The Experts below are selected from a list of 3264 Experts worldwide ranked by ideXlab platform
Yoshihiko Sawa - One of the best experts on this subject based on the ideXlab platform.
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induction of icam 1 and vcam 1 on the mouse lingual Lymphatic Endothelium with tnf α
Acta Histochemica Et Cytochemica, 2008Co-Authors: Kana Iwasawa, Hiroyuki Ishikawa, Takeshi Kameyama, Yoshihiko SawaAbstract:This study investigated the TNF-α-induced ICAM-1 and VCAM-1 expression on mouse lingual Lymphatic vessels. All podoplanin-positive Lymphatic vessels expressed PECAM-1. In the lamina propria mucosae of TNF-α-treated tongue, almost all initial Lymphatics expressed ICAM-1. There were initial Lymphatics with the VCAM-1 expression and also the vessels without the expression. In the tunica muscularis of TNF-α-treated tongue, collecting Lymphatic vessels expressed ICAM-1, but rarely expressed VCAM-1 whereas blood vessels simultaneously expressed ICAM-1 and VCAM-1. The ICAM-1-positive rate increased with TNF-α to 75% from 10% on initial Lymphatics, and to 40% from 0% on collecting Lymphatic vessels while it increased to 90% from 45% on blood vessels. The VCAM-1-positive rate increased with TNF-α to 30% from 0% on initial Lymphatics, and to 5% from 0% on collecting Lymphatic vessels while it increased to 75% from 5% on blood vessels. These findings suggest that the lingual Lymphatic Endothelium has the ability to express ICAM-1, and VCAM-1 to a lesser extent than the ICAM-1 induction with TNF-α, and that the ICAM-1 and VCAM-1 induction predominantly occurs in the initial Lymphatics compared with collecting Lymphatic vessels.
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Leukocyte adhesion molecule and chemokine production through lipoteichoic acid recognition by toll-like receptor 2 in cultured human Lymphatic Endothelium
Cell and Tissue Research, 2008Co-Authors: Yoshihiko Sawa, Eichi Tsuruga, Kana Iwasawa, Hiroyuki Ishikawa, Shigemitsu YoshidaAbstract:We have recently reported that the human Lymphatic Endothelium has toll-like receptor 4 (TLR4)-mediated lipopolysaccharide recognition mechanisms that induce the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Although ligand engagement with TLR2 enables activation of the MyD88-dependent pathway similarly to TLR4, whether TLR2 ligands such as lipoteichoic acid (LTA) trigger the activation of Lymphatic Endothelium remains unclear. This study has been designed to investigate the expression dynamics of LTA-induced leukocyte adhesion molecules and chemokines in cultured human Lymphatic Endothelium (LEC). Reverse transcription/polymerase chain reaction (RT-PCR) and real-time quantitative PCR analyses have shown that LEC usually expresses TLR2 and increases TLR2 gene expression on LTA treatment. Indeed, LTA-treated LEC increases the expression of E-selectin, ICAM-1, and VCAM-1 but does not alter the gene expression of ICAM-2, ICAM-3, junctional adhesion molecule-1 (JAM-1), JAM-3, or platelet endothelial cell adhesion molecule-1 (PECAM-1). The expression of LTA-induced E-selectin, ICAM-1, and VCAM-1 in LEC is suppressed by anti-TLR2 but not by anti-TLR4 and is also suppressed by TLR2-specific short interfering RNA (siRNA) but not by siRNA for TLR4. The expression of CCL2, CCL5, and CCL20 (Cys-Cys motif chemokines) and of CXCL1, CXCL3, CXCL5, CXCL6, and CXCL8 (Cys-X-Cys motif chemokines) was induced in LEC with LTA. These data suggest that the human Lymphatic endothelial phenotype has TLR2-mediated LTA-recognition mechanisms, resulting in increased expression of inflammatory leukocyte adhesion molecules and phagocyte-attractive chemokines. The human Lymphatic Endothelium may thus function to collect leukocytes from tissues into Lymphatic vessels by means of immunologically functional molecules.
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the expression of e selectin and chemokines in the cultured human Lymphatic Endothelium with lipopolysaccharides
Journal of Anatomy, 2008Co-Authors: Yoshihiko Sawa, Eichi TsurugaAbstract:This study investigated the expression of selectins and chemokines in cultured human Lymphatic endothelial cells stimulated with lipopolysaccharides. In microarray, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 gene expressions in the Lymphatic Endothelium with lipopolysaccharides did not change at 0.5 h but increased two- to three-fold at 12 h, whereas E-selectin increased 10-fold at 0.5 h and 68-fold at 12 h compared with untreated cells. The E-selectin mRNA and protein increased in the Lymphatic endothelial cells with lipopolysaccharides at more than two-fold levels compared with human umbilical vein endothelial cells. Induction of Cys-Cys chemokine ligand 2, 3, 5, 7, 8 and 20 mRNAs in the Lymphatic endothelial cells with lipopolysaccharides was detected in microarray and real-time PCR. The Cys-Cys chemokine ligand 2, 5 and 20 mRNA amounts in cells with high concentration lipopolysaccharides were larger in the Lymphatic endothelial cells than in human umbilical vein endothelial cells. The Cys-Cys chemokine ligand 3 and 8 mRNAs were not detected in human umbilical vein endothelial cells. Induction of Cys-X-Cys chemokine ligand 1, 3, 5, 6 and 8 mRNAs was detected in the Lymphatic endothelial cells with lipopolysaccharides. The Cys-X-Cys chemokine ligand 3, 5 and 8 mRNA amounts in cells with high concentration lipopolysaccharides were larger in the Lymphatic endothelial cells than in human umbilical vein endothelial cells. In conclusion, it was demonstrated that the cultured human Lymphatic endothelial cells express E-selectin and phagocyte-attractive chemokine genes.
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expression of junctional adhesion molecules on the human Lymphatic Endothelium
Microvascular Research, 2008Co-Authors: Takeshi Ueki, Hiroyuki Ishikawa, Kana Iwasawa, Yoshihiko SawaAbstract:Abstract Human Lymphatic vessels express several leukocyte adhesion molecules. The study here investigated the expression of three junctional adhesion molecules (JAM) which are a newly reported glycoprotein family of adhesion molecules on human Lymphatic Endothelium. In this study, JAM-1 and JAM-3 but not JAM-2 were detected in cultured human neonatal dermal Lymphatic endothelial cells (LEC) at the gene and protein levels by microarray, RT-PCR, real-time PCR, and immunohistochemical analysis. The JAM-1 and JAM-3 expression was not altered in the TNF-α-treated LEC or in the untreated cells. In human tissue, the expression of JAM-1, and the expression of JAM-1, JAM-2, and JAM-3 were observed in collecting Lymphatic vessels of uninflamed small intestine, and in initial Lymphatics of inflamed tongue and uninflamed gingival tissue. It is thought that JAM-2 mRNA could be produced in mature vascular Endothelium but not in cultured cells, and that human intestinal and oral Lymphatic vessels usually express JAM-1, JAM-2, and JAM-3. There were initial Lymphatics simultaneously expressing JAM-1, JAM-2, and JAM-3 in the mucosal connective tissue papillae of gingival tissue. The three JAM expressions on the Lymphatic Endothelium may contribute to both seal the cell–cell contact at interendothelial junctions and also allow lymphocytes to transmigrate into Lymphatic vessels from tissue, independent of inflammatory cytokines.
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effects of tnf α on leukocyte adhesion molecule expressions in cultured human Lymphatic Endothelium
Journal of Histochemistry and Cytochemistry, 2007Co-Authors: Yoshihiko Sawa, Hiroyuki Ishikawa, Takeshi Ueki, Yukitaka Sugimoto, Atuko Sato, Toshikazu Nagato, Shigemitsu YoshidaAbstract:TNF-alpha alters leukocyte adhesion molecule expression of cultured endothelial cells like human umbilical vein endothelial cells (HUVEC). This study was designed to investigate the changes in vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet endothelial cell adhesion molecule-1 (PECAM-1) expression with TNF-alpha stimulation in cultured human neonatal dermal Lymphatic endothelial cells (HNDLEC). The real-time quantitative PCR analysis on HNDLEC showed that TNF-alpha treatment leads to increases of VCAM-1 and ICAM-1 mRNAs to the 10.8- and 48.2-fold levels of untreated cells and leads to a reduction of PECAM-1 mRNA to the 0.42-fold level of untreated cells. Western blot and immunohistochemical analysis showed that TNF-alpha leads to VCAM-1 and ICAM-1 expressions that were inhibited by antiserum to human TNF receptor or by AP-1 inhibitor nobiletin. In flow cytometry analysis, the number of VCAM-1- and ICAM-1-positive cells increased, and PECAM-1-positive cells decreased with TNF-alpha treatment. Regarding protein amounts produced in cells and amounts expressed on the cell surface, VCAM-1 and ICAM-1 increased in HNDLEC and HUVEC, and PECAM-1 decreased in HNDLEC in a TNF-alpha concentration-dependent manner. VCAM-1, ICAM-1, and PECAM-1 protein amounts in TNF-alpha-stimulated cells were lower in HNDLEC than in HUVEC. This suggests that the Lymphatic Endothelium has the TNF-alpha-induced signaling pathway, resulting in increased VCAM-1 and ICAM-1 expression to a weaker extent than blood Endothelium and PECAM-1 reduction to a stronger extent than blood Endothelium.
Shigemitsu Yoshida - One of the best experts on this subject based on the ideXlab platform.
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Leukocyte adhesion molecule and chemokine production through lipoteichoic acid recognition by toll-like receptor 2 in cultured human Lymphatic Endothelium
Cell and Tissue Research, 2008Co-Authors: Yoshihiko Sawa, Eichi Tsuruga, Kana Iwasawa, Hiroyuki Ishikawa, Shigemitsu YoshidaAbstract:We have recently reported that the human Lymphatic Endothelium has toll-like receptor 4 (TLR4)-mediated lipopolysaccharide recognition mechanisms that induce the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Although ligand engagement with TLR2 enables activation of the MyD88-dependent pathway similarly to TLR4, whether TLR2 ligands such as lipoteichoic acid (LTA) trigger the activation of Lymphatic Endothelium remains unclear. This study has been designed to investigate the expression dynamics of LTA-induced leukocyte adhesion molecules and chemokines in cultured human Lymphatic Endothelium (LEC). Reverse transcription/polymerase chain reaction (RT-PCR) and real-time quantitative PCR analyses have shown that LEC usually expresses TLR2 and increases TLR2 gene expression on LTA treatment. Indeed, LTA-treated LEC increases the expression of E-selectin, ICAM-1, and VCAM-1 but does not alter the gene expression of ICAM-2, ICAM-3, junctional adhesion molecule-1 (JAM-1), JAM-3, or platelet endothelial cell adhesion molecule-1 (PECAM-1). The expression of LTA-induced E-selectin, ICAM-1, and VCAM-1 in LEC is suppressed by anti-TLR2 but not by anti-TLR4 and is also suppressed by TLR2-specific short interfering RNA (siRNA) but not by siRNA for TLR4. The expression of CCL2, CCL5, and CCL20 (Cys-Cys motif chemokines) and of CXCL1, CXCL3, CXCL5, CXCL6, and CXCL8 (Cys-X-Cys motif chemokines) was induced in LEC with LTA. These data suggest that the human Lymphatic endothelial phenotype has TLR2-mediated LTA-recognition mechanisms, resulting in increased expression of inflammatory leukocyte adhesion molecules and phagocyte-attractive chemokines. The human Lymphatic Endothelium may thus function to collect leukocytes from tissues into Lymphatic vessels by means of immunologically functional molecules.
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effects of tnf α on leukocyte adhesion molecule expressions in cultured human Lymphatic Endothelium
Journal of Histochemistry and Cytochemistry, 2007Co-Authors: Yoshihiko Sawa, Hiroyuki Ishikawa, Takeshi Ueki, Yukitaka Sugimoto, Atuko Sato, Toshikazu Nagato, Shigemitsu YoshidaAbstract:TNF-alpha alters leukocyte adhesion molecule expression of cultured endothelial cells like human umbilical vein endothelial cells (HUVEC). This study was designed to investigate the changes in vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet endothelial cell adhesion molecule-1 (PECAM-1) expression with TNF-alpha stimulation in cultured human neonatal dermal Lymphatic endothelial cells (HNDLEC). The real-time quantitative PCR analysis on HNDLEC showed that TNF-alpha treatment leads to increases of VCAM-1 and ICAM-1 mRNAs to the 10.8- and 48.2-fold levels of untreated cells and leads to a reduction of PECAM-1 mRNA to the 0.42-fold level of untreated cells. Western blot and immunohistochemical analysis showed that TNF-alpha leads to VCAM-1 and ICAM-1 expressions that were inhibited by antiserum to human TNF receptor or by AP-1 inhibitor nobiletin. In flow cytometry analysis, the number of VCAM-1- and ICAM-1-positive cells increased, and PECAM-1-positive cells decreased with TNF-alpha treatment. Regarding protein amounts produced in cells and amounts expressed on the cell surface, VCAM-1 and ICAM-1 increased in HNDLEC and HUVEC, and PECAM-1 decreased in HNDLEC in a TNF-alpha concentration-dependent manner. VCAM-1, ICAM-1, and PECAM-1 protein amounts in TNF-alpha-stimulated cells were lower in HNDLEC than in HUVEC. This suggests that the Lymphatic Endothelium has the TNF-alpha-induced signaling pathway, resulting in increased VCAM-1 and ICAM-1 expression to a weaker extent than blood Endothelium and PECAM-1 reduction to a stronger extent than blood Endothelium.
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immunoelectron microscopic study of pecam 1 expression on Lymphatic Endothelium of the human tongue
Tissue & Cell, 2001Co-Authors: N Ebata, Yoshihiko Sawa, Shigemitsu Yoshida, Yuji Yamaoka, Yoshinobu Nodasaka, Y TotsukaAbstract:Abstract The expression of platelet–endothelial cell adhesion molecule-1 (PECAM-1) on Lymphatic and blood vessels of the human tongue was examined with fluorescence and transmission electron microscopy (TEM). The study used anti-desmoplakins antiserum for light microscopic identification of the Lymphatic vessels, plus a pre-embedding immunogold electron microscopic technique for TEM observations. Before making TEM observations, cryostat serial sections were immunostained with anti-desmoplakins or anti-PECAM-1 and then embedded. Semithin sections from each cryostat section were photographed under a light microscope and compared in order to identify the Lymphatic vessels expressing PECAM-1. In fluorescence microscopy, PECAM-1 expression on Lymphatic vessels was weaker than that on blood vessels. TEM observations showed that PECAM-1 expression on the blood vessels was observed only on the luminal surface of the Endothelium. In Lymphatic vessels, PECAM-1 expression was found both on the luminal and abluminal surfaces of the Endothelium. The density ofthe PECAM-1 reaction products was lower in Lymphatic vessels than in blood vessels. The density of PECAM-1 reaction products on the luminal surface of Lymphatic vessels was higher than on the abluminal surfaces. The results suggest that blood vessels are more active than Lymphatic vessels in leukocyte migration. The expression of PECAM-1 on the abluminal surface of Lymphatic Endothelium may allow leukocytes to adhere to the Endothelium and interact in their migration from tissue into Lymphatic vessels.
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immunohistochemical study on leukocyte adhesion molecules expressed on Lymphatic Endothelium
Microvascular Research, 1999Co-Authors: Yoshihiko Sawa, Masatsugu Suzuki, Yuichi Ashikaga, Takenori Kim, Yuji Yamaoka, N Ebata, Shigemitsu YoshidaAbstract:Abstract Leukocyte adhesion molecules expressed on the Lymphatic Endothelium in human small intestine and submandibular lymph node were studied immunohistochemically. Lymphatic capillaries in the lamina propria, mucosal muscle layer, and submucosal connective tissue of the intestine and in the capsule of the lymph node showed strong expression of platelet–endothelial cell adhesion molecule-1 (PECAM-1). A few Lymphatic capillaries that weakly expressed intercellular adhesion molecule-1 (ICAM-1) were found in the capsule of the lymph node but in the small intestine, no Lymphatic capillaries expressed detectable amounts of ICAM-1. Lymphatic capillaries also did not express detectable amounts of endothelial cell–selectin in the small intestine and lymph node. When lymphocytes migrate from tissue into Lymphatic capillaries, multiple adhesion molecules may not be required for the migration. PECAM-1, however, may contribute to adherence of lymphocytes to Lymphatic Endothelium and the expression of adhesion molecules on Lymphatic Endothelium may be different between tissues.
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Lymphatic Endothelium of the human tongue expresses multiple leukocyte adhesion molecules
Tissue & Cell, 1999Co-Authors: N Ebata, Yoshihiko Sawa, Masatsugu Suzuki, Yuichi Ashikaga, Yuji Yamaoka, Y Totsuka, Shigemitsu YoshidaAbstract:The expression of leukocyte adhesion molecules on Lymphatic vessels of the human tongue was examined using histochemical and immunohistochemical methods. Three different types of Lymphatic vessels were distinguished: type I vessels expressed intercellular adhesion molecule-1 (ICAM-1), platelet-endothelial cell adhesion molecule-1 (PECAM-1), and endothelial cell-selectin (ELAM-1); type II vessels expressed ICAM-1 and PECAM-1; and type III vessels expressed PECAM-1 only. The Lymphatic vessels located very close to the oral epithelium (Lymphatic capillaries) and the other Lymphatic vessels near the oral epithelium were type I. The Lymphatic vessels in the submucosal connective tissue (collecting Lymphatic vessels) were type II and type III. The results suggest that there may be functional differences in the Lymphatic Endothelium, where Lymphatic capillaries are more active than collecting Lymphatic vessels in lymphocyte migration from tissue into the Lymphatic vessels.
David G. Jackson - One of the best experts on this subject based on the ideXlab platform.
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homodimerization of the lymph vessel endothelial receptor lyve 1 through a redox labile disulfide is critical for hyaluronan binding in Lymphatic Endothelium
Journal of Biological Chemistry, 2016Co-Authors: Suneale Banerji, William Lawrance, Clive Metcalfe, David Briggs, Akira Yamauchi, Omer Dushek, Anton P Van Der Merwe, Anthony J Day, David G. JacksonAbstract:The Lymphatic vessel endothelial receptor LYVE-1 is implicated in the uptake of hyaluronan (HA) and trafficking of leukocytes to draining lymph nodes. Yet LYVE-1 has only weak affinity for hyaluronan and depends on receptor clustering and higher order ligand organization for durable binding in Lymphatic Endothelium. An unusual feature of LYVE-1 not found in other HA receptors is the potential to form disulfide-linked homodimers. However, their influence on function has not been investigated. Here we show LYVE-1 homodimers are the predominant configuration in Lymphatic Endothelium in vitro and in vivo, and formation solely requires the unpaired cysteine residue Cys-201 within the membrane-proximal domain, yielding a 15-fold higher HA binding affinity and an ∼67-fold slower off-rate than the monomer. Moreover, we show non-dimerizing LYVE-1 mutants fail to bind HA even when expressed at high densities in Lymphatic endothelial cells or artificially cross-linked with antibody. Consistent with these findings, small angle X-ray scattering (SAXS) indicates the Cys-201 interchain disulfide forms a hinge that maintains the homodimer in an "open scissors" conformation, likely allowing arrangement of the two HA binding domains for mutual engagement with ligand. Finally, we demonstrate the Cys-201 interchain disulfide is highly labile, and selective reduction with TCEP-HCl disrupts LYVE-1 homodimers, ablating HA binding. These findings reveal binding is dependent not just on clustering but also on the biochemical properties of LYVE-1 homodimers. They also mark LYVE-1 as the first Link protein superfamily member requiring covalent homodimerization for function and suggest the interchain disulfide acts as a redox switch in vivo.
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The chemokine CX3CL1 promotes trafficking of dendritic cells through inflamed Lymphatics
Journal of Cell Science, 2013Co-Authors: Louise A. Johnson, David G. JacksonAbstract:Summary Tissue inflammation is characterised by increased trafficking of antigen-loaded dendritic cells (DCs) from the periphery via afferent Lymphatics to draining lymph nodes, with a resulting stimulation of ongoing immune responses. Transmigration across Lymphatic Endothelium constitutes the first step in this process and is known to involve the chemokine CCL21 and its receptor CCR7. However, the precise details of DC transit remain obscure and it is likely that additional chemokine-receptor pairs have roles in Lymphatic vessel entry. Here, we report that the transmembrane chemokine CX3CL1 (fractalkine) is induced in inflamed Lymphatic Endothelium, both in vitro in TNF-α-treated human dermal Lymphatic endothelial cells (HDLECs) and in vivo in a mouse model of skin hypersensitivity. However, unlike blood endothelial cells, which express predominantly transmembrane CX3CL1 as a leukocyte adhesion molecule, HDLECs shed virtually all CX3CL1 at their basolateral surface through matrix metalloproteinases. We show for the first time that both recombinant soluble CX3CL1 and endogenous secreted CX3CL1 promote basolateral-to-luminal migration of DCs across HDLEC monolayers in vitro. Furthermore, we show in vivo that neutralising antibodies against CX3CL1 dramatically reduce allergen-induced trafficking of cutaneous DCs to draining lymph nodes as assessed by FITC skin painting in mice. Finally, we show that deletion of the CX3CL1 receptor in Cx3cr1−/− DCs results in markedly delayed Lymphatic trafficking in vivo and impaired transLymphatic migration in vitro, thus establishing a previously unrecognised role for this atypical chemokine in regulating DC trafficking through the Lymphatics.
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inflammation induced secretion of ccl21 in Lymphatic Endothelium is a key regulator of integrin mediated dendritic cell transmigration
International Immunology, 2010Co-Authors: Louise A. Johnson, David G. JacksonAbstract:Tissue inflammation induces rapid mobilization of antigen-charged dendritic cells (DCs), which migrate to draining lymph nodes via afferent Lymphatics to elicit the immune response. This increase in DC trafficking has been shown to require integrin-dependent adhesion to ICAM-1 and VCAM-1, expressed on inflamed Lymphatic Endothelium. In addition, both constitutive- and inflammation-induced DC migration involves the chemokine CCL21, which most likely triggers integrin activation on DC via its receptor CCR7. Recently, however, conflicting evidence has suggested that DC entry occurs independently of integrins, implying that the role of CCL21 in Lymphatics is purely chemotactic. Hence, while CCL21 is reported to be inducible during inflammation, the details of this induction and the role of CCL21 during initial DC trafficking are unclear. Here, we have characterized both the production of CCL21 and the mechanism of its action in DC transmigration using primary human dermal Lymphatic endothelial cells (HDLECs) and a mouse model of skin contact hypersensitivity. We showed that CCL21 is constitutively expressed intracellularly but rapidly secreted after exposure to the inflammatory cytokine tumour necrosis factor (TNF) α following de novo RNA and protein synthesis. Furthermore, using in vitro transmigration assays, we showed that endogenous HDLEC-derived CCL21 stimulates DC transLymphatic migration by a predominantly chemotactic mechanism in resting HDLEC and by a β2 integrin-mediated mechanism in TNFα-stimulated HDLEC. These results imply a direct role for CCL21 in Lymphatic transmigration that involves the selective use of integrin activation in inflammation.
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mouse lyve 1 is an endocytic receptor for hyaluronan in Lymphatic Endothelium
Journal of Biological Chemistry, 2001Co-Authors: Remko Prevo, Suneale Banerji, David J P Ferguson, Steven Clasper, David G. JacksonAbstract:Abstract The glycosaminoglycan hyaluronan is a key substrate for cell migration in tissues during inflammation, wound healing, and neoplasia. Unlike other matrix components, hyaluronan (HA) is turned over rapidly, yet most degradation occurs not locally but within distant lymph nodes, through mechanisms that are not yet understood. While it is not clear which receptors are involved in binding and uptake of hyaluronan within the Lymphatics, one likely candidate is the Lymphatic endothelial hyaluronan receptor LYVE-1 recently described in our laboratory (Banerji, S., Ni, J., Wang, S., Clasper, S., Su, J., Tammi, R., Jones, M., and Jackson, D.G. (1999)J. Cell Biol. 144, 789–801). Here we present evidence that LYVE-1 is involved in the uptake of hyaluronan by Lymphatic endothelial cells using a new murine LYVE-1 orthologue identified from the EST data base. We show that mouse LYVE-1 both binds and internalizes hyaluronan in transfected 293T fibroblasts in vitro and demonstrate using immunoelectron microscopy that it is distributed equally among the luminal and abluminal surfaces of Lymphatic vessels in vivo. In addition, we show by means of specific antisera that expression of mouse LYVE-1 remains restricted to the Lymphatics in homozygous knockout mice lacking a functional gene for CD44, the closest homologue of LYVE-1 and the only other Link superfamily HA receptor known to date. Together these results suggest a role for LYVE-1 in the transport of HA from tissue to lymph and imply that further novel hyaluronan receptors must exist that can compensate for the loss of CD44 function.
Mihaela Skobe - One of the best experts on this subject based on the ideXlab platform.
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abstract lb 333 Lymphatic Endothelium increases antioxidant capacity of triple negative breast cancer cells and protects from cell death
Cancer Research, 2017Co-Authors: Mirela Berisa, Simona Podgrabinska, Jerry E Chipuk, Mihaela SkobeAbstract:Involvement of Lymphatic system with cancer and the extent of lymph node metastases are directly correlated with the poor patient outcome. However, it is not understood whether the presence of Lymphatic metastases is only indicative of an aggressive cancer or if the Lymphatic vessel microenvironment directly contributes to the metastatic progression. We demonstrate that soluble factors produced by Lymphatic endothelial cells (LECs) protect triple negative breast cancer cells from cell death in vitro. Co-culture with LECs or LEC-conditioned medium (LEC-CM) protected cancer cells from death induced by the loss of homotypic cell adhesion, nutrient deprivation, or loss of matrix attachment. High levels of reactive oxygen species (ROS) preceded cell death, and were significantly decreased in tumor cells upon treatment with LEC-CM. Furthermore, LEC-CM protected tumor cells from death induced by exogenous oxidative stress (H2O2), while treatment with the anti-oxidant N-acetyl-cysteine (NAC) recapitulated the cytoprotective effect of LEC-CM. RNA-Seq analysis revealed Nrf2 pathway as the most upregulated stress-pathway induced in tumor cells upon loss of adhesion. Nrf2 and other stress signaling pathways were significantly diminished in the presence of LEC-CM. Pharmacological inhibition of the pentose phosphate pathway (PPP) and the components of thioredoxin and glutathione scavanging systems increased ROS and cell death in LEC-CM indicating that the maintenance of redox homeostasis and cell viability by LEC-CM is dependent on the PPP pathway and in particular thioredoxin system. Furthermore, LEC-CM preserved integrity and function of mitochondria. These results demonstrate that soluble factors produced by Lymphatic Endothelium promote survival of triple-negative breast cancer cells under stress by regulating tumor cell redox homeostasis and promoting mitochondrial function. Citation Format: Mirela Berisa, Simona Podgrabinska, Jerry Chipuk, Mihaela Skobe. Lymphatic Endothelium increases antioxidant capacity of triple-negative breast cancer cells and protects from cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-333. doi:10.1158/1538-7445.AM2017-LB-333
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abstract 4368 tumor cell entry into the lymph node is controlled by ccl1 chemokine expressed by lymph node Lymphatic sinuses
Cancer Research, 2012Co-Authors: Suvendu Das, Eliana Sarrou, Melanie Cassella, Nikki Feirt, Mihaela SkobeAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The Lymphatic vessels are thought to contribute to metastasis primarily by serving as a transportation system. It is widely believed that tumor cells enter lymph nodes passively, by the flow of lymph. Here, we demonstrate that lymph node Lymphatic sinuses control tumor cell entry into the lymph node. In vitro, tumor migration to Lymphatic Endothelium (LECs) was inhibited by blocking CCR8 or CCL1. Recombinant CCL1 promoted migration of CCR8+ tumor cells. Pro-inflammatory mediators TNF-α, IL-1α and LPS increased CCL1 production by LECs as well as tumor cell migration to LECs. Blocking studies showed that CCL1 is a key molecule mediating tumor cell chemotaxis to inflamed Lymphatic Endothelium. In mouse and human tissues CCL1 protein was detected in lymph node Lymphatic sinuses, but not in the peripheral Lymphatics. In addition, CCR8 was strongly expressed by human malignant melanoma. In a mouse model, blocking CCR8 function decreased lymph node metastasis. Notably, inhibition of CCR8 led to the arrest of tumor cells in the collecting Lymphatic vessels at the junction with the lymph node subcapsular sinus. These data identify a novel function for CCL1/CCR8 in metastasis and lymph node LECs as a critical check-point for entry of metastases into the lymph nodes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4368. doi:1538-7445.AM2012-4368
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inflamed Lymphatic Endothelium suppresses dendritic cell maturation and function via mac 1 icam 1 dependent mechanism
Journal of Immunology, 2009Co-Authors: Simona Podgrabinska, Okebugwu Kamalu, Lloyd Mayer, Motomu Shimaoka, Hans Snoeck, Gwendalyn J Randolph, Mihaela SkobeAbstract:The Lymphatic system is essential for the generation of immune responses by facilitating immune cell trafficking to lymph nodes. Dendritic cells (DCs), the most potent APCs, exit tissues via Lymphatic vessels, but the mechanisms of interaction between DCs and the Lymphatic Endothelium and the potential implications of these interactions for immune responses are poorly understood. In this study, we demonstrate that Lymphatic endothelial cells (LECs) modulate the maturation and function of DCs. Direct contact of human monocyte-derived DCs with an inflamed, TNF-alpha-stimulated Lymphatic Endothelium reduced expression of the costimulatory molecule CD86 by DCs and suppressed the ability of DCs to induce T cell proliferation. These effects were dependent on adhesive interactions between DCs and LECs that were mediated by the binding of Mac-1 on DCs to ICAM-1 on LECs. Importantly, the suppressive effects of the Lymphatic Endothelium on DCs were observed only in the absence of pathogen-derived signals. In vivo, DCs that migrated to the draining lymph nodes upon inflammatory stimuli, but in the absence of a pathogen, showed increased levels of CD86 expression in ICAM-1-deficient mice. Together, these data demonstrate a direct role of LECs in the modulation of immune response and suggest a function of the Lymphatic Endothelium in preventing undesired immune reactions in inflammatory conditions.
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Lymphatic Endothelium morphological molecular and functional properties
Journal of Cell Biology, 2003Co-Authors: Michael S Pepper, Mihaela SkobeAbstract:The Lymphatic microvasculature is uniquely adapted for the continuous removal of interstitial fluid and proteins, and is an important point of entry for leukocytes and tumor cells. The traditional view that Lymphatic capillaries are passive participants in these tasks is currently being challenged. This overview highlights recent advances in our understanding of the molecular mechanisms underlying the formation and function of Lymphatic vessels.
Sirpa Jalkanen - One of the best experts on this subject based on the ideXlab platform.
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clever 1 mediates lymphocyte transmigration through vascular and Lymphatic Endothelium
Blood, 2004Co-Authors: Marko Salmi, Kaisa Koskinen, Tiina Henttinen, Kati Elima, Sirpa JalkanenAbstract:Common Lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1; also known as stabilin-1 or FEEL-1) is a large multifunctional glycoprotein implicated in scavenging, angiogenesis, and cell adhesion. Here we studied the function of human CLEVER-1 in leukocyte trafficking. Lymphatic vessels expressed CLEVER-1 constitutively in skin in vivo, whereas on vascular Endothelium it appeared only upon inflammation. On isolated vascular endothelial cells, CLEVER-1 supported rolling and transmigration of peripheral blood mononuclear cells (PBMCs) under physiologically relevant laminar shear stress. Intriguingly, CLEVER-1 also mediated transmigration of leukocytes through cultured Lymphatic Endothelium under static conditions. Thus, synthesis of CLEVER-1 is differentially regulated on the 2 anatomically distinct vascular beds, and CLEVER-1 mediates the transmigration step of the leukocyte traffic in both of them. Notably, CLEVER-1 is the first adhesion molecule shown to be involved in the PBMC transmigration through the Lymphatic arm of the immune system.
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mannose receptor mr and common Lymphatic endothelial and vascular endothelial receptor clever 1 direct the binding of cancer cells to the lymph vessel Endothelium
Cancer Research, 2003Co-Authors: Heikki Irjala, Reidar Grenman, Kalle Alanen, Paivi Heikkila, Heikki Joensuu, Sirpa JalkanenAbstract:Although ∼50% of cancers give rise to metastases via the Lymphatic system, the mechanisms mediating this process have remained unknown. In this study, we have investigated the role of two Lymphatic endothelial molecules, the mannose receptor (MR) and common Lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 in adhesion of malignant cells to the Lymphatic Endothelium, and analyzed their expression in two clinical series consisting of squamous cell cancers of the head and neck (n = 17) and breast cancers (n = 72). Affinity of the tested head and neck cancer cell lines to the Lymphatic Endothelium varied greatly, but adhesion of all cell lines was dependent on both the MR and CLEVER-1. Almost all cancer specimens contained peritumoral vessels that expressed CLEVER-1 and MR, and also the intratumoral lymph vessels often expressed them in both tumor types. However, only intratumoral expression of these molecules seems to be essential for metastatic spread to the regional lymph nodes. Only 8 (22%) of the 36 axillary node-negative breast carcinomas expressed the MR on the intratumoral lymph vessels as compared with 16 (50%) of the 32 node-positive carcinomas (P = 0.017), and all eight head and neck carcinoma patients with regional lymph node metastases at diagnosis had tumors that expressed CLEVER-1 on the intratumoral lymph vessels. These data suggest a role for both the MR and CLEVER-1 in directing the traffic of cancer cells within the Lymphatic system.
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mannose receptor is a novel ligand for l selectin and mediates lymphocyte binding to Lymphatic Endothelium
Journal of Experimental Medicine, 2001Co-Authors: Heikki Irjala, Evaliz Johansson, Reidar Grenman, Kalle Alanen, Marko Salmi, Sirpa JalkanenAbstract:Continuous lymphocyte recirculation between blood and lymphoid tissues forms a basis for the function of the immune system. Lymphocyte entrance from the blood into the tissues has been thoroughly characterized, but mechanisms controlling lymphocyte exit from the lymphoid tissues via efferent Lymphatics have remained virtually unknown. In this work we have identified mannose receptor (MR) on human Lymphatic Endothelium and demonstrate its involvement in binding of lymphocytes to Lymphatic vessels. We also show that the binding requires L-selectin, and L-selectin and MR form a receptor–ligand pair. On the other hand, L-selectin binds to peripheral lymph node addressins (PNAds) on high endothelial venules (HEVs) that are sites where lymphocytes enter the Lymphatic organs. Interestingly, MR is absent from HEVs and PNAds from Lymphatic Endothelium. Thus, lymphocyte L-selectin uses distinct ligand molecules to mediate binding at sites of lymphocyte entrance and exit within lymph nodes. Taken together, interaction between L-selectin and MR is the first molecularly defined mechanism mediating lymphocyte binding to Lymphatic Endothelium.
