+/-0.00 pg/ml, P<.001). Elevated TNF-alpha in serum then may be diagnostically useful in proliferative diabetic retinopathy. And inflammatory cytokines in vitreous may be pathogenically important in this concentration.
J Diabetes Complications
PMID:Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy. 1152

Hyperglycaemia, in insulin-dependent or independent diabetes mellitus, promotes endothelial cell (EC) dysfunction and is a major factor in the development of macro- or microvascular diseases. The mechanisms and the disease-related genes in vascular diseases resulting from hyperglycaemia are poorly understood. Macroarrays. bearing a total of 588 cDNA known genes, were used to analyze HUVEC gene transcription subjected to 25 or 5-mM glucose for 24 h. Isolated mRNA derived from treated first passage HUVEC were reverse transcribed, 32P labeled, and hybridized to the cDNA macroarrays. Results show that acute hyperglycaemia induces an up-regulation of seven major genes, four of which were not previously reported in the literature. Northern blot analyses, performed on these 4 genes, confirm macroarrays results for alphav, beta4, c-myc, and MUC18. Moreover, time course analysis (0, 2, 4, 8, 2, 16, 24 h) of alphav, beta4 c-myc, and MUC18 mRNA expression, observed by northern blot assays, showed a peak at time points situated between 2 to 8 h. The 3 other genes (ICAM-1, beta1, and IL-8), were shown by others to be significantly upregulated after glucose stimulation. Furthermore, ELISA assays performed on the supernatant of HUVEC culture medium showed a significant increase of IL-8 for cells treated with 25-mM compared to 5-mM glucose. Identified genes, upregulated in endothelial cells as a result of acute hyperglycaemia, may serve as therapeutic or diagnostic targets in vascular lesions present in diabetic patients. These results also demonstrate the use of cDNA macroarrays as an effective approach in identifying genes implicated in a diseased cell.
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PMID:Acute hyperglycaemia induces changes in the transcription levels of 4 major genes in human endothelial cells: macroarrays-based expression analysis. 1184 44

Innate immunity includes neutrophil inflammatory function, tissue destruction and regulatory cytokine production. Programmed cell death (apoptosis) is postulated to be a key mechanism for neutrophil elimination during inflammation. The aim of the present study was to evaluate the neutrophil apoptosis in relation to IL-8, IL-10 and IL-12 production in vitro by neutrophils of patients suffering from diabetes mellitus (DM)1 and the first-degree relatives of patients with DM1. The early stage of neutrophils apoptosis was assessed morphologically, and the later stage by DNA-binding dye propidium iodide, both after treatment with lipopolysaccharide (LPS), insulin or anti-CD95 antibody (Ab) as stimulators. CD16 (FcgammaRIII) receptor expression was also evaluated. Production of IL-8, IL-10, and IL-12 cytokine was evaluated in supernatant after neutrophil incubation for 21 h in culture medium alone, in medium in the presence of LPS, insulin or anti-CD95 antibody (Ab). Cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA) method using commercially available kits. Our study demonstrates that LPS inhibits the early stage of apoptosis (as evaluated morphologically) of healthy donors' neutrophils. The LPS-dependent early apoptosis inhibition of neutrophil of patients with DM1 or in prediabetics was decreased in comparison with control. The later stage of apoptosis of neutrophils treated in vitro with anti-CD95 Ab of patients suffering from DM1 was decreased in comparison with prediabetics and healthy donors (propidium iodide (PI) staining). LPS-induced production of anti-apoptotic cytokines IL-8, IL-10 by neutrophils of prediabetic and patients with DM1 was increased. The formyl-methionyl-leucyl-phenylalanine (fMLP)-induced proapoptotic reactive oxygen intermediates (ROI) production was significantly higher in DM1 patients. We have concluded that neutrophils from prediabetic and diabetic patients demonstrated the misbalance in anti-apoptotic IL-8 and IL-10 cytokine and proapoptotic ROI production. LPS-dependent IL-12 overproduction by neutrophils is responsible for the switch in T helper Th1/Th2 balance to Th1 and in this way may participate in inflammation and autoimmune DM1 progression.
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PMID:The effect of LPS on neutrophils from patients with high risk of type 1 diabetes mellitus in relation to IL-8, IL-10 and IL-12 production and apoptosis in vitro. 1189 38

Renal proximal tubular epithelial cells (PTEC) are target for LPS during sepsis and renal infections. In the present study, we evaluated whether stimulation of human PTEC by LPS is modulated through the soluble or the membrane form of the LPS receptor CD14. We found that PTEC lacked expression of the membrane form of CD14 and did not release soluble CD14 (sCD14). sCD14 was detected in the urine of normal subjects and it was increased in patients with renal sepsis or with proteinuria. In the presence of sCD14 and LPS binding protein (LBP), PTEC were 10 to 100-fold more sensitive to LPS activation, resulting in cytokine production (IL-6, IL-8 and TNF-alpha) and NO release. We found that sCD14 purified from urine was biologically active on PTEC. Moreover, the presence of sCD14 and LBP was required for cytotoxicity induced by low concentrations of LPS (1-10 ng/ml) in PTEC. Cell death showed the characteristics of both necrosis and apoptosis, as demonstrated by LDH release and by TUNEL and acridine orange staining and caspase-3 activation. Whereas the LPS alone was sufficient to induce necrosis, sCD14 and LBP were required for apoptosis. Our results suggest that sCD14 excreted in urine may participate with endotoxin in the activation and injury of renal proximal tubules. In particular, sCD14 may contribute to the tubulo-interstitial injury in clinical settings characterised by proteinuria and enhanced susceptibility to infections such as in diabetes.
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PMID:Urinary soluble CD14 mediates human proximal tubular epithelial cell injury induced by LPS. 1223 91

Chronic hyperglycemia is associated with the activation of aldose reductase (AR), an increase in cytokines such as TNF-alpha and IL-8 and oxidative stress. Alterations in this interdependent cascade of signals may be responsible for the diabetes-induced increase in the incidence and severity of cardiovascular diseases such as atherosclerosis and hypertension. We have previously shown that inhibition of AR prevents cultured vascular smooth muscle cell (VSMC) growth and restenosis of balloon-injured carotid arteries. To identify the mechanisms by which inhibition of AR prevents cell growth, we examined the effects of AR inhibition on mitogenic signaling by cytokines. Stimulation with TNF-alpha led to the activation of the transcription factor NF-kappaB and enhanced VSMC growth. Treatment with the AR inhibitors sorbinil or tolrestat, attenuated mitogen-induced activation of NF-kappaB and VSMC proliferation. In cultured VSMC, AR inhibitors prevented signaling events upstream of NF-kappaB activation, i.e. IkappaB-alpha phosphorylation and IkappaB-alpha degradation. Inhibition of AR also prevented protein kinase C (PKC) activation by TNF-alpha, but did not affect PKC activation by phorbol esters, indicating that inhibition of AR interrupts mitogenic signaling upstream of PKC. Together, these results indicate a pivotal role of AR or its reaction product(s) in the mitogenic signals initiated by cytokines that are elevated in diabetes and its cardiovascular complications such as atherosclerosis. These observations suggest a possible therapeutic use of AR inhibitors in these pathological conditions.
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PMID:Aldose reductase mediates the mitogenic signals of cytokines. 1260 44

Calcineurin (CaN), a calmodulin-dependent heterodimer, is, together with NAF-T, involved in the regulation of the Ca++ pump and in the transmission of the activation signal of the immune response. The CaN inhibitor drugs, such as cyclosporin A (CyA), carried by cyclophillin, and tacrolimus, carried by FK-binding protein-12 (FKBP-12), inhibit the binding with the regulatory subunit CaNB. A meta-analysis, comparing tacrolimus with cyclosporin A, has evidenced that tacrolimus significantly increases the diabetes prevalence one year after renal transplant. The diabetogenic effect is due to a direct effect of both drugs on the beta pancreatic cell, in particular on intracellular Ca++ metabolism, which is involved in the insulin secretion and in the reduction of the number of the secretor granules. Some immunological-hystochemical studies, performed on murine pancreas, have evidenced that the FKBP-12 content is higher in beta cells than in alpha cells. This fact allows a high intracellular store of tacrolimus, and a consequently more toxic effect, inside the insulin secreting structures. On the contrary, the low FKBP-12 content of alpha cells involves a higher content of calcineurin and a higher resistance to toxic effects. Finally, an increased incidence of islet cell antibodies (ICA) has been evidenced in patients treated with tacrolimus, as opposed to those treated with CyA.
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PMID:[Calcineurin inhibitors and mechanisms that are responsible for the appearance of post-transplant diabetes mellitus]. 1452 7


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