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PubMed2006

Alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: impact of chemokines and adhesion molecules.

Influenza A virus pneumonia is characterized by severe lung injury and high mortality. Early infection elicits a strong recruitment of monocytes from the peripheral blood across the endo-/epithelial barrier into the alveolar air space. However, it is currently unclear which of the infected resident lung cell populations, alveolar epithelial cells or alveolar macrophages, elicit monocyte recruitment during influenza A virus infection. In the current study, we investigated whether influenza A virus infection of primary alveolar epithelial cells and resident alveolar macrophages would elicit a basal-to-apical monocyte transepithelial migration in vitro. We found that infection of alveolar epithelial cells with the mouse-adapted influenza A virus strain PR/8 strongly induced the release of monocyte chemoattractants CCL2 and CCL5 followed by a strong monocyte transepithelial migration, and this monocytic response was strictly dependent on monocyte CCR2 but not CCR5 chemokine receptor expression. Analysis of the adhesion molecule pathways demonstrated a role of ICAM-1, VCAM-1, integrin-associated protein (CD47), and junctional adhesion molecule-c on the epithelial cell surface interacting with monocyte beta(1) and beta(2) integrins and integrin-associated protein in the monocyte transmigration process. Importantly, addition of influenza A virus-infected alveolar macrophages further enhanced monocyte transmigration across virus-infected epithelium in a TNF-alpha-dependent manner. Collectively, the data show an active role for virus-infected alveolar epithelium in the regulation of CCL2/CCR2-dependent monocyte transepithelial migration during influenza infection that is essentially dependent on both classical beta(1) and beta(2) integrins but also junctional adhesion molecule pathways.

Animals↗
PubMed2006

Liver sinusoidal endothelial cells that endocytose allogeneic cells suppress T cells with indirect allospecificity.

A portal venous injection of allogeneic donor cells is known to prolong the survival of subsequently transplanted allografts. In this study, we investigated the role of liver sinusoidal endothelial cells (LSECs) in immunosuppressive effects induced by a portal injection of allogeneic cells on T cells with indirect allospecificity. To eliminate the direct CD4+ T cell response, C57BL/6 (B6) MHC class II-deficient C2tatm1Ccum (C2D) mice were used as donors. After portal injection of irradiated B6 C2D splenocytes into BALB/c mice, the host LSECs that endocytosed the irradiated allogeneic splenocytes showed enhanced expression of MHC class II molecules, CD80, and Fas ligand (FasL). Due to transmigration across the LSECs from BALB/c mice treated with a portal injection of B6 C2D splenocytes, the naive BALB/c CD4+ T cells lost their responsiveness to stimulus of BALB/c splenic APCs that endocytose donor-type B6 C2D alloantigens, while maintaining a normal response to stimulus of BALB/c splenic APCs that endocytose third-party C3H alloantigens. Similar results were not observed for naive BALB/c CD4+ T cells that transmigrated across the LSECs from BALB/c FasL-deficient mice treated with a portal injection of B6 C2D splenocytes. Adaptive transfer of BALB/c LSECs that had endocytosed B6 C2D splenocytes into BALB/c mice via the portal vein prolonged the survival of subsequently transplanted B6 C2D hearts; however, a similar effect was not observed for BALB/c FasL-deficient LSECs. These findings indicate that LSECs that had endocytosed allogeneic splenocytes have immunosuppressive effects on T cells with indirect allospecificity, at least partially via the Fas/FasL pathway.

Animals↗
PubMedDate not supplied

Role of Kaposi's sarcoma cells in recruitment of circulating leukocytes: implications in pathogenesis.

OBJECTIVE: We sought to identify and characterize mechanisms of interaction between Kaposi's sarcoma cells and circulating leukocytes leading to leukocyte migration into the lesion. STUDY DESIGN/METHODS: By using static and dynamic adhesion models, we measured the ability of late-stage KSY1 cells to support adhesion and transmigration of peripheral blood lymphocytes (PBL). RESULTS: We showed that resting as well as TNF-alpha- or PMA-activated KSY1 cells supported adhesion and transmigration of PBL with a higher efficiency compared with normal endothelial cells. The LFA1/ICAM1 pathway was totally involved in PBL adhesion to resting or TNF-alpha-activated KSY1 cells and partially responsible for adhesion to PMA-activated KSY1 cells. No inhibition of adhesion was observed by blockage of the VLA4 pathway. Under flow conditions, PBL/KSY1 cell interaction was totally dependent on L-selectin. CONCLUSION: Our data indicate that KS cells mimic an endothelium-like structure by regulating extravasation of lymphocytes into lesions.

Cell Aggregation↗
PubMed1999

Cutting edge: combined treatment of TNF-alpha and IFN-gamma causes redistribution of junctional adhesion molecule in human endothelial cells.

Proinflammatory cytokines such as TNF-alpha and IFN-gamma induce cell adhesion molecules in endothelial cells and promote transmigration of leukocytes across endothelial cells. However, when those two were administered together, leukocyte transmigration paradoxically decreased. We cloned a human and bovine homologue of the junctional adhesion molecule (JAM), a novel molecule at the tight junction, and examined the effects of proinflammatory cytokines on JAM in HUVECs. The combined treatment of TNF-alpha plus IFN-gamma caused a disappearance of JAM from intercellular junctions. However, flow cytometry, cell ELISA, and subcellular fractionation analysis demonstrated that the amount of JAM was not reduced. This suggested that JAM changed its distribution in response to proinflammatory cytokines. This redistribution of JAM might be involved in a decrease in transendothelial migration of leukocytes at inflammatory sites.

Amino Acid Sequence↗
PubMed1999

Adoptive T-cell therapy for B-cell acute lymphoblastic leukemia: preclinical studies.

We have previously shown that leukemia-specific cytotoxic T cells (CTL) can be generated from the bone marrow of most patients with B-cell precursor acute leukemias. If these antileukemia CTL are to be used for adoptive immunotherapy, they must have the capability to circulate, migrate through endothelium, home to the bone marrow, and, most importantly, lyse the leukemic cells in a leukemia-permissive bone marrow microenvironment. We demonstrate here that such antileukemia T-cell lines are overwhelmingly CD8(+) and exhibit an activated phenotype. Using a transendothelial chemotaxis assay with human endothelial cells, we observed that these T cells can be recruited and transmigrate through vascular and bone marrow endothelium and that these transmigrated cells preserve their capacity to lyse leukemic cells. Additionally, these antileukemia T-cell lines are capable of adhering to autologous stromal cell layers. Finally, autologous antileukemia CTL specifically lyse leukemic cells even in the presence of autologous marrow stroma. Importantly, these antileukemia T-cell lines do not lyse autologous stromal cells. Thus, the capacity to generate anti-leukemia-specific T-cell lines coupled with the present findings that such cells can migrate, adhere, and function in the presence of the marrow microenvironment enable the development of clinical studies of adoptive transfer of antileukemia CTL for the treatment of ALL.

Blood Transfusion, Autologous↗
PubMed1999

Effect of anti-ICAM-1 antibodies on macromolecular leakage and leukocyte activation: a study of hindlimb allografts in the rat.

We investigated the ability of anti-ICAM-1 monoclonal antibodies to reduce endothelial cell damage by assessing microvascular permeability and microcirculatory function during the acute phase of allograft rejection. The composite rat hindlimb-cremaster muscle transplantation model was employed in three experimental groups of 18 animals each. Isograft control transplantations were performed between genetically identical Lewis (LEW, RT11) rats. Allograft transplantations were performed across a major histocompatibility barrier between Lewis-Brown-Norway (LBN, RT-11+n), and Lewis (LEW, RT11) rats. In addition, a third group of animals receiving allografts was treated with 1 mg/kg/day of anti-ICAM-1 monoclonal antibody. After 24 hours, 72 hours, and 7 days, we measured microvascular permeability, leukocyte activation, functional capillary perfusion, red blood cell velocity, vessel diameters, and endothelial edema index in six animals per each follow-up period. Endothelial cell damage was assessed by measuring graft permeability to fluorescein isothiocyanate-labeled albumin (0.2 ml/100 g body weight) with computer-aided image analysis. Mean microvascular permeability was lower in the treated allograft group than in untreated controls at all follow-up times (p<0.001). In addition, anti-ICAM-1 treatment significantly reduced the activation of sticking leukocytes at 24 and 72 hours (p<0.001) and the activation of transmigrating leukocytes at 72 hours and 7 days (p<0.05). The allografts presented a characteristic microcirculatory pattern of acute rejection as early as 24 hours after transplantation. The dysfunction of the endothelial cell barrier at all time points was indicated by significant increases in the degree of allograft macromolecular permeability and in the number of activated sticking and transmigrating leukocytes. Treatment with anti-ICAM-1 antibodies significantly reduced the surge of leukocytes in the allograft transplants and protected the endothelial barrier from the acute effects of transplantation trauma.

Animals↗
PubMed1999

Caco-2 monolayer as a model for transepithelial migration of the fungal pathogen Candida albicans.

A model for transepithelial migration of human fungal pathogens was established, in which Candida albicans was shown to migrate across a monolayer of Caco-2 intestinal cells in a two-chamber system. Electron microscopy revealed typical stages of epithelial penetration by C. albicans including phagocytosis at the apical side, intra- and intercellular migration and exit on the basolateral side of the monolayer. Hyphal growth forms appeared particularly involved in penetration of the Caco-2 monolayer. The model was examined using defined C. albicans mutants defective in hyphal development (efg1/efg1) or growth (ura3/ura3). Transmigration of the efg1/efg1 mutant strain was reduced, while transmigration of the ura3/ura3 strain was blocked completely in the absence of uridine. Because these results parallel virulence characteristics of the mutants the Caco-2 monolayer system appears a useful model for the study of fungal-human host cell interactions.

Caco-2 Cells↗
PubMed2000

Sequential migration of neutrophils across monolayers of endothelial and epithelial cells.

In the course of granulocyte-dominated lung inflammation, granulocytes migrate across the endothelium and epithelium of the lung and cause severe tissue damage. To study this process in more detail, we developed a bilayer transmigration model composed of primary human endothelial and lung epithelial cells, simultaneously cultured on opposite sides of Transwell filters. Electron microscopical analysis showed that the morphology of the cells and the expression of junctional proteins remained unaltered and that matrix components were deposited onto the filter. Intriguingly, neutrophil migration was more efficient across the bilayers than across single epithelial monolayers and did not differ from migration across single endothelial monolayers. Coculture experiments showed that endothelial cells stimulated epithelial cells to release IL-6 and that epithelial cells enhanced release of IL-8 from endothelial cells. Together these data reveal bidirectional signaling and enhanced neutrophil migration in a transmigration model of primary human epithelial and endothelial cells.

Adenocarcinoma↗
PubMed2001

Anti-inflammatory effects of the partially purified extract of radix Stephaniae tetrandrae: comparative studies of its active principles tetrandrine and fangchinoline on human polymorphonuclear leukocyte functions.

We hypothesized that prevention of neutrophil from activation may underlie the myocardial protective effect of the specially processed extract of radix Stephaniae tetrandrae (SPRST). Inflammatory responses in isolated peripheral human neutrophils were studied in the presence or absence of SPRST. SPRST (1-10 microg/ml) concentration-dependently prevented N-formyl-methionyl-leucyl-phenylalanine (fMLP)- or leukotriene B(4) (LTB(4))-induced neutrophil adhesion and transmigration. Comparable results were also observed in neutrophils pretreated with fangchinoline (Fan) or tetrandrine (Tet), two active components in SPRST. It has been reported that neutrophil adhesion/transmigration is mainly Mac-1 (CD11b/CD18)-dependent and could be modulated by reactive oxygen species (ROS) production. SPRST, Tet, and Fan diminished fMLP- or LTB4-induced Mac-1 up-regulation and ROS production. SPRST, Fan, Tet, and verapamil impaired fMLP-induced rapid intracellular alkalization, an essential mechanism for neutrophil ROS production, and [Ca(2+)](i) increment, suggesting that a calcium dependent pathway might be involved. Direct G protein activation by AlF(4)(-) also triggered [Ca(2+)](i) increment and adhesion that could be abolished by pertussis toxin and were partially reversed by SPRST, Fan, and Tet. These results reveal that inhibition of neutrophil adhesion and transmigration may account for SPRST's myocardial protective effect. This effect of SPRST may be mediated by component(s) in addition to Tet and Fan because combination of 0.1 microg/ml of Tet and Fan did not mimic the effect of SPRST. We conclude that SPRST exerts anti-inflammatory effects by interfering with ROS production and Ca(2+) influx through G protein modulation to prevent Mac-1 up-regulation in neutrophil activation.

Alkaloids↗
PubMed2000

[The state of vector-borne diseases in Indonesia].

From epidemiological point of view, Indonesia is an extremely interesting area owing its insular structure and ecological, anthropological, cultural and economical diversity. As everywhere, vector-borne diseases are the result of complex and variable epidemiological systems, subject both to biogeographical rules and human activity. Two main arboviroses are present in Indonesia: dengue and Japanese encephalitis. Dengue appears as an endemoepidemic disease and is mostly circumscribed to urban areas. Haemorrhagic cases were first observed in 1968; since then, the incidence has been constantly increasing and the disease is now one of the principal causes of child lethality. Japanese encephalitis is a rural endemic disease transmitted by rice-field mosquitoes; its incidence remains relatively low since pigs, which are usual link-hosts for the virus, are uncommon in this mainly Muslem country. Human clinical cases are recorded from non-Muslem islands such as Bali or Irian Jaya which raises the question of immunisation for travellers. Recently, Japanese encephalitis was observed on east of the Wallace line which had been considered as the eastern cut-off line. Malaria is common throughout the country, Plasmodium vivax being the most frequent species. Some of the Anopheline vectors are related to brackish water as are coastal species; others have been favoured by rice growing. Several species bite and rest outdoors, rendering control measures complex. Moreover, chloroquine resistance is increasing in both P. falciparum and P. vivax. All three filaria species responsible for human lymphatic filariasis exist in Indonesia. Bancroft filariasis is present in rather limited foci on most of the islands; malayan filariasis is very prevalent on many islands, mostly in coastal areas, and Timor filariasis exist only on a few small islands. These parasitic diseases are cumulative and do not practically endanger the health of travellers. In the past, plague was common on Java island, but today, human cases are very rare. Scrub typhus is prevalent everywhere, as is murine typhus, being very frequent in harbour cities and one of the main causes of hospitalisation for febrile syndromes.. On the whole, the situation of several of these diseases has been worsening in Indonesia for about thirty years. Although epidemiological situations constantly evolve, two recent occurrences should be paid particular attention: -transmigration which is now a national priority and greatly facilitates the spread of many pathogens, arboviroses or chloroquine-resistant plasmodia, but also of rats, mosquitoes, etc. -deforestation due either to land-farming by Javanese transmigrants or to sudden climatic changes such as El Niño in 1997. Such deep ecological transformations may have considerable and unforeseeable consequences on the epidemiology of vector-borne diseases in Indonesia.

Animals↗
PubMed2002

Neutrophils from MMP-9- or neutrophil elastase-deficient mice show no defect in transendothelial migration under flow in vitro.

Recent evidence has suggested a role for neutrophil proteases during certain inflammatory responses. We demonstrated previously that neutrophil proteases can degrade components of the adherens junctions during neutrophil-endothelial adhesion. We tested the hypothesis that degradation of VE-cadherin at lateral junctions by elastase or MMP-9 facilitates neutrophil transendothelial migration. Neutrophils from MMP-9 or elastase null mice and strain-matched control mice expressed high levels of LFA-1, Mac-1, and L-selectin on their cell surface. Under flow conditions, wild-type and deficient neutrophils rolled, arrested, and transmigrated activated murine endothelium. There was no difference in the total numbers of interacting neutrophils or in the percentage of transmigrated cells. In addition, deficient neutrophils remained capable of degrading murine endothelial VE-cadherin. These results indicate that although neutrophil proteases may play a role in the acute inflammatory response, neutrophil elastase or MMP-9 is not essential for neutrophil transendothelial migration in this murine system.

Animals↗
PubMed2003

Calpain-2 as a target for limiting prostate cancer invasion.

Mortality and morbidity of prostate cancer result from extracapsular invasion and metastasis. This tumor progression depends on active cell motility. Previous studies have shown that calpain-regulated rear detachment enabling forward locomotion is required for cell migration initiated by growth factor and adhesion receptors. Therefore, we asked whether calpain would be a target for limiting tumor progression, using as our model the PA DU-145 human prostate carcinoma cell line and a highly invasive subline, wild-type DU-145, derived from it. In vitro, the calpain-specific inhibitor CI-I (ALLN) and the preferential-but-less-specific inhibitor leupeptin decreased transmigration of both cell lines across a Matrigel barrier. These calpain inhibitors limited epidermal growth factor-induced motility but did not alter the growth rate of the tumor cells, as expected. Antisense down-regulation of the growth factor-activated calpain-2 (m-calpain) isoform also reduced transmigration and cell motility. These in vitro findings were then buttressed by in vivo studies, in which i.p. DU-145 tumor xenografts were treated with leupeptin. Tumor invasion into the diaphragm was reduced by leupeptin treatment for both the PA and wild-type DU-145 cells (from 1.7 to 0.78 for the parental line and 2.3 to 1.2 for the invasive derivative, respectively). Tumor cells of both types engineered to express calpain-2 antisense constructs also demonstrated a similar 50% reduced invasiveness in vivo. Finally, we found by gene expression survey of 53 human prostate tumors and 23 normal prostates that calpain was not up-regulated in relationship to invasiveness or metastatic activity, consistent with expectation from the biological role of this effector. Taken together, these results strongly suggest that epigenetic activation of calpain plays an important role in the invasion of human prostate cancer and that it can be targeted to reduce tumor progression.

Animals↗
PubMed1992

Eosinophil transendothelial migration induced by cytokines. I. Role of endothelial and eosinophil adhesion molecules in IL-1 beta-induced transendothelial migration.

IL-1 beta promotes adhesiveness in human umbilical vein endothelial cells (HuVEC) for eosinophils through expression of adhesion molecules including intercellular adhesion molecules-1 (ICAM-1), E-selectin, and vascular cell adhesion molecule-1 (VCAM-1). Using an in vitro endothelial monolayer system, we examined whether IL-1 beta or TNF-alpha can promote eosinophil transendothelial migration. We also evaluated the contributions of ICAM-1, E-selectin, VCAM-1, leukocyte adhesion complex (CD11/18), and very late Ag-4 (CD11b/18) (VLA-4) in this process using blocking mAb, and determined the changes in expression of CD11b and L-selectin on eosinophils that had undergone transmigration. IL-1 beta and TNF-alpha treatment of HuVEC (4 h, 5 ng/ml) induced significant transendothelial migration of eosinophils (a 4.1 +/- 0.4-fold (IL-1 beta) and 2.0 +/- 0.9-fold (TNF-alpha) increase from the spontaneous value of 3.2 +/- 0.3%). Increased CD11b expression and shedding of L-selectin were observed on eosinophils following IL-1 beta-induced eosinophil transendothelial migration. Studies with mAb revealed that blockade of either ICAM-1 or CD11/18 inhibited transmigration, while antibodies against VCAM-1 and VLA-4 had no inhibitory effect. Among antibodies which block beta 2 integrins, anti-CD18 mAb had the best inhibitory effect (88% inhibition). The combined inhibitory effect of anti-CD11a mAb and anti-CD11b mAb was roughly equal to that of anti-CD18, although anti-CD11a (31% inhibition) and anti-CD11b (52% inhibition) were less effective individually. Anti-ICAM-1 by itself inhibited IL-1 beta-induced eosinophil transendothelial migration (24% inhibition) whereas neither anti-E-selectin nor anti-VCAM-1 were effective inhibitors. Interestingly, the combination of anti-E-selectin and anti-VCAM-1 with anti-ICAM-1 inhibited IL-1 beta-induced eosinophil transendothelial migration significantly better (53% inhibition) than anti-ICAM-1 alone. These results suggest that although the initial attachment of eosinophils to IL-1 beta-activated endothelial cells involves VCAM-1, E-selectin, and ICAM-1, the subsequent transendothelial migration process relies heavily on ICAM-1 and CD11/18. Finally, the changes that eosinophils have been observed to undergo during infiltration in vivo, namely increased expression of CD11/18 and shedding of L-selectin, appear to take place as a direct result of the interaction between eosinophils and endothelial cells.

Antibodies, Monoclonal↗
PubMed1985

Transperitoneal migration and ovum capture in rabbits.

It is not fully understood how eggs are captured by the fallopian tube. The close proximity of tube and ovary, and the movements of the fimbria across the ovarian surface during ovulation, are believed to contribute to ovum pickup. We studied the efficiency of ovum capture when contact between fimbria and ovary is prevented and the extent to which ovum transmigration may contribute to fertility. Unilateral right oophorectomy was performed in 55 rabbits, which were divided into three groups: in Group A, the contralateral oviduct was left intact; in Group B, the ampulla of the contralateral oviduct was occluded; in Group C, contralateral total salpingectomy was performed. None of the rabbits in Group A conceived on the oophorectomized side. Seven of 19 animals became pregnant in Group B and 15 of 18 conceived in Group C. The results indicate that direct fimbrial-ovarian contact is not essential for ovum capture, and that ovum transmigration could contribute to fertility.

Animals↗
PubMed1993

Neutrophil adhesion to endothelial cells.

The emigration of neutrophils at sites of inflammation apparently requires intercellular adhesion. Initially, leukocyte adherence is observed in postcapillary venules where neutrophils roll along the luminal surface of the endothelial cells before stopping, changing shape, and migrating into the perivascular tissue. Recent evidence indicates that the adhesion molecules supporting the rolling phenomenon are distinct from those required for stopping and transmigration. The contribution of E-selectin (ELAM-1) to neutrophil adhesion and rolling was investigated using anti-E-selectin monoclonal antibody in an in vitro adhesion assay of isolated human neutrophils to murine L-cell monolayers stably transfected with human E-selectin cDNA. Isolated human neutrophils adhered to E-selectin expressing L-cell monolayers under physiological wall shear stress of 1.85 dynes/cm2 but not to untransfected L-cells or ICAM-1 expressing L-cells. 47.8 +/- 6.0% of these adherent cells were rolling at an average rolling velocity of 10.6 +/- 1.7 microns/second. This adhesion and rolling was almost completely blocked by anti-E-selectin monoclonal antibody. Monoclonal antibody to L-selectin also reduced adhesion to E-selectin expressing cells by 70%. Chemotactic stimulation of neutrophils reduced both the number of adherent and rolling cells and the average velocity of the rolling cells without influencing the percentage of attached cells that were rolling. Pretreatment with anti-CD18 monoclonal antibody did not reduce the adhesion of the activated neutrophils but reversed the reduction in velocity caused by activation of these cells. The inhibitory potential of the anti-E-selectin monoclonal antibody was much less pronounced in adhesion of isolated neutrophils to human umbilical vein endothelial cell monolayers under conditions of flow and was limited to one third of the total adhesion. The proportion of the adherent neutrophils which transmigrated to the subluminal space of the endothelial cell monolayers was independent of pretreatment with anti-E-selectin monoclonal antibody.

Animals↗
PubMed1994

Leukocyte recruitment into human skin transplanted onto severe combined immunodeficient mice induced by TNF-alpha is dependent on E-selectin.

In order to study the in vivo role of E-selectin in human inflammation, we have developed a model in which human skin is transplanted onto severe combined immunodeficient (SCID) mice. The grafted skin closely resembles normal skin and retains its human vasculature. After intradermal injection of rTNF-alpha, human E-selectin was rapidly up-regulated on dermal microvessels, with significant expression (determined immunohistochemically) at 1 h postinjection and maximum expression at 2 h postinjection. To study the functional role of E-selectin, a murine Ab against human E-selectin (mAb HEL 3/2) was developed that inhibited the in vitro adhesion of both human U937 cells and murine 32D cells to TNF-alpha-stimulated human endothelial cells. After intradermal injection of TNF-alpha, large numbers of murine leukocytes migrated into the grafts within 2 h. Intravenous injection of the antihuman E-selectin mAb 3/2 completely inhibited murine white blood cell (WBC) transmigration into the skin grafts, but an isotype-matched control Ab that also bound to human endothelium had no effect. Antihuman E-selectin mAb 3/2 was also able to inhibit the migration of i.v. 51Cr-labeled human neutrophils. These findings demonstrate that E-selectin is important in early white blood cell adhesion events and is required for TNF-alpha-induced white blood cell transmigration in the human/SCID mouse chimeric model.

Animals↗
PubMed1994

Suppressive effect of basic fibroblast growth factor on transendothelial emigration of CD4(+) T-lymphocyte.

The effect of basic fibroblast growth factor (b-FGF), one of the commonest angiogenic factors in various cancer types, on lymphocyte adhesion and transmigration across the endothelial cell monolayer was investigated using human umbilical vein-derived endothelial cells (HUVEC) and type I collagen gel. Forty-eight h exposure of HUVEC with 2 ng/ml b-FGF significantly decreased the basal adhesion of lymphocytes to endothelial cells. The decrease ratio is further enhanced by the addition of shear stress in this assay system. When HUVEC was stimulated for the last 24 h with optimal conditions of recombinant interleukin 1 beta, the percentages of transmigration as well as adhesion were also decreased significantly by the presence of b-FGF. The expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 was down-regulated by b-FGF exposure in both resting and activated conditions by recombinant interleukin 1 beta, supposedly the main reason for this phenomenon. The migrating cells across b-FGF-stimulated HUVEC contained a markedly lower percentage of CD4(+) T-cells than those across non-treated HUVEC, although the 4B4(+)/2H4(+) ratio in CD4(+) T-cell populations did not differ significantly. These facts suggest that the presence of b-FGF in the angiogenic area suppresses lymphocyte emigration, especially that of CD4(+) T-cells, and thus causes insufficient helper function in local immune response. This effect of b-FGF was possibly one of the critical mechanisms by which cancer cells escape from the host immune reactions in the angiogenic stage of tumor development.

CD4-Positive T-Lymphocytes↗
PubMed1994

Characterization of a spontaneously transformed human endothelial cell line.

BACKGROUND: A line of cells was isolated from a focus observed in a human umbilical vein endothelial cell (HUVEC) culture, presumably the result of a spontaneous transformation event. EXPERIMENTAL DESIGN: The cell line was continuously cultured for 16 months, after which time, the proliferative rate, capacity to be cloned, and ability to be transfected was investigated. The cell line was analyzed for expression of endothelial cell markers, von Willebrand Factor, P selectin, and scavenger receptor. We also examined the tumor necrosis factor (TNF)-mediated upregulation of E-selectin, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. We evaluated the levels of expression and types of TNF-alpha receptor expressed by the cell line, and the cell lines response to interleukin-4 and interferon-gamma. CD34 expression of this cell line and the ability of transforming growth factor-beta to inhibit the TNF-alpha induction of E-selectin was examined. The ability to support neutrophil adhesion and transmigration, and generate capillary-like tubes in vitro was assessed. Finally, the karyotype and tumourigenicity of this line was established. RESULTS: This cell line (C11STH) has a doubling time comparable to that of normal HUVECs and has a trisomy of chromosome 8 and 11. The cell line is capable of generating colonies at clonal density, and is transfectable with efficiencies comparable to normal HUVECs. C11STH expresses von Willebrand factor, P-selectin, and scavenger receptor to an extent similar to passaged HUVECs and can be induced to express E-selectin, VCAM, and ICAM with TNF-alpha. C11STH expresses both the p55 and p75 subunits of TNF-alpha receptor at levels similar to HUVECs. The ability of interleukin-4 to enhance the expression of VCAM and reduce the TNF-alpha-mediated expression of E-selectin is maintained in this cell line. C11STH cells are unable to induce class II major histocompatibility antigen in response to interferon-gamma. However, interferon-gamma is able to synergize with TNF to enhance the expression of E-selectin. C11STH cells do not express CD34 or show transforming growth factor-beta inhibition of TNF-alpha induced E-selectin expression, functions indicative of primary, or early passage HUVECs. The cell line retains the ability to support neutrophil adhesion and transmigration and can generate patent tubes when seeded onto complex basement membrane gels. However, the cell line no longer has the ability to generate capillary-like vessels when seeded onto collagen gels in the presence of phorbol 12-myristate 13-acetate. CONCLUSIONS: C11STH has retained many of the normal characteristics of endothelial cells, is able to proliferate at clonal density, and is easily transfectable. The line will provide a useful resource for endothelial cell biology. Its ability to make capillary-like tubes on basement membrane gels, but not on collagen will provide a powerful tool with which to further analyze the processes involved in angiogenesis, and will enable us to define the role of specific proteins in angiogenesis. Since C11STH shows tube competence on Matrigel, but is not tube competent on collagen, our studies suggest that capillary-tube formation on Matrigel and collagen occur via qualitatively different mechanisms. Thus, this cell line provides the opportunity to examine the signalling mechanisms required to generate capillary tube formation. These may include the involvement of matrix molecules, the production of proteases and inhibitors, gene regulation and kinases or phosphatases.

Cell Adhesion↗