Biomedical subjects

Ji-Won Yoon

Publications and source records attributed to Ji-Won Yoon.

27 records · Page 2Linked to original sources

PubMed2002

Novel role for calcium-independent phospholipase A(2) in the macrophage antiviral response of inducible nitric-oxide synthase expression.

The double-stranded (ds) RNA-dependent protein kinase (PKR) is a primary regulator of antiviral responses; however, the ability of dsRNA to activate nuclear factor-kappa B (NF-kappa B) and dsRNA + interferon gamma (IFN-gamma) to stimulate inducible nitric-oxide synthase (iNOS) expression by macrophages isolated from PKR(-/-) mice suggests that signaling pathways in addition to PKR participate in antiviral activities. We have identified a novel phospholipid-signaling cascade that mediates macrophage activation by dsRNA and viral infection. Bromoenol lactone (BEL), a selective inhibitor of the calcium-independent phospholipase A(2) (iPLA(2)), prevents dsRNA- and virus-induced iNOS expression by RAW 264.7 cells and mouse macrophages. BEL does not modulate dsRNA-induced interleukin 1 expression, nor does it affect dsRNA-induced NF-kappa B activation. Protein kinase A (PKA) and the cAMP response element binding protein (CREB) are downstream targets of iPLA(2), because selective PKA inhibition prevents dsRNA-induced iNOS expression, and the inhibitory actions of BEL on dsRNA-induced iNOS expression are overcome by the direct activation of PKA. In addition, BEL inhibits dsRNA-induced CREB phosphorylation and CRE reporter activation. PKR does not participate in iPLA(2) activation or iNOS expression, because dsRNA stimulates iPLA(2) activity and dsRNA + IFN-gamma induces iNOS expression and nitric oxide production to similar levels by macrophages isolated from PKR(+/+) and PKR(-/-) mice. These findings support a PKR-independent signaling role for iPLA(2) in the antiviral response of macrophages.

Animals↗

PubMed2002

Molecular mechanisms for gender differences in susceptibility to T cell-mediated autoimmune diabetes in nonobese diabetic mice.

Nonobese diabetic (NOD) mice spontaneously develop diabetes with a strong female prevalence; however, the mechanisms for this gender difference in susceptibility to T cell-mediated autoimmune diabetes are poorly understood. This investigation was initiated to find mechanisms by which sex hormones might affect the development of autoimmune diabetes in NOD mice. We examined the expression of IFN-gamma, a characteristic Th1 cytokine, and IL-4, a characteristic Th2 cytokine, in islet infiltrates of female and male NOD mice at various ages. We found that the most significant difference in cytokine production between sexes was during the early stages of insulitis at 4 wk of age. IFN-gamma was significantly higher in young females, whereas IL-4 was higher in young males. CD4(+) T cells isolated from lymph nodes of female mice and activated with anti-CD3 and anti-CD28 Abs produced more IFN-gamma, but less IL-4, as compared with males. Treatment of CD4(+) T cells with estrogen significantly increased, whereas testosterone treatment decreased the IL-12-induced production of IFN-gamma. We then examined whether the change in IL-12-induced IFN-gamma production by treatment with sex hormones was due to the regulation of STAT4 activation. We found that estrogen treatment increased the phosphorylation of STAT4 in IL-12-stimulated T cells. We conclude that the increased susceptibility of female NOD mice to the development of autoimmune diabetes could be due to the enhancement of the Th1 immune response through the increase of IL-12-induced STAT4 activation by estrogen.

Aging↗

PubMed2002

4-1BB-like molecule is expressed in islet-infiltrating mononuclear cells and in the gray matter of the brain.

4-1BB is an inducible costimulatory molecule that can exert regulatory effects on T cells. Polyclonal antibodies against oligopeptides representing an evolutionarily-conserved region of murine 4-1BB, were prepared and used to stain tissues in normal and inflammatory conditions. The 4-1BB mRNA was detected in the PMA-treated spleen and heart, and constitutively in the brain, kidneys and lungs. The 4-1BB-like protein (BBLP) was expressed on mononuclear cells infiltrating islet cells in the pancreata of NOD mice. Expression was prominent in the early phase of insulitis and the level of expression diminished or disappeared in the later phase. BBLP was identified in the gray matter of brain where neuronal cell bodies, dendrites, and fiber terminals reside but was almost entirely absent in the white matter where axonal fibers dwell. A peculiar rosette pattern was observed in a granular layer of cerebellum and scattered in the stria terminalis. The staining pattern strongly resembled the receptor/nerve terminals in the brain and in the peripheral nervous system. Taken together, BBLP may be associated with the early phase of inflammation and with brain function.

Amino Acid Sequence↗

PubMed2002

Gamma interferon paradoxically inhibits the development of diabetes in the NOD mouse.

Gamma interferon (IFN-gamma) has been thought to play an important role in the pathogenesis of diabetes. This report determines if rIFN-gamma administration to NOD mice paradoxically inhibits the development of diabetes. Injections of recombinant rIFN-gamma of 5 x 10(3), 20 x 10(3), and 100 x 10(3) units, dose dependently inhibited the development of diabetes. The maximal rIFN-gamma dose decreased the incidence of diabetes from 74% in control animals to 42%. 100x10(3) unit rIFN-gamma dose significantly decreased insulitis score, and increased islet number. The development of diabetes in irradiated NOD mice was slower in animals injected with spleen cells from rIFN-gamma treated than from saline treated NOD mice suggesting that rIFN-gamma decreases anti-islet effector cell activity. The susceptibility to apoptosis was increased in splenic cells of rIFN-gamma treated mice. The expressions of the co-stimulatory molecules B7-2 and ICAM-1 were significantly increased in spleen cells of rIFN-gamma treated mice while the expression of MHC class I was decreased. In vitro studies demonstrated that NOD mouse mononuclear spleen cells preincubated with rIFN-gamma and subsequently cocultured with responder cells, potently inhibited responder T-cell proliferative responses. rIFN-gamma administration decreased IL-12 and IL-2 mRNA expression in spleen cells while increasing IL-1 expression. In conclusion, rIFN-gamma inhibits the diabetic process in NOD mice by decreasing anti-islet effector activity and in turn decreasing insulitis and islet destruction. The suppression of Th1 cell related cytokines and/or augmentation of the macrophage cytokine IL-1 may play a role in the diabetes sparing effect of rIFN-gamma.

Animals↗

PubMed2002

Recent advances in insulin gene therapy for type 1 diabetes.

Type 1 diabetes results from the loss of insulin-producing pancreatic beta cells following the action of beta-cell-specific autoimmune responses. One possible treatment for type 1 diabetes is the development of beta-cell substitutes by introducing an insulin-producing gene into non-beta cells, which would evade the beta-cell-specific autoimmune attack. However, this approach has been hampered by the absence of (1) an appropriate glucose-sensing system to regulate insulin gene transcription; (2) enzymes that process proinsulin to insulin; and (3) glucose-regulatable exocytosis in the target cells. Recent attempts to solve these problems have sought new methods for effective gene transfer and have addressed issues such as the expression and release of insulin in response to the physiological stimulus of glucose, the production of biologically active insulin, and the selection of an ideal target cell for the expression of the insulin gene.

Animals↗

PubMed2002

Modulation of glucocorticoid-induced GAD expression in pancreatic beta-cells by transcriptional activation of the GAD67 promoter and its possible effect on the development of diabetes.

GAD is a pancreatic beta-cell autoantigen in humans and nonobese diabetic (NOD) mice. Modulation of GAD expression in pancreatic beta-cells has been suggested to be associated with the development of autoimmune diabetes. Hormonal changes through environmental stimuli are considered to influence the expression of the disease. We determined whether steroid hormones would modulate the expression of GAD in pancreatic beta-cells. We treated NOD mouse beta-cells (MIN6N8a cells) with various steroids, including testosterone, estradiol, progesterone, and cortisol, and examined the expression of GAD67 mRNA. We found that only cortisol enhanced the expression of GAD67, whereas the other steroid hormones had no effect. When we treated MIN6N8a cells with a synthetic glucocorticoid, dexamethasone, we found that GAD67 mRNA expression was stimulated in a dose- and time-dependent manner. Cells treated with 100 nmol/l dexamethasone for 6 h showed a 10-fold increase in the expression of GAD67 mRNA and an increase in GAD67 protein. The upregulation of GAD67 expression in beta-cells by dexamethasone was found to be due to the transcriptional activation of the GAD67 promoter. We then examined whether dexamethasone would influence the development of diabetes in NOD mice. Injection of dexamethasone into neonatal NOD mice resulted in a significant increase in the expression of GAD67 mRNA in pancreatic beta-cells and the development of insulitis and diabetes. We conclude that glucocorticoid hormones can modulate GAD expression by the transcriptional activation of the GAD promoter and may influence the development of autoimmune diabetes in NOD mice.

Animals↗

PubMedDate not supplied

A new look at viruses in type 1 diabetes.

Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells. Genetic factors are believed to be a major component for the development of T1D, but the concordance rate for the development of diabetes in identical twins is only about 40%, suggesting that nongenetic factors play an important role in the expression of the disease. Viruses are one environmental factor that is implicated in the pathogenesis of T1D. To date, 14 different viruses have been reported to be associated with the development of T1D in humans and animal models. Viruses may be involved in the pathogenesis of T1D in at least two distinct ways: by inducing beta cell-specific autoimmunity, with or without infection of the beta cells, [e.g. Kilham rat virus (KRV)] and by cytolytic infection and destruction of the beta cells (e.g. encephalomyocarditis virus in mice). With respect to virus-mediated autoimmunity, retrovirus, reovirus, KRV, bovine viral diarrhoea-mucosal disease virus, mumps virus, rubella virus, cytomegalovirus and Epstein-Barr virus (EBV) are discussed. With respect to the destruction of beta cells by cytolytic infection, encephalomyocarditis virus, mengovirus and Coxsackie B viruses are discussed. In addition, a review of transgenic animal models for virus-induced autoimmune diabetes is included, particularly with regard to lymphocytic choriomeningitis virus, influenza viral proteins and the Epstein-Barr viral receptor. Finally, the prevention of autoimmune diabetes by infection of viruses such as lymphocytic choriomeningitis virus is discussed.

Animals↗

PubMedDate not supplied

Streptozotocin upregulates GAD67 expression in MIN6N8a mouse beta cells.

Glutamic acid decarboxylase (GAD) is one major autoantigen involved in the pathogenesis of autoimmune insulin dependent diabetes mellitus (IDDM). Molecular mechanisms regulating GAD expression in pancreatic beta cell are still ill-defined. Here we investigated the effect of streptozotocin (STZ), a beta cell-specific toxin, on the expression of GAD67 in MIN6N8a mouse beta cell. A 5-6-fold increase in the expression GAD67 mRNA was found in cells treated with 1.25mM STZ for 12h. Addition of NAD+ to the incubation medium slightly reduced the STZ-induced upregulation of GAD67. STZ increased p53 levels that in turn up-modulated GAD67 expression. This effect was abolished upon addition of the antioxidant N-acetyl cysteine (NAC). STZ also activated NF-kappaB and blockade of NF-kappaB activation inhibited the STZ-mediated upregulation of GAD67 expression. As a whole these data show that low dose of STZ up-regulates GAD67 expression in mouse bate cell and that NF-kappaB activation through oxidative stress plays a key role in this phenomenon. They also suggest that various stimuli promoting NF-kappaB activation may up-regulate expression of GAD autoantigen in mouse beta cells.

Animals↗

PubMedDate not supplied

Autoimmune destruction of pancreatic beta cells.

Type 1 diabetes results from the destruction of insulin-producing pancreatic beta cells by a beta cell-specific autoimmune process. Beta cell autoantigens, macrophages, dendritic cells, B lymphocytes, and T lymphocytes have been shown to be involved in the pathogenesis of autoimmune diabetes. Beta cell autoantigens are thought to be released from beta cells by cellular turnover or damage and are processed and presented to T helper cells by antigen-presenting cells. Macrophages and dendritic cells are the first cell types to infiltrate the pancreatic islets. Naive CD4+ T cells that circulate in the blood and lymphoid organs, including the pancreatic lymph nodes, may recognize major histocompatibility complex and beta cell peptides presented by dendritic cells and macrophages in the islets. These CD4+ T cells can be activated by interleukin (IL)-12 released from macrophages and dendritic cells. While this process takes place, beta cell antigen-specific CD8+ T cells are activated by IL-2 produced by the activated TH1 CD4+ T cells, differentiate into cytotoxic T cells and are recruited into the pancreatic islets. These activated TH1 CD4+ T cells and CD8+ cytotoxic T cells are involved in the destruction of beta cells. In addition, beta cells can also be damaged by granzymes and perforin released from CD8+ cytotoxic T cells and by soluble mediators such as cytokines and reactive oxygen molecules released from activated macrophages in the islets. Thus, activated macrophages, TH1 CD4+ T cells, and beta cell-cytotoxic CD8+ T cells act synergistically to destroy beta cells, resulting in autoimmune type 1 diabetes.

Animals↗