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Results for “Lymphotoxin beta Receptor”

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At least 109 records · Page 6Linked to original sources

PubMed2006

BAFF induces a hyper-IgA syndrome in the intestinal lamina propria concomitant with IgA deposition in the kidney independent of LIGHT.

BAFF is a peripheral B cell survival factor and can mediate antibody (Ab) class switching. Over-expression of BAFF in mice results in B cell hyperplasia, elevated serum immunoglobulin (Ig), spontaneous germinal centre (GC) reactions and mild glomerulonephritis (GN). Here we show that, in addition to driving excessive levels of serum IgA, BAFF over-expression results in increased IgA levels within the intestinal lamina propria (LP) and deposition of IgA immune complexes in the renal glomerular mesangium. LIGHT has been previously shown to mediate a similar phenotype via signaling through the lymphotoxin-beta receptor (LTbetaR). We evaluated if LIGHT and BAFF cooperate in the etiology of a hyper-IgA syndrome in BAFF-overexpressing transgenic (BAFF-Tg) mice. We find that LIGHT-deficient BAFF-Tg mice exhibit similar levels of IgA in the serum, gut and kidney and develop nephritis to the same degree as LIGHT-sufficient BAFF-Tg mice. Therefore, in the context of BAFF over-expression, LIGHT is dispensable for the generation of a hyper-IgA syndrome accompanied by nephritis.

Aging↗

PubMed2001

Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway.

Here we have addressed the role that zetaPKC plays in NF-kappaB activation using mice in which this kinase was inactivated by homologous recombination. These mice, although grossly normal, showed phenotypic alterations in secondary lymphoid organs reminiscent of those of the TNF receptor-1 and of the lymphotoxin-beta receptor gene-deficient mice. The lack of zetaPKC in embryonic fibroblasts (EFs) severely impairs kappaB-dependent transcriptional activity as well as cytokine-induced phosphorylation of p65. Also, a cytokine-inducible interaction of zetaPKC with p65 was detected which requires the previous degradation of IkappaB. Although in zetaPKC-/- EFs this kinase is not necessary for IKK activation, in lung, which abundantly expresses zetaPKC, IKK activation is inhibited.

Acetylcysteine↗

PubMed2000

The Drosophila tumor necrosis factor receptor-associated factor-1 (DTRAF1) interacts with Pelle and regulates NFkappaB activity.

A member of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family was identified in Drosophila. DTRAF1 contains 7 zinc finger domains followed by a TRAF domain, similar to mammalian TRAFs and other members of the family identified in data bases from Caenorhabditis elegans, Arabidopsis, and Dictyostelium. Analysis of DTRAF1 binding to different members of the human TNF receptor family showed that this protein can interact through its TRAF domain with the p75 neurotrophin receptor and weakly with the lymphotoxin-beta receptor. DTRAF1 can also self-associate and binds to human TRAF1, TRAF2, and TRAF4. Interestingly, DTRAF1 interacts with human cIAP-1 and cIAP-2 but not with Drosophila DIAP-1 and -2. By itself, DTRAF1 did not induce significant NFkappaB activation when overexpressed in mammalian cells, although it specifically increased NFkappaB induction by TRAF6. In contrast, TRAF2-mediated NFkappaB induction was partially inhibited by DTRAF1. Mutants of DTRAF1 lacking the N-terminal region inhibited NFkappaB induction by either TRAF2 or TRAF6. DTRAF1 specifically associated with the regulatory N-terminal domain of Pelle, a Drosophila homolog of the human kinase interleukin-1 receptor-associated kinase (IRAK). Interestingly, though Pelle and DTRAF1 individually were unable to induce NFkappaB in a human cell line, co-expression of Pelle and DTRAF1 resulted in significant NFkappaB activity. Interactions of DTRAF1 with human TRAF-, TNF receptor-, and IAP-family proteins imply strong evolutionary conservation of TRAF protein structure and function throughout Metazoan evolution.

Amino Acid Sequence↗

PubMed2002

LIGHT, a member of the tumor necrosis factor ligand superfamily, prevents tumor necrosis factor-alpha-mediated human primary hepatocyte apoptosis, but not Fas-mediated apoptosis.

LIGHT is a member of tumor necrosis factor (TNF) superfamily, and its receptors have been identified as lymphotoxin-beta receptor (LTbetaR) and the herpesvirus entry mediator (HVEM)/ATAR/TR2, both of which lack the cytoplasmic sequence termed the "death domain." The present study has demonstrated that LIGHT inhibits TNFalpha-mediated apoptosis of human primary hepatocytes sensitized by actinomycin D (ActD), but not Fas- or TRAIL-mediated apoptosis. Furthermore, LIGHT does not prevent some cell lines such as HepG2 or HeLa from undergoing ActD/TNFalpha-induced apoptosis. This protective effect requires LIGHT pretreatment at least 3 h prior to ActD sensitization. LIGHT stimulates nuclear factor-kappaB (NF-kappaB)-dependent transcriptional activity in human hepatocytes like TNFalpha. The time course of NF-kappaB activation after LIGHT administration is similar to that of the pretreatment required for the anti-apoptotic effect of LIGHT. LIGHT inhibits caspase-3 processing on the apoptotic protease cascade in TNFalpha-mediated apoptosis but not Fas-mediated apoptosis. In addition, increased caspase-3 and caspase-8 activities in ActD/TNFalpha-treated cells are effectively blocked by LIGHT pretreatment. However, LIGHT does not change the expression of TNFRp55, TNFRp75, and Fas. These results indicate that LIGHT may act as an anti-apoptotic agent against TNFalpha-mediated liver injury by blocking the activation of both caspase-3 and caspase-8.

Antigens, CD↗

PubMed1998

TRAF-4 expression in epithelial progenitor cells. Analysis in normal adult, fetal, and tumor tissues.

TRAF-4 was discovered because of its expression in breast cancers and is a member of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family of putative signal-transducing proteins. In vitro binding assays demonstrated that TRAF-4 interacts with the cytosolic domain of the lymphotoxin-beta receptor (LT beta R) and weakly with the p75 nerve growth factor receptor (NGFR) but not with TNFR1, TNFR2, Fas, or CD40. Immunofluorescence analysis of TRAF-4 in transfected cells demonstrated localization to cytosol but not nucleus. Immunohistochemical assays of normal human adult tissues revealed prominent cytosolic immunostaining in thymic epithelial cells and lymph node dendritic cells but not in lymphocytes or thymocytes, paralleling the reported patterns of LT beta R expression. The basal cell layer of most epithelia in the body was very strongly TRAF-4 immunopositive, including epidermis, nasopharynx, respiratory tract, salivary gland, and esophagus. Similar findings were obtained in 12- to 18-week human fetal tissue, indicating a highly restricted pattern of expression even during development in the mammary gland, epithelial cells of the terminal ducts were strongly TRAF-4 immunopositive whereas myoepithelial cells and most of the mammary epithelial cells lining the extralobular ducts were TRAF-4 immunonegative. Of 84 primary breast cancers evaluated, only 7 expressed TRAF-4. Ductal carcinoma in situ (DCIS) lesions were uniformly TRAF-4 immunonegative (n = 21). In the prostate, the basal cells were strongly immunostained for TRAF-4, whereas the secretory epithelial cells were TRAF-4 negative. Basal cells in prostate hypertrophy (n = 6) and prostatic intraepithelial neoplasia (PIN; n = 6) were strongly TRAF-4 positive, but none of the 32 primary and 16 metastatic prostate cancer specimens examined contained TRAF-4-positive malignant cells. Although also expressed in some types of mesenchymal cells, these findings suggest that TRAF-4 is a marker of normal epithelial stem cells, the expression of which often ceases on differentiation and malignant transformation.

Adult↗

PubMed1999

Reversal of virus-induced systemic shock and respiratory failure by blockade of the lymphotoxin pathway.

At present, little is known about the pathogenesis of acute virus-induced shock and pulmonary failure. A chief impediment in understanding the underlying disease mechanisms and developing treatment strategies has been the lack of a suitable animal model. This study describes a mouse model of virus-induced systemic shock and respiratory distress, and shows that blockade of the lymphotoxin beta receptor pathway reverses the disease.

Animals↗

PubMed2004

Presumptive lymph node organizers are differentially represented in developing mesenteric and peripheral nodes.

During murine embryogenesis, the formation of Peyer's patches (PPs) is initiated by CD45(+)CD4(+)CD3(-) lymphoid tissue inducers that trigger adhesion molecule expression and specific chemokine production from an organizing stromal cell population through ligation of the lymphotoxin-beta receptor. However, the steps involved in the development of lymph nodes (LNs) are less clear than those of PPs, and the characteristics of the organizing cells within the LN anlagen have yet to be documented. In this study, we show for the first time that the early anlage is bordered by an endothelial layer that retains a mixed lymphatic and blood vascular phenotype up to embryonic day 16.5. This in turn encompasses CD45(+)CD4(+)CD3(-) cells interspersed with ICAM-1/VCAM-1/mucosal addressin cell adhesion molecule-1, lymphotoxin-beta receptor-positive, chemokine-producing cells analogous to the organizing population previously observed in PPs. Moreover, these LN organizers also express the TNF family member, TRANCE. Lastly, we show that the ICAM-1/VCAM-1/mucosal addressin cell adhesion molecule-1 cells present in peripheral and mesenteric LN form two discrete populations expressing either intermediate or high levels of these adhesion molecules but that the former population is specifically reduced in PLN. These findings provide a possible explanation for the well-known differences in developmental requirements for nodes at peripheral or mesenteric locations.

Animals↗

PubMed2005

AIRE deficiency in thymus of 2 patients with Omenn syndrome.

Omenn syndrome is a severe primary immunodeficiency with putative autoimmune manifestations of the skin and gastrointestinal tract. The disease is caused by hypomorphic mutations in recombination-activating genes that impair but do not abolish the process of VDJ recombination, leading to the generation of autoreactive T cells with a highly restricted receptor repertoire. Loss of central tolerance in genetically determined autoimmune diseases, e.g., autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, is associated with defective expression by medullary thymic epithelial cells of AIRE, the transcription activator that induces thymic expression of tissue-specific antigens. Analysis of AIRE expression in the thymi of 2 Omenn syndrome patients and 1 SCID patient, by real-time RT-PCR and immunohistochemistry, demonstrated a profound reduction in the levels of AIRE mRNA and protein in patients as compared with a normal control subject. Lack of AIRE was associated with normal or even increased levels of keratin and lymphotoxin-beta receptor mRNAs, while mRNAs of the self-antigens insulin, cytochrome P450 1a2, and fatty acid-binding protein were undetectable in thymi from immunodeficiency patients. These results demonstrate that deficiency of AIRE expression is observed in severe immunodeficiencies characterized by abnormal T cell development and suggest that in Omenn syndrome, the few residual T cell clones that develop may escape negative selection and thereafter expand in the periphery, causing massive autoimmune reactions.

Animals↗

PubMed2003

Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR.

Thymocytes depend on the interaction with thymic epithelial cells for the generation of a diverse, nonautoreactive T cell repertoire. In turn, thymic epithelial cells acquire their three-dimensional cellular organization via instructive signals from developing thymocytes. The nature of these signals has been elusive so far. We show that thymocytes and medullary epithelial cells (MECs) communicate via the lymphotoxin beta receptor (LTbetaR) signaling axis. Normal differentiation of thymic MECs requires LTbetaR ligand on thymocytes and LTbetaR together with nuclear factor-kappaB-inducing kinase (Nik) in thymic epithelial cells. Impaired lympho-epithelial cross talk in the absence of the LTbetaR causes aberrant differentiation and reduced numbers of thymic MECs, leads to the retention of mature T lymphocytes, and is associated with autoimmune phenomena, suggesting an unexpected role for LTbetaR signaling in central tolerance induction.

Animals↗

PubMed2005

Massive destruction of malaria-parasitized red blood cells despite spleen closure.

It is currently accepted that malaria-parasitized red blood cells (pRBC) are eliminated, like senescent erythrocytes, phagocytically by macrophages in the red pulp of the spleen. Here, however, we show that self-healing Plasmodium chabaudi malaria activates spleen closure in C57BL/6 mice. Confocal laser scanning microscopy revealed that spleen closing was manifested by elimination of entry into the red pulp of 3-microm polystyrol particles, pRBC, and nonparasitized red blood cells but not of bovine serum albumin. This spleen closure did not reflect a reduction in the number of phagocytic cells, as shown by flow cytometry, whereas marginal zone macrophages (MZM) were lost and red pulp macrophages entered the white pulp. Splenic trapping of pBRC was strongly reduced in the absence of MZM and marginal metallophilic macrophages (MMM), as it is in noninfected mice with a disrupted lymphotoxin beta receptor (LTbetaR(-/-)), and it was still significantly reduced when the number of MZM and MMM was diminished, as in tumor necrosis factor alpha-deficient (TNF-alpha(-/-)) mice. Moreover, mice deficient in TNF-alpha, tumor necrosis factor receptor I (TNFRI(-/-)), and LTbetaR exhibited progressive impairment in malaria-induced spleen closing. Treatment of C57BL/6 mice with TNF-alpha induced loss of MZM and spleen closing by about 20%. Our data indicate that TNF/TNFRI signaling is involved in regulating malaria-induced spleen closure, which is maximal during crisis, when parasitemia declines more than 100-fold. Consequently, the vast majority of pRBC cannot be destroyed by the spleen during crisis, suggesting that the known sophisticated sequestration system of Plasmodium parasites did not evolve to avoid splenic clearance.

Animals↗

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↗

PubMed2004

Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers.

IkappaB Kinase (IKK)alpha is required for activation of an alternative NF-kappaB signaling pathway based on processing of the NF-kappaB2/p100 precursor protein, which associates with RelB in the cytoplasm. This pathway, which activates RelB:p52 dimers, is required for induction of several chemokine genes needed for organization of secondary lymphoid organs. We investigated the basis for the IKKalpha dependence of the induction of these genes in response to engagement of the lymphotoxin beta receptor (LTbetaR). Using chromatin immunoprecipitation, we found that the promoters of organogenic chemokine genes are recognized by RelB:p52 dimers and not by RelA:p50 dimers, the ubiquitous target for the classical NF-kappaB signaling pathway. We identified in the IKKalpha-dependent promoters a novel type of NF-kappaB-binding site that is preferentially recognized by RelB:p52 dimers. This site links induction of organogenic chemokines and other important regulatory molecules to activation of the alternative pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2004

The role of LIGHT in T cell-mediated immunity.

This review focuses on the role of homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for HVEM on T cells (LIGHT) in T-cell immunity and T cell-mediated diseases. LIGHT binds to lymphotoxin-beta receptor (LTbetaR), and cooperates with LTbeta in lymphoid organogenesis and development of lymphoid structure. Previous findings establish a crucial biological role for LIGHT, a T cell-derived costimulatory ligand, in T-cell activation and expansion via a T-T cell-dependent manner. Transgenic studies demonstrated that the dysregulation of LIGHT activity results in the disturbance of T-cell homeostasis and ultimately the breakdown of peripheral tolerance. Furthermore, the blockade of LIGHT activity ameliorates the severity of T cell-mediated diseases indicating the essential involvement of LIGHT in various pathological conditions. Here, we review the recent studies about LIGHT mainly in the context of autoimmunity and conclude with a discussion of the potential mechanisms by which LIGHT promotes autoimmunity.

Animals↗

PubMed2004

Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy.

Whether and how T cells contribute to the pathogenesis of immunoglobulin A nephropathy (IgAN) has not been well defined. Here, we explore a murine model that spontaneously develops T cell-mediated intestinal inflammation accompanied by pathological features similar to those of human IgAN. Intestinal inflammation mediated by LIGHT, a ligand for lymphotoxin beta receptor (LTbetaR), not only stimulates IgA overproduction in the gut but also results in defective IgA transportation into the gut lumen, causing a dramatic increase in serum polymeric IgA. Engagement of LTbetaR by LIGHT is essential for both intestinal inflammation and hyperserum IgA syndrome in our LIGHT transgenic model. Impressively, the majority of patients with inflammatory bowel disease showed increased IgA-producing cells in the gut, elevated serum IgA levels, and severe hematuria, a hallmark of IgAN. These observations indicate the critical contributions of dysregulated LIGHT expression and intestinal inflammation to the pathogenesis of IgAN.

Animals↗

PubMed2005

Follicular dendritic cell dedifferentiation reduces scrapie susceptibility following inoculation via the skin.

Transmissible spongiform encephalopathies (TSEs) are a group of subacute infectious neurodegenerative diseases that are characterized by the accumulation in affected tissues of PrP(Sc), an abnormal isoform of the host prion protein (PrPc). Following peripheral exposure, TSE infectivity and PrP(Sc) usually accumulate in lymphoid tissues prior to neuroinvasion. Studies in mice have shown that exposure through scarified skin is an effective means of TSE transmission. Following inoculation via the skin, a functional immune system is critical for the transmission of TSEs to the brain, but until now, it has not been known which components of the immune system are required for efficient neuroinvasion. Temporary dedifferentiation of follicular dendritic cells (FDCs) by treatment with an inhibitor of the lymphotoxin-beta receptor signalling pathway (LTbetaR-Ig) 3 days before or 14 days after inoculation via the skin, blocked the early accumulation of PrP(Sc) and TSE infectivity within the draining lymph node. Furthermore, in the temporary absence of FDCs before inoculation, disease susceptibility was reduced and survival time significantly extended. Treatment with LTbetaR-Ig 14 days after TSE inoculation also significantly extended the disease incubation period. However, treatment 42 days after inoculation did not affect disease susceptibility or survival time, suggesting that the infection may have already have spread to the nervous system. Together these data show that FDCs are essential for the accumulation of PrP(Sc) and infectivity within lymphoid tissues and subsequent neuroinvasion following TSE exposure via the skin.

Animals↗

PubMed2001

Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis.

Mice deficient in lymphotoxin beta receptor (LTbetaR) or interleukin 7 receptor alpha (IL-7Ralpha) lack Peyer's patches (PPs). Deficiency in CXC chemokine receptor 5 (CXCR5) also severely affects the development of PPs. A molecular network involving these three signaling pathways has been implicated in PP organogenesis, but it remains unclear how they are connected during this process. We have shown that PP organogenesis is initiated at sites containing IL-7Ralpha(+) lymphoid cells and vascular cell adhesion molecule (VCAM)-1/intercellular adhesion molecule (ICAM)-1 expressing nonlymphoid elements. Here we characterize these lymphoid and nonlymphoid components in terms of chemokine signals. The lymphoid population expresses CXCR5 and has a strong chemotactic response to B lymphocyte chemoattractant (BLC). Importantly, chemokines produced by VCAM-1(+)ICAM-1(+) nonlymphoid cells mediate the recruitment of lymphoid cells. Furthermore, we show that these VCAM-1(+)ICAM-1(+) cells are mesenchymal cells that are activated by lymphoid cells through the LTbetaR to express adhesion molecules and chemokines. Thus, promotion of PP development relies on mutual interaction between mesenchymal and lymphoid cells.

Animals↗

PubMed2004

Attenuation of graft arterial disease by manipulation of the LIGHT pathway.

OBJECTIVE: The tumor necrosis factor (TNF) superfamily member LIGHT, which binds herpes virus entry mediator (HVEM) and lymphotoxin beta receptor (LTbetaR), plays important roles in regulating the immune response. To clarify the mechanism underlying graft arterial disease (GAD), we investigated the role of the LIGHT pathway in the progression of GAD. METHODS AND RESULTS: Hearts from Bm12 mice were transplanted into C57BL/6 (B/6) mice (class II mismatch). Recipients were injected intraperitoneally with HVEMIg (100 microg per treatment) every 7 days for 8 weeks. Treatment with HVEMIg significantly attenuated GAD (luminal occlusion=16.5+/-7.7% versus control allograft=62.6+/-12.1%, P<0.05), and significantly decreased intragraft IL-4, IL-6, and interferon-gamma (IFN-gamma) mRNA expression compared with controls. LTbetaR was expressed in smooth muscle cells (SMCs) with or without cytokine stimulation, whereas HVEM was detected in SMCs stimulated by IFN-gamma. Coculture of SMCs with T cells after transplantation induced SMC proliferation, and addition of HVEMIg resulted in inhibition of SMC proliferation. CONCLUSIONS: These results indicate that the LIGHT pathway plays important roles in the regulation not only of T-cell activation but also of SMC proliferation. Blockade of the LIGHT pathway is a promising avenue for the prevention of GAD.

Animals↗

PubMed2005

Deletion of LTbetaR augments male susceptibility to Plasmodium chabaudi.

SUMMARY Disruption of the lymphotoxin beta receptor (LTbetaR) gene has been shown to result in enhanced resistance of female mice to blood-stage Plasmodium chabaudi malaria. Here, we investigate the effect of LTbetaR deletion on host defence of males. In contrast to females, male LTbetaR(-/-) mice do not exhibit any increase in resistance. Conversely, they are even more susceptible than wild-type C57BL/6 mice, which becomes evident after lowering circulating levels of testosterone by castration, which makes C57BL/6 males resistant, whereas LTbetaR(-/-) remain susceptible. Gene-expression analysis using cDNA arrays revealed no differences in immunological responses in spleen of malaria-resistant female and malaria-susceptible castrated male LTbetaR(-/-) mice. In the liver, however, expression levels of plasminogen activator inhibitor PAI1, chemokine CXCL10, dual specificity phosphatase DUSP1, and hydroxysteroid-specific sulfotransferases Sult2a1/2 were decreased 6- to 85-fold in susceptible castrated male LTbetaR(-/-) mice in comparison to resistant female LTbetaR(-/-) mice at maximal parasitaemia, as evidenced by Northern blot analyses. The present data support our previous view that the liver is involved in the combat against malarial blood stages and that down-regulation of the genes DUSP1 and Sult2a1/2 signals dysregulation of protective liver responses, thus possibly contributing to male susceptibility of LTbetaR(-/-) mice.

Animals↗