scholarly journals Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient

2006 ◽  
Vol 397 (3) ◽  
pp. 461-471 ◽  
Author(s):  
Krishnan Venkataraman ◽  
Shobha Thangada ◽  
Jason Michaud ◽  
Myat Lin Oo ◽  
Youxi Ai ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Immune Cell ◽  
Umbilical Vein ◽  
Wild Type Mouse ◽  
Receptor Internalization ◽  
Lipid Mediator ◽  
Cell Trafficking ◽  
Hek 293 ◽  
Human Embryonic Kidney Cells ◽  
Mouse Plasma

Sphingosine 1-phosphate (S1P), produced by Sphks (sphingosine kinases), is a multifunctional lipid mediator that regulates immune cell trafficking and vascular development. Mammals maintain a large concentration gradient of S1P between vascular and extravascular compartments. Mechanisms by which S1P is released from cells and concentrated in the plasma are poorly understood. We recently demonstrated [Ancellin, Colmont, Su, Li, Mittereder, Chae, Stefansson, Liau and Hla (2002) J. Biol. Chem. 277, 6667–6675] that Sphk1 activity is constitutively secreted by vascular endothelial cells. In the present study, we show that among the five Sphk isoforms expressed in endothelial cells, the Sphk-1a isoform is selectively secreted in HEK-293 cells (human embryonic kidney cells) and human umbilical-vein endothelial cells. In sharp contrast, Sphk2 is not secreted. The exported Sphk-1a isoform is enzymatically active and produced sufficient S1P to induce S1P receptor internalization. Wild-type mouse plasma contains significant Sphk activity (179 pmol·min−1·g−1). In contrast, Sphk1−/− mouse plasma has undetectable Sphk activity and approx. 65% reduction in S1P levels. Moreover, human plasma contains enzymatically active Sphk1 (46 pmol·min−1·g−1). These results suggest that export of Sphk-1a occurs under physiological conditions and may contribute to the establishment of the vascular S1P gradient.

Stabilin-1 and Stabilin-2 Are Expressed in Bone Marrow Sinusoidal Endothelial Cells and Mediate Scavenging and Cell Adhesive Functions

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1368-1368
Author(s):  
Hong Qian ◽  
Sophie Johansson ◽  
Peter McCourt ◽  
Bård Smedsrød ◽  
Marja Ekblom ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Cell Trafficking ◽  
Tissue Remodelling ◽  
Sinusoidal Endothelial Cells ◽  
Recognition Mechanism ◽  
Hek 293 ◽  
Human Embryonic Kidney Cells ◽  
Transfected Cells ◽  
Specific Recognition

Abstract Stabilin-1 and stabilin-2 have been identified as scavenging receptors in sinusoidal capillaries in some tissues, including liver and spleen. They function as endocytic receptors for SPARC and hyaluronan, respectively, and for several other ligands. In the present study, we show by real-time PCR, Western blot and immunohistochemistry that bone marrow (BM) sinusoidal endothelial cells (SECs) ubiquitously express stabilin-1 and stabilin-2. To test the ability of BM SECs to function as a scavenging endothelium, we analyzed the uptake of specific scavenger receptor ligands after intravenous injection. Accumulation of TRITC labelled formaldehyde-treated serum albumin (FSA) was observed one hour after the injection in the BM SECs. Injection of unlabelled FSA together with TRITC-FSA reduced the fluorescence in the SECs, indicating that the uptake was due to specific recognition of FSA. Likewise, FITC-conjugated advanced glycation end products (AGEs)-modified BSA accumulated in BM SECs. These two ligands are primarily cleared by the stabilins. These results suggested that bone marrow SECs have a scavenging function. Stabilin-2 has been identified as a major receptor for hyaluronan. Hyaluronan is synthesized by primitive hematopoietic cells and has been shown to influence stem and progenitor (HSPC) functions, including mobilization and homing into BM (Nilsson et al., Blood.2003;101:856). Consequently, it is possible that adhesion of hyaluronan on HSPCs to stabilin-2 is a recognition mechanism in BM SECs, directing circulating HSPCs into BM. To investigate this, we studied adhesion of mouse BM lin-Sca-1+Kit+ (LSK) HSPCs to stabilin-1 or stabilin-2 transfected human embryonic kidney cells (HEK 293 cells). We found increased adhesion of LSK cells to stabilin-2 expressing cells, as compared to stabilin-1 expressing or non-transfected cells. Notably, hyaluronidase treatment abolished the increased adhesion of the LSK cell to stabilin-2 transfected cells. These findings indicate that stabilin-2 mediates adhesion of HSPCs to bone marrow SECs. In conclusion, this study shows a novel function for BM SECs as a scavenging endothelium expressing stabilin-1 and stabilin-2. The specific function of stabilins in recognition and endocytosis of extracellular matrix molecules, including hyaluronan and SPARC (Kzhyshkowska J et al., J Cell Mol Med.2006;10:635), suggests that these receptors are involved in tissue remodelling and cell trafficking in BM. Importantly, hyaluronan-mediated binding of HSPCs to SEC stabilin-2 may be a specific recognition mechanism for HSPCs in BM sinusoids. Similarly, binding of tumour cell-associated hyaluronan by stabilin-2 might cause tumour cells in blood to halt in bone marrow, thereby increasing the likelihood for metastasis at this site.

scholarly journals Dengue Virus Induces Novel Changes in Gene Expression of Human Umbilical Vein Endothelial Cells

2003 ◽  
Vol 77 (21) ◽  
pp. 11822-11832 ◽  
Author(s):  
Rajas V. Warke ◽  
Kris Xhaja ◽  
Katherine J. Martin ◽  
Marcia F. Fournier ◽  
Sunil K. Shaw ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Dengue Virus ◽  
Immune Cell ◽  
Umbilical Vein ◽  
Oligoadenylate Synthetase ◽  
Functional Responses ◽  
Human Umbilical Vein ◽  
Phospholipid Scramblase ◽  
Umbilical Vein Endothelial Cells

ABSTRACT Endothelial cells are permissive to dengue virus (DV) infection in vitro, although their importance as targets of DV infection in vivo remains a subject of debate. To analyze the virus-host interaction, we studied the effect of DV infection on gene expression in human umbilical vein endothelial cells (HUVECs) by using differential display reverse transcription-PCR (DD-RTPCR), quantitative RT-PCR, and Affymetrix oligonucleotide microarrays. DD identified eight differentially expressed cDNAs, including inhibitor of apoptosis-1, 2′-5′ oligoadenylate synthetase (OAS), a 2′-5′ OAS-like (OASL) gene, galectin-9, myxovirus protein A (MxA), regulator of G-protein signaling, endothelial and smooth muscle cell-derived neuropilin-like protein, and phospholipid scramblase 1. Microarray analysis of 22,000 human genes confirmed these findings and identified an additional 269 genes that were induced and 126 that were repressed more than fourfold after DV infection. Broad functional responses that were activated included the stress, defense, immune, cell adhesion, wounding, inflammatory, and antiviral pathways. These changes in gene expression were seen after infection of HUVECs with either laboratory-adapted virus or with virus isolated directly from plasma of DV-infected patients. Tumor necrosis factor alpha, OASL, and MxA and h-IAP1 genes were induced within the first 8 to 12 h after infection, suggesting a direct effect of DV infection. These global analyses of DV effects on cellular gene expression identify potentially novel mechanisms involved in dengue disease manifestations such as hemostatic disturbance.

scholarly journals Pravastatin Alleviates Radiation Proctitis by Regulating Thrombomodulin in Irradiated Endothelial Cells

2020 ◽  
Vol 21 (5) ◽  
pp. 1897
Author(s):  
Hyosun Jang ◽  
Seo-Young Kwak ◽  
Sunhoo Park ◽  
Kyuchang Kim ◽  
Young-heon Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Leukocyte Adhesion ◽  
Umbilical Vein ◽  
Endothelial Damage ◽  
Radiation Proctitis ◽  
Radiation Induced ◽  
Lowering Drug ◽  
Adhesive Molecules

Although radiotherapy plays a crucial in the management of pelvic tumors, its toxicity on surrounding healthy tissues such as the small intestine, colon, and rectum is one of the major limitations associated with its use. In particular, proctitis is a major clinical complication of pelvic radiotherapy. Recent evidence suggests that endothelial injury significantly affects the initiation of radiation-induced inflammation. The damaged endothelial cells accelerate immune cell recruitment by activating the expression of endothelial adhesive molecules, which participate in the development of tissue damage. Pravastatin, a cholesterol lowering drug, exerts persistent anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells and inhibits the interaction of leukocytes and damaged endothelial cells. Here, we aimed to investigate the effects of pravastatin on radiation-induced endothelial damage in human umbilical vein endothelial cell and a murine proctitis model. Pravastatin attenuated epithelial damage and inflammatory response in irradiated colorectal lesions. In particular, pravastatin improved radiation-induced endothelial damage by regulating thrombomodulin (TM) expression. In addition, exogenous TM inhibited leukocyte adhesion to the irradiated endothelial cells. Thus, pravastatin can inhibit endothelial damage by inducing TM, thereby alleviating radiation proctitis. Therefore, we suggest that pharmacological modulation of endothelial TM may limit intestinal inflammation after irradiation.

scholarly journals TAL-1/SCL and Its Partners E47 and LMO2 Up-Regulate VE-Cadherin Expression in Endothelial Cells

2007 ◽  
Vol 27 (7) ◽  
pp. 2687-2697 ◽  
Author(s):  
Virginie Deleuze ◽  
Elias Chalhoub ◽  
Rawan El-Hajj ◽  
Christiane Dohet ◽  
Mikaël Le Clech ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Ectopic Expression ◽  
Intercellular Junctions ◽  
Hek 293 ◽  
Helix Loop Helix ◽  
293 Cells ◽  
Functional Consequences ◽  
Bona Fide

ABSTRACT The basic helix-loop-helix TAL-1/SCL essential for hematopoietic development is also required during vascular development for embryonic angiogenesis. We reported that TAL-1 acts positively on postnatal angiogenesis by stimulating endothelial morphogenesis. Here, we investigated the functional consequences of TAL-1 silencing in human primary endothelial cells. We found that TAL-1 knockdown caused the inhibition of in vitro tubulomorphogenesis, which was associated with a dramatic reduction in vascular endothelial cadherin (VE-cadherin) at intercellular junctions. Consistently, silencing of TAL-1 as well as of its cofactors E47 and LMO2 down-regulated VE-cadherin at both the mRNA and the protein level. Endogenous VE-cadherin transcription could be activated in nonendothelial HEK-293 cells by the sole concomitant ectopic expression of TAL-1, E47, and LMO2. Transient transfections in human primary endothelial cells derived from umbilical vein (HUVECs) demonstrated that VE-cadherin promoter activity was dependent on the integrity of a specialized E-box associated with a GATA motif and was maximal with the coexpression of the different components of the TAL-1 complex. Finally, chromatin immunoprecipitation assays showed that TAL-1 and its cofactors occupied the VE-cadherin promoter in HUVECs. Together, these data identify VE-cadherin as a bona fide target gene of the TAL-1 complex in the endothelial lineage, providing a first clue to TAL-1 function in angiogenesis.

scholarly journals Interleukin-1βExpression Is Required for Lysophosphatidic Acid-Induced Lymphangiogenesis in Human Umbilical Vein Endothelial Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Chih-Hsin Lin ◽  
JenHer Lu ◽  
Hsinyu Lee
Keyword(s):  
Endothelial Cells ◽  
Lysophosphatidic Acid ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Lipid Mediator ◽  
Vascular Endothelial ◽  
Human Umbilical Vein ◽  
Umbilical Vein Endothelial Cells ◽  
Endothelial Growth Factor

Lysophosphatidic acid (LPA) is a lipid mediator which binds to G-protein-coupled receptors and regulates various cellular responses, including inflammation of endothelial cells. Interleukin- (IL-) 1β, a proinflammatory cytokine, is elevated upon LPA treatment in human umbilical vein endothelial cells (HUVECs). Previous studies indicated that LPA upregulates vascular endothelial growth factor- (VEGF-) C and lymphatic marker expressions in HUVECs. However, the relationships between LPA-induced VEGF-C and IL-1βexpressions are not clear. In this paper, we demonstrated that, in the presence of AF12198, an inhibitor of the IL-1 receptor abolished LPA-induced VEGF-C and lymphatic marker expressions in HUVECs. Furthermore, LPA-inducedin vitrotube formation of HUVECs was also suppressed by pretreatment with AF12198. Our results suggest that LPA-stimulated lymphangiogenesis in HUVECs is mediated through IL-1β-induced VEGF-C expression.

HIV Envelope Protein gp120 Stimulates Expression of Specific Chemokines in Lymphatic Endothelial Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3102-3102
Author(s):  
Xuefeng Zhang ◽  
Jian Feng Wang ◽  
Jerome E. Groopman
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Cell ◽  
Cell Trafficking ◽  
Lymphatic Endothelial Cells ◽  
Infected Cells ◽  
Hiv Envelope ◽  
Hiv 1

Abstract Lymphoid organs are the major anatomical home of HIV, where the virus replicates during both the acute and chronic phases of infections. In this regard, there are significantly more infected cells in lymph nodes (LNs) than in circulating blood, and these infected cells are a major reservoir of infectious HIV. Certain chemokines like CCL19 (MIP-3β) and CCL21 (SLC) play key roles in immune cell trafficking to LNs. They induce specific homing of naïve T cells and dendritic cells into the T cell zone of secondary lymphoid organs. There, the T cells become activated by the dendritic cells. A network of channels composed of lymphatic endothelium exists in LNs that provides a route for this dendritic cell and T cell movement. To date, how this lymphatic endothelium may contribute to the pathogenesis of HIV infection has not been studied. This prompted us to investigate whether HIV may alter immune cell trafficking via interaction with this lymphatic network. Lymphatic endothelial cells (LEC) were separated from primary dermal microvascular endothelial cells. The phenotype of LEC was confirmed by immunostaining with specific lymphatic markers including VEGFR-3, LYVE-1, and podoplanin. Since HIV envelope proteins are presented to endothelial cells in the microenvironment, we studied the effects of X4 gp120 on LEC. Using a pathway specific cDNA array, we detected enhanced expression of a restricted repertoire of chemokines in LEC upon HIV-1 gp120 stimulation. Gp120 upregulated expression of the chemokine genes GRO-α, GRO-γ, MIP-3β, and SDF-1α and β in LEC. These chemokines can act to enhance T cell and dendritic cell homing to LNs. Furthermore, we also detected GRO-α, SDF-1, and SLC proteins in culture supernatants of the gp120-treated LEC. We did not observe upregulation of the chemokines RANTES and MCP-1 upon gp120 stimulation. Since dendritic cells mediate the HIV infectivity of CD4+ T cells by presenting HIV particles, our study suggests that HIV-1 gp120-induced production of a restricted repertoire of chemokines in LEC may accelerate the trafficking of infected dendritic cells to LNs and foster HIV infection in this reservoir.

scholarly journals Sphingosine 1-phosphate: Lipid signaling in pathology and therapy

Science ◽  
2019 ◽  
Vol 366 (6463) ◽  
pp. eaar5551 ◽  
Author(s):  
Andreane Cartier ◽  
Timothy Hla
Keyword(s):  
Immune Cell ◽  
Clinical Medicine ◽  
Lipid Mediator ◽  
Cell Trafficking ◽  
Multidisciplinary Research ◽  
Adaptive Immune ◽  
The Past ◽  
Sphingosine 1 Phosphate ◽  
Fibrotic Diseases ◽  
G Protein Coupled

Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein–coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases.

Endothelial intercellular adhesion molecule (ICAM)–2 regulates angiogenesis

Blood ◽  
2005 ◽  
Vol 106 (5) ◽  
pp. 1636-1643 ◽  
Author(s):  
Miao-Tzu Huang ◽  
Justin C. Mason ◽  
Graeme M. Birdsey ◽  
Valerie Amsellem ◽  
Nicole Gerwin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Adhesion Molecule ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Cell Contact ◽  
Cell Trafficking ◽  
Endothelial Junctions

Abstract Endothelial junctions maintain endothelial integrity and vascular homeostasis. They modulate cell trafficking into tissues, mediate cell-cell contact and regulate endothelial survival and apoptosis. Junctional adhesion molecules such as vascular endothelial (VE)–cadherin and CD31/platelet endothelial cell adhesion molecule (PECAM) mediate contact between adjacent endothelial cells and regulate leukocyte transmigration and angiogenesis. The leukocyte adhesion molecule intercellular adhesion molecule 2 (ICAM-2) is expressed at the endothelial junctions. In this study we demonstrate that endothelial ICAM-2 also mediates angiogenesis. Using ICAM-2–deficient mice and ICAM-2–deficient endothelial cells, we show that the lack of ICAM-2 expression results in impaired angiogenesis both in vitro and in vivo. We show that ICAM-2 supports homophilic interaction, and that this may be involved in tube formation. ICAM-2–deficient cells show defective in vitro migration, as well as increased apoptosis in response to serum deprivation, anti-Fas antibody, or staurosporine. ICAM-2 signaling in human umbilical vein endothelial cells (HUVECs) was found to activate the small guanosine triphosphatase (GTPase) Rac, which is required for endothelial tube formation and migration. These data indicate that ICAM-2 may regulate angiogenesis via several mechanisms including survival, cell migration, and Rac activation. Our findings identify a novel pathway regulating angiogenesis through ICAM-2 and a novel mechanism for Rac activation during angiogenesis.

Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages

Blood ◽  
2009 ◽  
Vol 113 (11) ◽  
pp. 2605-2613 ◽  
Author(s):  
Shinae Kang ◽  
Seung-Pyo Lee ◽  
Kyung Eun Kim ◽  
Hak-Zoo Kim ◽  
Sylvie Mémet ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessel ◽  
Immune Cell ◽  
Lymphatic Vessels ◽  
Nuclear Factor Κb ◽  
Cell Trafficking ◽  
Lymphatic Endothelial Cells ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling

The lymphatic vessel is a major conduit for immune cell transport; however, little is known about how lymphatic vessels regulate immune cell trafficking and how lymphatic vessels themselves respond to inflammation. Toll-like receptor 4 (TLR4) plays a central role in lipopolysaccharide (LPS)–induced inflammation, but the role of TLR4 in lymphatic endothelial cells (LECs) is poorly understood. Here, we found that LECs express high amounts of TLR4 in the intracellular region, and that the TLR4 of LECs is the main mediator of nuclear factor–κB (NF-κB) activation by LPS. LPS-TLR4 signaling in LECs resulted in the production of various chemokines for chemotaxis of macrophage. In addition, TLR4 in LECs actively contributed to the recruitment of macrophages to the draining lymphatic vessel. Furthermore, the macrophages that infiltrated into the lymphatic vessel induced lymphangiogenesis by secreting lymphangiogenic growth factors. These phenomena were largely attenuated not only in the mice defective in TLR4 signaling but also in the chimeric mice defective in TLR4 signaling that were recipients for bone marrow transplantation from normal TLR4-signaling mice. In conclusion, TLR4 in LECs plays an essential role in LPS-induced inflammatory lymphangiogenesis by chemotactic recruitment of macrophages.

scholarly journals Immune cell trafficking across the blood-brain barrier in the absence and presence of neuroinflammation

2020 ◽  
Vol 2 (1) ◽  
pp. H1-H18 ◽  
Author(s):  
Luca Marchetti ◽  
Britta Engelhardt
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Immune Cells ◽  
Immune Cell ◽  
Brain Barrier ◽  
Proper Function ◽  
Cell Trafficking ◽  
Immune Cell Trafficking ◽  
Blood Brain

To maintain the homeostatic environment required for proper function of CNS neurons the endothelial cells of CNS microvessels tightly regulate the movement of ions and molecules between the blood and the CNS. The unique properties of these blood vascular endothelial cells are termed blood-brain barrier (BBB) and extend to regulating immune cell trafficking into the immune privileged CNS during health and disease. In general, extravasation of circulating immune cells is a multi-step process regulated by the sequential interaction of adhesion and signalling molecules between the endothelial cells and the immune cells. Accounting for the unique barrier properties of CNS microvessels, immune cell migration across the BBB is distinct and characterized by several adaptations. Here we describe the mechanisms that regulate immune cell trafficking across the BBB during immune surveillance and neuroinflammation, with a focus on the current state-of-the-art in vitro and in vivo imaging observations.

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