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Klaus Pfeffer - One of the best experts on this subject based on the ideXlab platform.
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Background
2016Co-Authors: Kristina Behnke, Ursula R Sorg, Diran Herebian, Dieter Häussinger, Verena Keitel, Klaus PfefferAbstract:The Lymphotoxin Beta Receptor (LTbR) is a prototypic member of the TNF/TNFR superfamily and has diverse functions in regulating immune responses against patho-gens, in organogenesis and maintenance of structural integrity of secondary lymphoid tissues [1]. Mice deficient in LTbR (LTbR-/-) show impaired resistance to intracellu-lar pathogens and defects in peripheral lymphoid tissues [2,3]. Importantly, LTbR-/- mice also exhibit markedly reduced survival after partial (70%) hepatectomy (PHx) [4], compared to WT controls. Liver mass is tightly regu-lated to 5 % of the body weight and the liver retains a remarkable capacity for regeneration in response to acute injury. Loss of at least 30 % of liver mass leads to synchro-nized proliferation of normally quiescent mature hepato-cytes (compensatory hyperplasia) until physiologic live
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Critical Roles for LIGHT and Its Receptors in Generating T Cell-Mediated Immunity during Leishmania donovani Infection
2016Co-Authors: Amanda C Stanley, Fabian De Labastida Rivera, Ashraful Haque, Meru Sheel, Fiona H. Amante, Patrick T. Bunn, Klaus Pfeffer, Yonghong Zhou, Louise M. R, Stefanie ScheuAbstract:LIGHT (TNFSF14) is a member of the TNF superfamily involved in inflammation and defence against infection. LIGHT signals via two cell-bound Receptors; herpes virus entry mediator (HVEM) and Lymphotoxin-Beta Receptor (LTbR). We found that LIGHT is critical for control of hepatic parasite growth in mice with visceral leishmaniasis (VL) caused by infection with the protozoan parasite Leishmania donovani. LIGHT-HVEM signalling is essential for early dendritic cell IL-12/IL-23p40 production, and the generation of IFNc- and TNF-producing T cells that control hepatic infection. However, we also discovered that LIGHT-LTbR interactions suppress anti-parasitic immunity in the liver in the first 7 days of infection by mechanisms that restrict both CD4+ T cell function and TNF-dependent microbicidal mechanisms. Thus, we have identified distinct roles for LIGHT in infection, and show that manipulation of interactions between LIGHT and its Receptors may b
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atheroprotective effects of Lymphotoxin Beta Receptor deletion in apoe deficient mice
European Heart Journal, 2013Co-Authors: M Grandoch, Klaus Pfeffer, J R Goethert, N Nagy, Jens W FischerAbstract:Lymphotoxin (LT) α and β cytokines belong to the tumor necrosis factor (TNF) superfamily and are critically involved in chronic inflammatory disorders via LTβ Receptor (LTβR) signalling. The underlying mechanisms however remain to be defined, specifically the inflammatory cell subsets and signalling pathways that are involved. This study investigated the hitherto unknown role of LTβR during atherogenesis and progression. Male ApoE/LTβR double-deficient mice, representing a murine model of accelerated atherosclerosis, were fed a western-type diet beginning at 8 weeks of age. Atherosclerotic plaque size was analysed after 15 weeks on diet by Oil Red-O staining of the aorta. Mice deficient in LTβR developed significantly less atherosclerotic lesions in comparison to their wild-type littermates (ApoE-/-/LTβR-/-: 6.6±0.68% positive area fraction and ApoE-/-/LTβR+/+: 8.9±0.6; positive area fraction). After four weeks on western diet, resembling an early time point in atherogenesis, macrophage invasion into the developing plaques of LTβR deficient mice was significantly reduced as quantified by Mac2 staining of the aortic root (ApoE-/-/LTβR+/+: 20.12±2.82% versus ApoE-/-/LTβR-/-: 11.08±2.40%, expressed as positive area fraction). In addition, also plasma concentration of TNFα were reduced in LTβR-deficient mice as detected by ELISA (ApoE-/-/LTβR-/-: 6377±1099 pg/ml versus 10530±1390 pg/ml in ApoE-/-/LTβR+/+). Despite these observations however, flow cytometry analysis of circulating blood cell subsets revealed increased numbers of both high inflammatory monocytes (CD115+/Ly6chigh; ApoE-/-/LTβR-/-:0.98±0.16 cells/nl blood versus ApoE-/-/LTβR+/+:0.26±0.08 cells/nl blood) and low inflammatory monocytes (CD115+/Ly6clow; ApoE-/-/LTβR-/-: 1.65±0.34 cells/nl blood versus ApoE-/-/LTβR+/+: 0.55±0.06 cells/nl blood) in LTβR-deficient mice indicating a disturbed efflux of inflammatory cells into the tissue. In summary, LTβR appears to be critically involved in atherogenesis and atheroprogression by promoting the invasion of inflammatory macrophages into developing atherosclerotic lesions.
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Lymphotoxin Beta Receptor activation on macrophages ameliorates acute dss induced intestinal inflammation in a trim30α dependent manner
Molecular Immunology, 2012Co-Authors: Nadin Wimmer, Barbara Huber, Anja K Wege, Nicola Barabas, Johann Rohrl, Klaus PfefferAbstract:Abstract Our previous studies indicated that LTβR activation mainly by T cell derived LTα1β2 is crucial for the control and down-regulation of intestinal inflammation. In order to dissect the cellular and molecular role of LTβR activation in the experimental model of DSS-induced intestinal inflammation, we have generated cell type-specific LTβR-deficient mice with specific ablation of LTβR expression on macrophages/neutrophils (LTβR(flox/flox) × LysM-Cre). These mice develop an exacerbated intestinal inflammation in our experimental model indicating that LTβR expression on macrophages/neutrophils is responsible for the control and down-regulation of the inflammatory reaction. These results were verified by adoptive transfer experiments of BMDM from wild-type and LTβR-deficient mice. Furthermore, transfer of activated CD4+ T cells derived from wild-type mice, but not from LTβR ligand-deficient mice attenuated the signs of intestinal inflammation. Finally, we demonstrate that LTβR activation on BMDM results in induction of TRIM30α, a negative regulator of NFκB activation. Concordantly, ablation of LTβR signaling results in the inability to induce TRIM30α expression concomitant with an increased expression of pro-inflammatory cytokines in our experimental model. Taken together, our data demonstrate that LTβR activation on macrophages by CD4+ T cell derived LTαβ controls the pro-inflammatory response by activation of a TRIM30α-dependent signaling pathway, crucial for the down-regulation of the inflammatory response in this experimental model.
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Critical Roles for LIGHT and Its Receptors in Generating T Cell-Mediated Immunity during Leishmania donovani Infection
PLOS Pathogens, 2011Co-Authors: Amanda C Stanley, Fabian De Labastida Rivera, Ashraful Haque, Meru Sheel, Fiona H. Amante, Patrick T. Bunn, Louise M. Randall, Klaus Pfeffer, Yonghong Zhou, Stefanie ScheuAbstract:LIGHT (TNFSF14) is a member of the TNF superfamily involved in inflammation and defence against infection. LIGHT signals via two cell-bound Receptors; herpes virus entry mediator (HVEM) and Lymphotoxin-Beta Receptor (LTβR). We found that LIGHT is critical for control of hepatic parasite growth in mice with visceral leishmaniasis (VL) caused by infection with the protozoan parasite Leishmania donovani. LIGHT-HVEM signalling is essential for early dendritic cell IL-12/IL-23p40 production, and the generation of IFNγ- and TNF-producing T cells that control hepatic infection. However, we also discovered that LIGHT-LTβR interactions suppress anti-parasitic immunity in the liver in the first 7 days of infection by mechanisms that restrict both CD4+ T cell function and TNF-dependent microbicidal mechanisms. Thus, we have identified distinct roles for LIGHT in infection, and show that manipulation of interactions between LIGHT and its Receptors may be used for therapeutic advantage.
Daniela N Mannel - One of the best experts on this subject based on the ideXlab platform.
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blocking Lymphotoxin Beta Receptor signalling exacerbates acute dss induced intestinal inflammation opposite functions for surface Lymphotoxin expressed by t and b lymphocytes
Molecular Immunology, 2008Co-Authors: Michaela Jungbeck, Peter Stopfer, Frauke Bataille, Sergei A Nedospasov, Daniela N MannelAbstract:The Lymphotoxin Beta Receptor (LTBetaR) signalling pathway is involved in the development of secondary lymphoid organs and the maintenance of organized lymphoid tissues. Additionally, previous studies clearly demonstrated the involvement of the LTBetaR interaction with its ligands in promoting intestinal inflammation. In order to dissect the role of LTBetaR activation in the mouse model of acute DSS-induced colitis we treated mice with a functional inhibitor of LTBetaR activation (LTBetaR:Ig) and compared it to disease in LTBetaR-deficient and LTalphaBeta-deficient mice. All these modes of LTBetaR signalling ablation resulted in significant aggravation of the disease and in release of inflammatory cytokines such as TNF, IL-6, and IFNgamma. Finally, using mice with conditionally ablated expression of membrane bound LTBeta on T or B cells, respectively, distinct and opposite contributions of surface LTBeta expressed on T or B cells was found. Thus, activation of LTBetaR by LTalphaBeta mainly expressed on T lymphocytes is crucial for the down regulation of the inflammatory response in this experimental model.
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blocking Lymphotoxin β Receptor activation diminishes inflammation via reduced mucosal addressin cell adhesion molecule 1 madcam 1 expression and leucocyte margination in chronic dss induced colitis
Clinical and Experimental Immunology, 2004Co-Authors: Peter Stopfer, Daniela N Mannel, Florian Obermeier, Nadja Dunger, Werner Falk, S Farkas, M Janotta, A Moller, Thomas HehlgansAbstract:The Lymphotoxin-Beta Receptor (LTBetaR) pathway is critical for maintenance of organized lymphoid structures and is involved in the development of colitis. To investigate the mechanisms by which LTBetaR activation contributes to the pathology of chronic inflammation we used a soluble LTBetaR-Ig fusion protein as a competitive inhibitor of LTBetaR activation in the mouse model of chronic colitis induced by oral administration of dextran sulphate sodium. Strong expression of LTBeta which constitutes part of the LTalpha(1)Beta(2) ligand complex was detected in colonic tissue of mice with chronic colitis. Treatment with LTBetaR-Ig significantly attenuated the development and histological manifestations of the chronic inflammation and reduced the production of inflammatory cytokines such as TNF, IL-1Beta, and IL-6. Moreover, LTBetaR-Ig treatment significantly down-regulated mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression, leading to reduced leucocyte rolling and sticking in postcapillary and collecting venules and reduced extravasation into the intestinal mucosa as quantified by in vivo fluorescence microscopy. Thus, LTBetaR pathway inhibition ameliorates DSS-induced experimental chronic colitis in mice by MAdCAM-1 down-regulation entailing reduced lymphocyte margination and extravasation into the inflamed mucosa. Therefore, a combined treatment with reagents blocking T cell-mediated perpetuation of chronic inflammation such as LTBetaR-Ig together with direct anti-inflammatory reagents such as TNF inhibitors could constitute a promising treatment strategy for chronic colitis.
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activation of the Lymphotoxin Beta Receptor induces nfκb dependent interleukin 6 and mip 2 secretion in mouse fibrosarcoma cells
European Cytokine Network, 2003Co-Authors: Thomas Hehlgans, Peter Stopfer, Peter Muller, Daniela N MannelAbstract:Activation of the Lymphotoxin Beta-Receptor (LTBetaR), a member of the tumor necrosis factor Receptor family, plays a crucial role in lymphoid organogenesis and tumor development. Lymphotoxin alpha(1)Beta(2) (LTalpha(1)Beta(2)) and LIGHT have been identified as membrane anchored ligands for the LTBetaR. While LTBetaR is expressed on a wide range of cell types e.g. fibroblasts and monocytes, the ligands are expressed only on activated lymphocytes and NK cells. In order to characterize LTBetaR expression and the biological consequences of LTBetaR activation rat anti-mouse LTBetaR monoclonal antibodies were generated. These antibodies recognized a mouse LTBetaR-Ig fusion protein as well as endogenous LTBetaR on a variety of mouse fibroblast and fibrosarcoma cell lines. Specificity was demonstrated by the lack of binding to LTBetaR-deficient embryonic fibroblasts. Competitive binding studies revealed that three different epitopes were recognized by the monoclonal antibodies. Two of the monoclonals activated the LTBetaR and induced activation of NFkappaB and secretion of MIP-2 and IL-6 in L929 mouse fibroblast cells. MIP-2 and IL-6 secretion was NFkappaB-dependent because IkappaB-transfected cells released significantly reduced amounts of both mediators.
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Lymphotoxin Beta Receptor immune interaction promotes tumor growth by inducing angiogenesis
Cancer Research, 2002Co-Authors: Benjamin Stoelcker, Klaus Pfeffer, Peter Stopfer, Sergei A Nedospasov, Peter Muller, Grigore Cernaianu, Markus Guba, M Steinbauer, Daniela N MannelAbstract:Growth of solid fibrosarcoma tumors in mice was inhibited by the release of a solubleLymphotoxin-β Receptor inhibitor (LTβR-immunoglobulin fusion protein) from the tumor cells. Tumor growth arrest in mice deficient in the ligand LTα1β2 demonstrated the requirement for activation of the LTβR on the tumor cells by host cell-derived LTα1β2. Activation of the LTβR resulted in enhanced release of macrophage inflammatory protein-2. Blocked angiogenesis was revealed in LTβR inhibitor-producing tumor nodules by immunohistochemistry and in vivo microscopy. The growth arrest of LTβR inhibitor-producing fibrosarcomas was overcome by forced MIP-2 expression in the tumor cells. Thus, LTβR activation on tumor cells by activated host lymphocytes can initiate a novel proangiogenic pathway leading to organized tumor tissue development.
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functional characterization of the mouse Lymphotoxin Beta Receptor promoter
European Cytokine Network, 2001Co-Authors: Peter Muller, Daniela N Mannel, Thomas HehlgansAbstract:The Lymphotoxin Beta-Receptor (LT Beta R), a member of the tumor necrosis factor (TNF) Receptor family, plays a crucial role in lymphoid organogenesis by signaling through its functional ligand LT alpha(1)Beta(2). While the Receptor is expressed on a wide range of cell types e.g. fibroblasts and monocytes, the ligand is expressed only on activated T, B and NK cells. Remarkably, no cell type has been identified so far that expresses both the Receptor and the ligand. In order to characterize the mouse LT Beta R gene expression on a molecular level, we isolated about 1 kb of the 5' flanking region of the LT Beta R gene. Primer extension analysis revealed one transcriptional start site located at - 60 upstream of the ATG-containing first exon. Northern blot analysis showed that the LT Beta R is abundantly expressed in the mouse fibroblast cell line NIH 3T3, and to a lesser extent, in the mouse macrophage-like cell line RAW 264.7. To determine whether the 5' flanking region exerts functional promoter activity, we generated deletion mutants fused to the luciferase reporter gene. Transfection experiments using these reporter gene constructs showed that the isolated 5' flanking region is transcriptionally active in NIH 3T3 and RAW 264.7 cells, and determined a minimum length required for the transcriptional activity of the LT Beta R promoter in these cells. Further sequence analysis of the isolated 5' flanking region identified a number of putative DNA-binding sites for transcription factors. Interestingly, incubation of NIH 3T3 cells with dexamethasone resulted in an elevated mRNA level of the LT Beta R gene. This effect was abolished by using the specific glucocorticoid Receptor inhibitor RU486, indicating an increased transcriptional activity of the LT Beta R promoter after glucocorticoid stimulation.
Mathias Heikenwalder - One of the best experts on this subject based on the ideXlab platform.
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the unexpected role of Lymphotoxin Beta Receptor signaling in carcinogenesis from lymphoid tissue formation to liver and prostate cancer development
Oncogene, 2010Co-Authors: M Wolf, Mathias Heikenwalder, Nicolas Zeller, Gitta SeleznikAbstract:The cytokines Lymphotoxin (LT) α, β and their Receptor (LTβR) belong to the tumor necrosis factor (TNF) superfamily, whose founder—TNFα—was initially discovered due to its tumor necrotizing activity. LTβR signaling serves pleiotropic functions including the control of lymphoid organ development, support of efficient immune responses against pathogens due to maintenance of intact lymphoid structures, induction of tertiary lymphoid organs, liver regeneration or control of lipid homeostasis. Signaling through LTβR comprises the noncanonical/canonical nuclear factor-κB (NF-κB) pathways thus inducing chemokine, cytokine or adhesion molecule expression, cell proliferation and cell survival. Blocking LTβR signaling or Fcγ-Receptor mediated immunoablation of LT-expressing cells was demonstrated to be beneficial in various infectious or noninfectious inflammatory or autoimmune disorders. Only recently, LTβR signaling was shown to initiate inflammation-induced carcinogenesis, to influence primary tumorigenesis and to control reemergence of carcinoma in various cancer models through distinct mechanisms. Indeed, LTβR signaling inhibition has already been used as efficient anti-inflammatory, anti-cancer therapy in some experimental models. Here, we review the pleiotropic functions attributed to LT, the effects of its deregulation and extensively discuss the recent literature on LT's link to carcinogenesis.
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the unexpected role of Lymphotoxin Beta Receptor signaling in carcinogenesis from lymphoid tissue formation to liver and prostate cancer development
Oncogene, 2010Co-Authors: M Wolf, Mathias Heikenwalder, Nicolas Zeller, Gitta SeleznikAbstract:The cytokines Lymphotoxin (LT) alpha, Beta and their Receptor (LTBetaR) belong to the tumor necrosis factor (TNF) superfamily, whose founder-TNFalpha-was initially discovered due to its tumor necrotizing activity. LTBetaR signaling serves pleiotropic functions including the control of lymphoid organ development, support of efficient immune responses against pathogens due to maintenance of intact lymphoid structures, induction of tertiary lymphoid organs, liver regeneration or control of lipid homeostasis. Signaling through LTBetaR comprises the noncanonical/canonical nuclear factor-kappaB (NF-kappaB) pathways thus inducing chemokine, cytokine or adhesion molecule expression, cell proliferation and cell survival. Blocking LTBetaR signaling or Fcgamma-Receptor mediated immunoablation of LT-expressing cells was demonstrated to be beneficial in various infectious or noninfectious inflammatory or autoimmune disorders. Only recently, LTBetaR signaling was shown to initiate inflammation-induced carcinogenesis, to influence primary tumorigenesis and to control reemergence of carcinoma in various cancer models through distinct mechanisms. Indeed, LTBetaR signaling inhibition has already been used as efficient anti-inflammatory, anti-cancer therapy in some experimental models. Here, we review the pleiotropic functions attributed to LT, the effects of its deregulation and extensively discuss the recent literature on LT's link to carcinogenesis.
Carl F Ware - One of the best experts on this subject based on the ideXlab platform.
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vascular endothelial growth factor promotes macrophage apoptosis through stimulation of tumor necrosis factor superfamily member 14 tnfsf14 light
Wound Repair and Regeneration, 2008Co-Authors: Melissa Petreaca, Carl F Ware, Manuela MartinsgreenAbstract:: Resolution of inflammation is critical for normal wound healing. Inflammation is prolonged and fails to resolve properly in chronic wounds. We used in vivo and in vitro approaches to show that vascular endothelial growth factor (VEGF) induces macrophage apoptosis and to delineate mechanisms involved in this process. VEGF inhibition during wound healing leads to an increased number of macrophages remaining in wounds, suggesting the involvement of VEGF in removal of these cells from the wound. If this effect has physiological relevance, it likely occurs via apoptosis. We show that VEGF increases apoptosis of macrophages in vitro using Annexin V-FITC staining and caspase activation. Microarray analysis, reverse transcription-polymerase chain reaction, and immunoblotting showed that VEGF increases the expression of tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT) in macrophages. We also show that in macrophages LIGHT promotes apoptosis through the Lymphotoxin Beta Receptor. Moreover, inhibition of LIGHT prevents VEGF-induced death, suggesting that LIGHT mediates VEGF-induced macrophage apoptosis. Taken together, our results identify a novel role for VEGF and for LIGHT in macrophage apoptosis during wound healing, an event critical in the resolution of inflammation. This finding may lead to the development of new strategies to improve resolution of inflammation in problematic wounds.
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the Lymphotoxin β Receptor induces different patterns of gene expression via two nf κb pathways
Immunity, 2002Co-Authors: Emmanuel Dejardin, Michael Karin, Carl F Ware, Nathalie Droin, Mireille Delhase, Elvira Haas, Yixue Cao, Constantin Makris, Douglas R GreenAbstract:The Lymphotoxin-Beta Receptor (LTBetaR) plays critical roles in inflammation and lymphoid organogenesis through activation of NF-kappaB. In addition to activation of the classical NF-kappaB, ligation of this Receptor induces the processing of the cytosolic NF-kappaB2/p100 precursor to yield the mature p52 subunit, followed by translocation of p52 to the nucleus. This activation of NF-kappaB2 requires NIK and IKKalpha, while NEMO/IKKgamma is dispensable for p100 processing. IKKBeta-dependent activation of canonical NF-kappaB is required for the expression but not processing of p100 and for the expression of proinflammatory molecules including VCAM-1, MIP-1Beta, and MIP-2 in response to LTBetaR ligation. In contrast, IKKalpha controls the induction by LTBetaR ligation of chemokines and cytokines involved in lymphoid organogenesis, including SLC, BLC, ELC, SDF1, and BAFF.
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expression of the Lymphotoxin Beta Receptor on follicular stromal cells in human lymphoid tissues
Cell Death & Differentiation, 1998Co-Authors: Jeffrey L. Browning, Carl F Ware, Barbara N Walter, Marianne Murphy, Larry Pikenobile, Neil A Fanger, Paul M Guyre, Lois B EpsteinAbstract:The Lymphotoxin β Receptor (LTβR), and its ligand, LTα1β2, have been proposed to play a key role in the development and organization of lymphoid tissues. The LTβR is expressed on a variety of human primary and transformed cells, but strikingly absent on T or B lymphocytes and primary monocytes or peripheral dendritic cells, although LTβR is detected on some myeloid leukemic lines. In the developing thymus LTβR is prominent along the trabeculae and into the medulla upto corticomedullary junction. In the spleen, LTβR is prominently expressed by cells in the red pulp and along the borders of red and white pulp which colocalizes with reticular stromal cells. The LTβR is expressed on a human follicular dendritic cell line, FDC-1, and signals expression of CD54 when ligated with the LTα1β2 complex. These results support the concept that directional interactions between LTα1β2 bearing lymphocytes and LTβR bearing stromal cells are involved in the organization of lymphoid tissue.
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hepatitis c virus core protein interacts with the cytoplasmic tail of Lymphotoxin Beta Receptor
Journal of Virology, 1997Co-Authors: Masayuki Matsumoto, Tsaiyuan Hsieh, Nongliao Zhu, T Vanarsdale, Soon B Hwang, Kingsong Jeng, Alexander E Gorbalenya, Carl F Ware, Michael M C LaiAbstract:Hepatitis C virus (HCV) core protein is a multifunctional protein. We examined whether it can interact with cellular proteins, thus contributing to viral pathogenesis. Using the HCV core protein as a bait to screen a human liver cDNA library in a yeast two-hybrid screening system, we have isolated several positive clones encoding cellular proteins that interact with the HCV core protein. Interestingly, more than half of these clones encode the cytoplasmic domain of Lymphotoxin-Beta Receptor (LT BetaR), which is a member of the tumor necrosis factor Receptor family. Their binding was confirmed by in vitro glutathione S-transferase fusion protein binding assay and protein-protein blotting assay to be direct and specific. The binding sites were mapped within a 58-amino-acid region of the cytoplasmic tail of LT BetaR. The binding site in the HCV core protein was localized within amino acid residues 36 to 91 from the N terminus, corresponding to the hydrophilic region of the protein. In mammalian cells, the core protein was found to be associated with the membrane-bound LT BetaR. Since the LT BetaR is involved in germinal center formation and developmental regulation of peripheral lymphoid organs, lymph node development, and apoptotic signaling, the binding of HCV core protein to LT BetaR suggests the possibility that this viral protein has an immunomodulating function and may explain the mechanism of viral persistence and pathogenesis of HCV.
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mouse Lymphotoxin Beta Receptor molecular genetics ligand binding and expression
Journal of Immunology, 1995Co-Authors: Walker R Force, Jeffrey L. Browning, R Tizard, Barbara N Walter, Catherine Hession, C A Kozak, Carl F WareAbstract:Lymphotoxin (LT) -alpha Beta heterotrimer is a membrane-anchored ligand expressed by activated T cells which binds specifically to the LT Beta Receptor (LT Beta R), a member of the TNFR family. The LT Beta R is implicated as a critical element in controlling lymph node development and cellular immune reactions. To address this hypothesis we have isolated a mouse cDNA encoding a single transmembrane protein of 415 amino acids with 76% identity to human LT Beta R. The Receptor function of this molecule was demonstrated by the ability of the extracellular domain, constructed as a chimera with the Fc region of IgG7, to bind to LT alpha Beta complexes expressed on the surface of activated T cells or insect cells infected with baculoviruses containing LT alpha and LT Beta cDNAs. The gene encoding mouse LT Beta R, Ltbr, contains 10 exons spanning 6.9 kb and maps to mouse chromosome 6, which is closely linked to Tnfr1, consistent with the tight linkage of the human homologue of these genes on chromosome 12p13. Mouse LT Beta R mRNA is expressed by cell lines of monocytic and epithelial origin but not by a CTL line, and in vivo it is constitutively expressed in visceral and lymphoid tissues. The delineation of the structure of the mouse LT Beta R will aid investigations into the role of this cytokine-Receptor system in immune function and development.
Nicola L Harris - One of the best experts on this subject based on the ideXlab platform.
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Interactions between fibroblastic reticular cells and B cells promote mesenteric lymph node lymphangiogenesis.
Nature Communications, 2017Co-Authors: Lalit Kumar Dubey, Praneeth Karempudi, Burkhard Ludewig, Sanjiv A Luther, Nicola L HarrisAbstract:Lymphatic growth (lymphangiogenesis) within lymph nodes functions to promote dendritic cell entry and effector lymphocyte egress in response to infection or inflammation. Here we demonstrate a crucial role for Lymphotoxin-Beta Receptor (LTβR) signaling to fibroblastic reticular cells (FRCs) by Lymphotoxin-expressing B cells in driving mesenteric lymph node lymphangiogenesis following helminth infection. LTβR ligation on fibroblastic reticular cells leads to the production of B-cell-activating factor (BAFF), which synergized with interleukin-4 (IL-4) to promote the production of the lymphangiogenic factors, vascular endothelial growth factors (VEGF)-A and VEGF-C, by B cells. In addition, the BAFF-IL-4 synergy augments expression of Lymphotoxin by antigen-activated B cells, promoting further B cell–fibroblastic reticular cell interactions. These results underlie the importance of Lymphotoxin-dependent B cell–FRC cross talk in driving the expansion of lymphatic networks that function to promote and maintain immune responsiveness. The growth of lymph nodes in response to infection requires lymphangiogenesis. Dubey et al. show that the mesenteric lymph node lymphangiogenesis upon helminth infection depends on the signaling loop between the B and fibroblastic reticular cells (FRCs), whereby the FRCs respond to Lymphotoxin secreted by B cells by releasing B cell activating factor.
