Biomedical subjects

Youhai H Chen

Publications and source records attributed to Youhai H Chen.

18 recordsLinked to original sources

PubMed2006

Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis.

LIGHT is an important costimulatory molecule for T cell immunity. Recent studies have further implicated its role in innate immunity and inflammatory diseases, but its cellular and molecular mechanisms remain elusive. We report here that LIGHT is upregulated and functions as a proinflammatory cytokine in 2 independent experimental hepatitis models, induced by concanavalin A and Listeria monocytogenes. Molecular mutagenesis studies suggest that soluble LIGHT protein produced by cleavage from the cell membrane plays an important role in this effect through the interaction with the lymphotoxin-beta receptor (LTbetaR) but not herpes virus entry mediator. NK1.1+ T cells contribute to the production, but not the cleavage or effector functions, of soluble LIGHT. Importantly, treatment with a mAb that specifically interferes with the LIGHT-LTbetaR interaction protects mice from lethal hepatitis. Our studies thus identify a what we believe to be a novel function of soluble LIGHT in vivo and offer a potential target for therapeutic interventions in hepatic inflammatory diseases.

Animals↗

PubMed2006

Induction of oral tolerization in CD86 deficient mice: a role for CD86 and B cells in the up-regulation of TGF-beta.

Feeding myelin oligodendrocyte glycoprotein (MOG) followed by immunization results in induction of oral tolerance evidenced by the amelioration of experimental autoimmune encephalomyelitis (EAE). Oral tolerization is characterized by the suppression of Th1 responses and up-regulation of Th2 responses and TGF-beta. To identify the costimulatory molecules and cell types involved in cytokine-mediated suppression we examined wild type mice and mice deficient for either CD86 (CD86-/-) or B cells (muMT). Oral tolerance was found in CD86-/- mice evidenced by amelioration of disease severity, decreased proliferative responses and IFN-gamma production and increased IL-4. TGF-beta was not up-regulated in CD86-/- or muMT mice but was increased in wild type mice. Analysis of the gut associated lymphoid tissue (GALT) of different mouse strains (C57BL/6 and PLJxSJL F1) fed distinct myelin antigens (MOG and myelin basic protein, MBP) showed that TGF-beta was increased in wild type mice of both strains by 3 days post-immunization and further increased with time. In contrast, no up-regulation of TGF-beta was found in the GALT of CD86-/- or muMT mice. These results demonstrate that CD86 is not required for oral tolerization and that both CD86 and B cells are important for the up-regulation of TGF-beta following oral antigen.

Animals↗

PubMed2006

A novel mechanism of nuclear factor-kappaB regulation by adenoviral protein 14.7K.

Viruses have evolved many different ways to evade immune attacks. The adenoviral E3 protein 14.7K effectively inhibits antiviral immunity and inflammation. However, the underlying mechanism for this effect is unclear. Here we show that 14.7K is a potent inhibitor of nuclear factor (NF)-kappaB transcriptional activity following Toll-like receptor (TLR) or tumour necrosis factor (TNF) receptor signalling. The inhibition of the NF-kappaB activity occurs downstream of IkappaBalpha degradation and NF-kappaB translocation into the nucleus. Analysis of NF-kappaB DNA binding reveals that 14.7K specifically inhibits p50 homodimer DNA binding and that this inhibition is mediated through the interaction of 14.7K with p50. We propose that 14.7K inhibits NF-kappaB activity through directly blocking p50 binding to DNA and that this is the basis for its anti-inflammatory properties. Our data also indicate a role for p50 homodimer-dependent transcription in inflammation.

Adenovirus E3 Proteins↗

PubMed2005

Essential roles of the Fas-associated death domain in autoimmune encephalomyelitis.

The Fas-associated death domain (FADD) protein mediates apoptosis by coupling death receptors with the caspase cascade. Paradoxically, it also promotes cell mitosis through its C-terminal region. Apoptosis and mitosis are opposing processes that can have radically different consequences. To determine which of the FADD effects prevails in T cell-mediated autoimmune diseases, we studied myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) using mice that express a dominant-negative FADD (FADD-DN) transgene in the T cell lineage. We found that FADD blockade in T cells prevented the development of autoimmune encephalomyelitis and inhibited both Th1 and Th2 type responses. Myelin oligodendrocyte glycoprotein-specific T cell proliferation was also dramatically reduced in FADD-DN mice despite the resistance of T cells to activation-induced cell death. These results indicate that although FADD expressed by T cells is involved in regulating both mitosis and apoptosis, its effect on mitosis prevails in EAE, and that strategies inhibiting FADD functions in T cells could be effective in preventing the disease.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Disabling TNF receptor signaling by induced conformational perturbation of tryptophan-107.

We have disabled TNF receptor (TNFR) function by inducing allosteric modulation of tryptophan-107 (W107) in the receptor. The allosteric effect operates by means of an allosteric cavity found a short distance from a previously identified loop involved in ligand binding. Occupying this cavity by small molecules leads to perturbation of distal W107 and disables functions of the TNFR, a molecule not known to undergo conformational change upon binding TNF-alpha. TNF-alpha-induced NF-kappaB and p38 kinase activities and clinical symptoms of collagen-induced arthritis in mice were all diminished. Thus, disabling receptor function by induced conformational changes of active binding surfaces represents an innovative paradigm in structure-based drug design.

Allosteric Site↗

PubMed2005

Tumor suppressor p53 inhibits autoimmune inflammation and macrophage function.

The tumor suppressor p53 regulates apoptosis, cell cycle, and oncogenesis. To explore the roles of p53 in autoimmunity, we studied type 1 diabetes and innate immune responses using C57BL/6 mice deficient in p53. We found that p53-deficient mice were more susceptible to streptozotocin-induced diabetes than control mice, and they produced higher levels of interleukin-1, -6, and -12. The innate immune response of p53-/- macrophages to lipopolysaccharides and gamma-interferon was significantly enhanced compared with p53+/+ cells. p53-/- macrophages produced more proinflammatory cytokines and higher levels of total and phosphorylated signal transducer and activator of transcription (STAT)-1. These results indicate that p53 inhibits autoimmune diabetes and innate immune responses through downregulating STAT-1 and proinflammatory cytokines.

Animals↗

PubMed2004

Reduced apoptosis and ameliorated listeriosis in TRAIL-null mice.

Listeriosis is an infectious disease caused by the bacterium Listeria monocytogenes. Although it is well recognized that apoptosis plays a critical role in the pathogenesis of the disease, the molecular mechanisms of cell death in listeriosis remain to be established. We report in this study that mice deficient in TRAIL were partially resistant to primary listeriosis, and blocking TRAIL with a soluble death receptor 5 markedly ameliorated the disease. The numbers of Listeria in the liver and spleen of TRAIL+/+ mice were 10-100 times greater than those in TRAIL-/- mice following primary Listeria infection. This was accompanied by a significant increase in the survival rate of TRAIL-/- mice. Lymphoid and myeloid cell death was significantly inhibited in TRAIL-/- mice, which led to marked enlargement of the spleen. These results establish a critical role for TRAIL in apoptosis during listeriosis.

Animals↗

PubMed2004

Critical roles of TRAIL in hepatic cell death and hepatic inflammation.

The TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis of tumor cells but not most normal cells. Its role in hepatic cell death and hepatic diseases is not clear. In vitro studies suggest that murine hepatocytes are not sensitive to TRAIL-induced apoptosis, indicating that TRAIL may not mediate hepatic cell death. Using two experimental models of hepatitis, we found that hepatic cell death in vivo was dramatically reduced in TRAIL-deficient mice and mice treated with a blocking TRAIL receptor. Although both TRAIL and its death receptor 5 were constitutively expressed in the liver, TRAIL expression by immune cells alone was sufficient to restore the sensitivity of TRAIL-deficient mice to hepatitis. Thus, TRAIL plays a crucial role in hepatic cell death and hepatic inflammation.

Animals↗

PubMed2003

Transcriptional regulation of type I diabetes by NF-kappa B.

Development of type I diabetes requires coordinated expression of myriad genes responsible for the initiation and progression of the disease. Expression of these genes are regulated by a small number of transcription factors including the Rel/NF-kappaB family. To determine the roles of the Rel/NF-kappaB family in type I diabetes, we studied multiple low-dose streptozotocin-induced diabetes in mice deficient in either c-Rel or NF-kappaB1. We found that mice deficient in each of these NF-kappaB subunits were resistant to streptozotocin-induced diabetes. However, the mechanisms of the disease resistance may differ in different cases. Deficiency in c-Rel selectively reduced Th1, but not Th2 responses, whereas NF-kappaB1 deficiency had little effect on T cell responses to anti-CD3 stimulation. Death of dendritic cells was accelerated in the absence of NF-kappaB1, whereas death of macrophages and granulocytes was affected primarily by c-Rel deficiency. Furthermore, Stat-1 expression was significantly reduced in macrophages deficient in NF-kappaB1, but not c-Rel. These results indicate that both c-Rel and NF-kappaB1are essential for the development of type I diabetes and that strategies targeting each of these subunits would be effective in preventing the disease.

Animals↗

PubMed2003

Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL-/- mice.

TRAIL, the tumor necrosis factor-related apoptosis-inducing ligand, selectively induces apoptosis of tumor cells, but not most normal cells. Its role in normal, nontransformed tissues is not clear. We report here that mice deficient in TRAIL have a severe defect in thymocyte apoptosis-thus, thymic deletion induced by T cell receptor ligation is severely impaired. TRAIL-deficient mice are also hypersensitive to collagen-induced arthritis and streptozotocin-induced diabetes and develop heightened autoimmune responses. Thus, TRAIL mediates thymocyte apoptosis and is important in the induction of autoimmune diseases.

Animals↗

PubMed2003

Arginase and autoimmune inflammation in the central nervous system.

Using a high throughput gene microarray technology that detects approximately 22 000 genes, we found that arginase I was the most significantly up-regulated gene in the murine spinal cord during experimental autoimmune encephalomyelitis (EAE). By Northern blot and arginase enzyme assay, we detected high levels of arginase I mRNA and protein, respectively, in the spinal cord of EAE mice, but not in the spinal cord of normal mice or mice that had recovered from EAE. In vitro, both microglia and astrocytes produced arginase and nitric oxide synthase, two enzymes that are involved in arginine metabolism. To explore the roles of arginase in EAE, we injected the arginase inhibitor amino-6-boronohexanoic acid (ABH) into mice during the inductive and effector phases of the disease. Compared with mice that received vehicle control, mice treated with ABH developed milder EAE with delayed onset, reduced disease score and expedited recovery. Spleen mononuclear cells from ABH-treated mice produced more nitric oxide and secreted less interferon-gamma and tumour necrosis factor-alpha as compared to control mice. These results indicate that arginase plays important roles in autoimmune inflammation in the central nervous system.

Aminocaproates↗

PubMed2003

Genes and genomics of autoimmune inflammation: from Rel to TRAIL.

Development of autoimmune diseases requires coordinated expression of a myriad of genes. To explore the spectrum and global patterns of gene expression during autoimmune inflammation, we have recently performed functional genomic studies of autoimmune inflammation in the central nervous system (CNS). Inflammation in the CNS not only induced the expression of many immune-related genes, but also significantly altered the gene expression profile of neural cells. A number of unique clusters of genes were identified, which represent putative immune and nervous responses in autoimmune inflammation. This review will focus on two clusters of genes that we have been studying during the past few years: the Rel/nuclear factor (NF)-kappaB family and the tumor necrosis factor (TNF) family.

Animals↗

PubMed2003

TRAIL, Bim, and thymic-negative selection.

Negative selection is a process whereby autoreactive lymphocytes are deleted through apoptosis. Negative selection is essential for self-tolerance and its breakdown may lead to the development of autoimmune diseases. Although the phenomenon of negative selection is well-recognized, its underlying molecular mechanisms are unclear. Recent studies using gene-knockout mice have provided new insights into the mechanisms of negative selection. In this review, we discuss the newly discovered roles of TRAIL and Bim in negative selection. Our main focus will be on T cells and T cell mediated autoimmune diseases.

Animals↗

PubMed2003

Blockade of tumor necrosis factor-related apoptosis-inducing ligand exacerbates type 1 diabetes in NOD mice.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is expressed in different tissues and cells, including pancreas and lymphocytes, and can induce apoptosis in various tumor cells but not in most normal cells. The specific roles of TRAIL in health and disease remain unclear. Here we show by cDNA array analyses that TRAIL gene expression is upregulated in pancreatic islets during the development of autoimmune type 1 diabetes in nonobese diabetic (NOD) mice and in Min6 islet beta-cells activated by TNF-alpha + interferon-gamma. However, stimulation of freshly isolated pancreatic islets or Min6 cells with TRAIL did not induce their apoptosis. TRAIL blockade exacerbates the onset of type 1 diabetes in NOD.Scid recipients of transferred diabetogenic T-cells and in cyclophosphamide-treated NOD mice. TRAIL inhibits the proliferation of NOD diabetogenic T-cells by suppressing interleukin (IL)-2 production and cell cycle progression, and this inhibition can be rescued in the presence of exogenous IL-2. cDNA array and Western blot analyses indicate that TRAIL upregulates the expression of the cdk inhibitor p27(kip1). Our data suggest that TRAIL is an important immune regulator of the development of type 1 diabetes.

Animals↗

PubMed2003

Critical roles of tumor necrosis factor-related apoptosis-inducing ligand in type 1 diabetes.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of tumor cells but not most normal cells. Its roles in normal nontransformed tissues are not clear. To explore the potential roles of TRAIL in type 1 diabetes, we examined the consequences of TRAIL blockade or TRAIL deficiency in two animal models of autoimmune diabetes. In the first model, NOD mice received an injection of a soluble TRAIL receptor to block TRAIL function. This significantly accelerated the diabetes and increased the degree of autoimmune inflammation in both pancreatic islets and salivary glands. The GAD65-specific immune responses were also significantly enhanced in animals that received the soluble TRAIL receptor. In the second model, we treated normal and TRAIL-deficient C57BL/6 mice with multiple low-dose streptozotocin to induce diabetes. We found that both the incidence and the degree of islet inflammation were significantly enhanced in TRAIL-deficient animals. On the basis of these observations, we conclude that TRAIL deficiency accelerates autoimmune diabetes and enhances autoimmune responses.

Animals↗

PubMed2002

DUG is a novel homologue of translation initiation factor 4G that binds eIF4A.

To elucidate the molecular mechanisms of cell death, we have cloned a new gene, designated death-upregulated gene (DUG), from rat insulinoma cells. DUG is constitutively expressed at very low levels in normal cells but is dramatically upregulated in apoptotic cells following serum/glucose starvation or death receptor ligation by Fas ligand. The DUG mRNA is present in two splicing forms: a long form that encodes a protein of 469 amino acids and a short form that gives rise to a polypeptide of 432 amino acids. The predicted DUG protein sequence contains two putative nuclear localization signals and multiple phosphorylation sites for protein kinases and two conserved MA3 domains. Importantly, DUG is homologous to eukaryotic translation initiation factor (eIF) 4G and binds to eIF4A presumably through MA3 domains. Upon transfection, DUG inhibits both intrinsic and extrinsic pathways of apoptosis. Thus, DUG is a novel homologue of eIF4G that regulates apoptosis.

Amino Acid Sequence↗

PubMed2002

Genomic scale profiling of autoimmune inflammation in the central nervous system: the nervous response to inflammation.

Using gene microarray technology, we found that inflammation in the central nervous system (CNS) not only induced the expression of many immune-related genes, but also significantly altered the gene expression profile of neural cells. Two unique groups of CNS genes were identified. The first group includes genes encoding ion channels, neural transmitters and growth factors. The second group includes genes that are important for nervous tissue regeneration. Additionally, a distinct pattern of gene expression was also identified in recovering animals. Thus, during autoimmune inflammation, the CNS actively responds to immune attacks by activating its own defense and repair genes.

Animals↗

PubMed2002

Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation.

Different members of the Rel/NF-kappaB family may play different roles in immunity and inflammation. We report here that c-Rel-deficient mice are resistant to autoimmune encephalomyelitis and are defective in Th1, but not Th2 responses. The Th1 deficiency appears to be caused by selective blockade of IL-12 production by c-Rel-deficient antigen-presenting cells, as well as by a complete abrogation of IFN-gamma expression in c-Rel-deficient T cells. Interestingly, c-Rel deficiency does not affect T-bet expression, suggesting that c-Rel may act downstream of T-bet during Th1 cell differentiation. Thus, unlike NF-kappaB1, which selectively regulates Th2 cell differentiation, c-Rel is essential for Th1 cell differentiation and Th1 cell-mediated autoimmune inflammation.

Animals↗