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

Normal mouse islet cells express low levels of MHC class I molecules and undetectable or extremely low levels of MHC class II molecules. Class I expression was dose-dependently augmented by incubation with interferon-gamma (IFN-gamma) or tumor necrosis factor (TNF). Although neither IFN-gamma nor TNF alone induce class II molecules on islet cells, synergistic interaction of IFN-gamma (200 U/ml) and TNF (200 U/ml) may induce class II expression on approximately 50% of islet cells. Niacinamide and 3-aminobenzamide, both inhibitors of ADP ribosylation and scavengers of free radicals, attenuated the class II expression induced by IFN-gamma and TNF. Twenty millimolar niacinamide and 10 mM 3-aminobenzamide reduced the rates of class II antigen-positive cells to mean +/- SD 3.6 +/- 0.3 and 6.1 +/- 1.9%, respectively. The agents did not affect the cytokine-induced augmentation of class I antigens. The inhibition of class II molecule expression may at least partly account for the preventive effect of niacinamide on autoimmune-associated beta-cell damage in NOD mice.
Diabetes 1990 Sep
PMID:Inhibition of cytokine-induced MHC class II but not class I molecule expression on mouse islet cells by niacinamide and 3-aminobenzamide. 214 88

Mouse islet cell monolayers were damaged when cultured for five days in a medium containing 200 U/ml of recombinant murine interferon-gamma (IFN-gamma) and 300 U/ml of recombinant tumor necrosis factor (TNF). The cells formed granular clusters and ultimately floated in the medium; the floating cells proved to be dead by the trypan-blue dye-exclusion method. When 20 mM of nicotinamide or 5 mM of 3-aminobenzamide was supplemented to the medium, islet cell monolayers remained in the presence of the cytokines. 51Cr release studies showed that specific 51Cr release during five-day incubation with 200 U/ml of IFN-gamma and 300 U/ml of TNF was 30 +/- 4% (mean +/- SE). In a medium containing 20 mM of nicotinamide, together with IFN-gamma and TNF, specific 51Cr release was significantly reduced (12 +/- 3%, p less than 0.01). 3-aminobenzamide was effective at the level of 5 mM; specific 51Cr release was 2 +/- 5% (p less than 0.01). These results suggest that the mechanism by which IFN-gamma and TNF damage islet cells may be similar to that of streptozotocin and/or alloxan.
Diabetes Res 1990 Feb
PMID:Protective effect of nicotinamide and 3-aminobenzamide on islet cell damage induced by gamma-interferon and tumor necrosis factor. 215 Nov 29

A significant segment of the Black population is affected by chronic diabetes, and most of them are subjected to severe cardiovascular, renal, and neurological complications that shorten survival and diminish quality of life. One of the important pathogenetic mechanisms under intensive investigation is advanced tissue glycosylation. Tissue and cell surface proteins modified nonenzymatically by glucose are shown to be highly active in protein cross-linking and have been implicated in tissue damage. Such protein-glucose interactions, called advanced glycosylation end products (AGEs), are processed by macrophages through a high-affinity receptor. Coupling of AGE proteins to their AGE receptors results in their degradation and removal and, simultaneously, in synthesis and secretion of pluripotential cytokines such as tumor necrosis factor and interleukin 1. This suggests that AGE may act normally as a signal for growth-promoting factor secretion in a coordinated replacement process during tissue remodeling. In chronic diabetes, however, where accelerated accumulation of tissue AGE occurs, a disturbance of this balance may lead to several pathological, lytic, and/or proliferative responses like those in the vasculopathy of diabetes. Progress has been made with the discovery of aminoguanidine HCl, an AGE inhibitor, which has prevented significant pathology in short-term diabetic animal studies.
Diabetes Care 1990 Nov
PMID:Chronic diabetic complications and tissue glycosylation. Relevant concern for diabetes-prone black population. 226 39

Cell line IgSV195, derived from a pancreatic tumor that arose in an SV40 T-antigen transgenic mouse, retains certain morphological and physiological characteristics of pancreatic beta-cells throughout in vitro and in vivo passage. Insulin secretion is stimulated by exposure of these cells to fetal bovine serum and a combination of 3-isobutyl-1-methylxanthine and glutamine but not by concentrations of glucose in the physiological range. Insulin processing appears to be intact. Neither class I nor class II major histocompatibility complex (MHC) antigens are routinely expressed at the cell surface; however, MHC class I--but not class II--encoded gene products are detected after treatment with recombinant interferon-gamma (IFN-gamma) alone or in combination with tumor necrosis factor. Cytolysis of IgSV195 cells by SV40 T-antigen-specific H-2b-restricted lymphocytes is similarly dependent on IFN-gamma pretreatment. These results emphasize that SV40 T-antigen transgenic mice are likely sources of cell lines that retain their differentiated function in vitro. The IgSV195 cell line provides an accessible model in which to investigate the control of gene expression and function of pancreatic beta-cells.
Diabetes 1989 Aug
PMID:Functional pancreatic beta-cell line from SV40 T-antigen transgenic mouse. 250 59

Polypeptide products of mononuclear cells of the immune system (cytokines) have been reported to be cytotoxic to the insulin-producing pancreatic islet beta-cells. The objective of this study was to distinguish between reversible effects of cytokines on insulin secretion and irreversible cytotoxic effects on the islet beta-cells. When tested as single agents or added together at very low concentrations, interleukin 1 (IL-1), tumor necrosis factor (TNF), and interferon gamma (IFN-gamma) inhibited insulin release from rat islet cell monolayer cultures during 4 day incubations; however, this secretory function improved after the cytokines were removed. In contrast, combinations of slightly higher concentrations of IL-1, TNF, and IFN-gamma produced irreversible inhibition of insulin release, as well as decreased cell insulin content and proportional increase in cell lysis, measured as release of 51Cr from labeled islet cell cultures. These findings suggest that cytokine products of T lymphocytes (IFN-gamma) and macrophage/monocytic cells (IL-1, TNF) infiltrating pancreatic islets in "autoimmune" diabetes may interact synergistically to produce functional inhibition or lethal cytocidal effects on islet beta-cells, possibly accounting for reversible and irreversible stages of insulin-dependent diabetes.
 ...
PMID:Effects of cytokines on rat pancreatic islet cell monolayer cultures: distinction between functional and cytotoxic effects on islet beta-cells. 251 61

Proteins of extracellular matrix undergo over time multiple reactions with glucose to form advanced glycosylation endproducts (AGEs) which are highly active in protein crosslinking, and have been implicated in tissue damage associated with aging and diabetes. A macrophage/monocyte receptor for AGE moieties mediates the uptake of AGE-modified proteins by a process that also induces cachectin/tumor necrosis factor (TNF) and IL-1 secretion. Reasoning that cytokines might regulate this AGE-receptor system, we have evaluated the effect of cachectin/TNF, IL-1, and IFN-gamma on AGE-protein processing. We report that cachectin/TNF induced a severalfold enhancement of binding, endocytosis, and degradation of AGE-BSA by both murine peritoneal macrophages and human blood monocytes in vitro, and that cachectin/TNF enhanced the rate of disappearance of AGE-modified red blood cells in vivo. IL-1 and IFN-gamma alone did not increase AGE processing, but IFN-gamma consistently enhanced cachectin/TNF-induced changes in AGE-receptor kinetics. Similar effects were induced by AGE-BSA and FFI-BSA, a chemically synthesized AGE, when used as macrophage stimulants, possibly via cachectin/TNF induction. All upregulatory responses were blocked by anticachectin/TNF monoclonal antibody. These data suggest that AGE-induced cachectin/TNF, in addition to influencing tissue regeneration and remodelling, may also normally regulate the disposal of tissue damaging AGE-proteins through an autocrine upregulation.
 ...
PMID:Macrophage/monocyte receptor for nonenzymatically glycosylated protein is upregulated by cachectin/tumor necrosis factor. 255 47

The mononuclear-phagocyte system includes promonocytes and their precursors in the bone marrow, monocytes in circulation and macrophages in tissues. After maturation in the bone marrow newly formed monocytes enter the circulation and migrate into different tissues; the half-life of monocytes in the blood stream is approximately three days. Once in the tissue monocytes undergo transformation into tissue macrophages with functional properties that are characteristic for the environment in which they reside. Macrophages play a central role in the immune regulation by presenting antigen to T-lymphocytes; they participate in ingestion and killing of various invading microorganisms. In addition, macrophages synthesize a great number of substances involved in host defense and inflammation i.e. complement components, prostaglandins, IL-1, tumor necrosis factor-alpha and others. During infection, macrophages have the capacity to become "activated" by lymphokines and different bacterial products; "activated" macrophages have an increased tumoricidal and microbicidal activity against various microorganisms, synthesis and secretion of immune mediators is enhanced. Monocyte-macrophage dysfunctions have been described in various disorders: defective chemotaxis (corticosteroids, drug induced immunosuppression, AIDS, diabetes), defective phagocytosis (lupus erythematosus, deficiency of a membrane glycoprotein), microbicidal defect (chronic granulomatous disease), decreased cytotoxicity (Wiskott-Aldrich-Syndrome), deficiencies in the clearance of physiologic substrates in lysosomal diseases.
 ...
PMID:[The monocyte-macrophage system in the human]. 267 85

Viruses are implicated in the pathogenesis of beta-cell destruction in type I (insulin-dependent) diabetes. The aim of our study was to investigate whether reovirus 1 or reovirus 3, which are known to infect beta-cells and induce autoimmunity in susceptible mice, could alter the expression of the major histocompatibility complex (MHC) proteins by human beta-cells and rat insulinoma RINm5F cells. Forty-eight hours after infection of either human beta-cells or RINm5F cells with reovirus 1 or reovirus 3, cytopathic effects were noted. By flow-cytofluorometric analysis, infected RINm5F cells exhibited a seven- to eightfold increase in the surface expression of class I MHC proteins. Upregulation of class I MHC proteins on reovirus 3-infected RINm5F cells was inhibited by 80% after preexposure of the virus to reovirus 3 antiserum. When analyzed by double-indirect immunofluorescence microscopy, human beta-cells infected with reoviruses 1 or 3 also exhibited markedly increased levels of class I MHC proteins. Reovirus infection of human beta-cells or RINm5F cells was not accompanied by the induction of class II MHC proteins. These findings suggest that 1) in addition to direct cytopathic effects, reovirus infection may contribute to beta-cell destruction by increasing expression of class I MHC proteins and therefore reactivity with cytotoxic T-lymphocytes; and 2) some viruses may increase MHC protein expression independent of and before the action of cytokines (e.g., interferon-gamma and tumor necrosis factor) released by immunoinflammatory cells.
Diabetes 1988 Mar
PMID:Reovirus infection enhances expression of class I MHC proteins on human beta-cell and rat RINm5F cell. 283 51

An assay was developed to detect the cytotoxic effects of cytokines on rat pancreatic islet cells in monolayer culture. Cell lysis was detected by a 51Cr-release assay after 4 days of incubation with various cytokines. When tested alone, murine (rat and mouse) interferon-gamma (mIFN-gamma) produced a small dose-dependent lysis of islet cells; human IFN-gamma, mouse IFN-alpha/beta, interleukins 1 and 2 (IL-1 and IL-2), tumor necrosis factor (TNF), and lymphotoxin (LT) were inactive. When added together, the following combinations of cytokines showed synergistic cytotoxic effects: TNF (or LT) plus IL-1, TNF (or LT) plus mIFN-gamma, and IL-1 plus mIFN-gamma. These results indicate that the cytokine products of mononuclear cells of the immune system, IFN-gamma, TNF, LT, and IL-1 have strong synergistic cytotoxic effects on islet cells and therefore may act as direct chemical mediators of islet beta-cell destruction in type I (insulin-dependent) diabetes.
Diabetes 1988 Jan
PMID:Destruction of rat islet cell monolayers by cytokines. Synergistic interactions of interferon-gamma, tumor necrosis factor, lymphotoxin, and interleukin 1. 312 15

Previous studies have established that the cytokine interleukin 1 (IL-1) is selectively cytotoxic for isolated human and rat pancreatic beta-cells. This observation raises the possibility that insulin-dependent diabetes mellitus is in part due to immunologically mediated mechanisms involving IL-1. However, other cytokines are produced during immunologic responses. To study possible modulatory effects of other cytokines on IL-1-mediated beta-cell cytotoxicity, we added human recombinant IL-1 alpha and beta (rIL-1 alpha, rIL-1 beta), tumor necrosis factor (rTNF), lymphotoxin (rLT), and interferon-gamma (rIFN-gamma) separately or in combinations to the culture medium of isolated rat islets of Langerhans. A half-maximal inhibition of glucose-stimulated insulin release after 7 days of culture was obtained with 100 pg/ml of rIL-1 beta, whereas 1000 pg/ml of rIL-1 alpha were necessary to obtain an equivalent effect. While ineffective in causing inhibition of beta-cell function or morphologic damage to islets alone 2.5 to 25 ng/ml of rTNF, but not 40 ng/ml of rLT, or 25 ng/ml of rIFN-gamma markedly potentiated the inhibition of beta-cell secretory response and dissolution of islet integrity caused by rIL-1 alpha and beta. The potentiating effect of rTNF was more pronounced if the rTNF was added after 60 min of preincubation of the islets with rIL-1 beta, than if rIL-1 beta was added after 60 min of preincubation with rTNF. rTNF did not interfere with the activity of rIL-1 alpha or beta on lymphocytes. Combinations of rIFN-gamma and rTNF or rLT did not affect beta-cell function. In conclusion, rTNF strongly potentiates the functional inhibition of beta-cells and the morphologic disintegration of islets caused by rIL-1 in vitro. These data, seen in context with previous observations of rIL-1-mediated beta-cell cytotoxicity, suggest that macrophages present in the intra-islet mononuclear cell infiltrate in insulin-dependent diabetes mellitus may secrete monokines that could be important effector molecules in beta-cell destruction.
 ...
PMID:Human tumor necrosis factor potentiates human interleukin 1-mediated rat pancreatic beta-cell cytotoxicity. 332 Feb 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>