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PubMed2000

In vitro studies on the trafficking of dendritic cells through endothelial cells and extra-cellular matrix.

Dendritic cells (DC) are antigen presenting cells (APC) with the unique ability to initiate an immune response. Immature DC are localized in peripheral tissues where they exert a sentinel function for incoming antigens (Ag). After Ag capture and exposure to inflammatory stimuli DC undergo maturation and migrate to regional lymph nodes where the presentation of antigenic peptides to T lymphocytes takes place. Thus their correct functioning as APC involves localization in tissues and trafficking via the lymph or blood to lymphoid organs. In the present study we have investigated the ability of DC to interact in vitro with human vascular endothelial cells (EC) and extracellular matrix (ECM). DC are differentiated from monocytes by in vitro exposure to GM-CSF and IL-13 for 7 days. In adhesion assays a considerable proportion of DC binds to resting EC monolayers and this adhesion is inhibited by anti-CD11a and CD11b, but not anti-CD11c mAbs. Binding to a natural ECM, derived from cultured EC involves VLA-4 and VLA-5 integrins. In a transmigration assay, 10% of input cells are able to cross the EC monolayer in the absence of exogenous stimuli. The amount of DC transmigrated through a monolayer of EC was increased of 2-3 fold by C-C chemokines RANTES, MIP1alpha, and MIP-1beta. Most importantly, in view of the trafficking pattern of these cells, a significant proportion of DC can migrate in a reverse transmigration assay, i.e. across the endothelial basement membrane and subsequently, across endothelial cells. Upon exposure to immune or inflammatory signals peripheral DC undergo maturation and migration to lymphoid organs. Functional maturation is associated with loss of responsiveness to chemokines present at sites of inflammation (e.g. MIP1alpha, MIP1beta and RANTES) and acquisition of a receptor repertoire which renders these cells responsive to signals which guide their localization in lymphoid organs (e.g. MIP3beta). A better understanding of the molecular basis of DC trafficking may provide molecular and conceptual tools to direct and modulate DC localization as a strategy to upregulate and orient specific immunity.

Cell Adhesion↗
PubMed2002

Junctional adhesion molecules and interendothelial junctions.

Similar to epithelia, endothelial cells are linked to each other via intercellular junctional complexes including gap junctions, adherens junctions and tight junctions. While polarized epithelial cells show a high degree of spatial sorting of junctional complexes, endothelia organize their junctions randomly. For this reason the nature of endothelial contacts may be highly adaptable to the need of permeability and leukocyte transmigration. For instance, high endothelial venules (HEVs) in lymphoid organs, where lymphocytes continuously exit the bloodstream, generally show more leaky contacts than brain with its impermeable blood-brain barrier. We recently identified an Ig superfamily molecule named JAM-2 which is specifically expressed in junctions of lymphatic endothelial cells and HEVs. We showed that JAM-2 belongs to the novel CTX molecular family and we now cloned the human equivalent of JAM-2. The presence of JAM-2 at sites of constitutive lymphocyte circulation argues for a role of this molecule in facilitating transmigration. This is supported by the increased transmigration in vitro across endothelial cells overexpressing JAM-2 at intercellular contacts.

Amino Acid Sequence↗
PubMed2004

Oxidized omega-3 fatty acids inhibit pro-inflammatory responses in glomerular endothelial cells.

BACKGROUND: Omega-3 fatty acids have beneficial effects in chronic inflammatory diseases that are characterized by accumulation of leukocytes and leukocyte-mediated tissue injury. Accumulation of leukocytes occurs, in part, due to pro-inflammatory responses in endothelial cells, such as increase in expression of leukocyte adhesion receptors and chemokines, such as MCP-1 and IL-8. METHODS: omega-3 fatty acids, such as EPA, are highly polyunsaturated and readily undergo auto-oxidation. We studied the effect of oxidized EPA and unoxidized (native) EPA on leukocyte-glomerular endothelial cell interactions using adhesion assays, ELISA assays and transmigration assays. We used electrophoresis mobility shift assays to determine the effect of oxidized and unoxidized EPA on cytokine-induced nuclear factor-kappaB (NF-kappaB) activation. RESULTS: Oxidized EPA but not unoxidized EPA dose-dependently inhibits cytokine-induced leukocyte adhesion receptors on glomerular endothelial cells, which correlates with inhibition of leukocyte-glomerular endothelial cell interactions. Oxidized EPA but not unoxidized EPA inhibits cytokine-induced glomerular endothelial and mesangial cell expression of MCP-1, and to a lesser extent IL-8. Transmigration assays show that oxidized EPA but not unoxidized EPA inhibits leukocyte transmigration across glomerular endothelial cells. Oxidized EPA but not unoxidized EPA potently inhibited cytokine-induced activation of NF-kappaB in glomerular endothelial and mesangial cells. CONCLUSIONS: These studies show that the beneficial effects of fish oil in chronic inflammatory diseases, including IgA nephropathy, may result from the inhibitory effects of oxidized omega-3 fatty acids on pro-inflammatory events in endothelial cells via inhibition of NF-kappaB activation.

Capillaries↗
PubMed2005

Leukocyte infiltration of the periarterial space of the lung after allergen provocation in a rat asthma model.

The periarterial space has recently been described and its physiological and pathophysiological role during inflammatory and allergic reactions has been reviewed. The present studies used a light-/electron-microscopic approach to characterize the periarterial space in an asthma model in Brown Norway rats. After repeated sensitization with ovalbumin and heat-killed Bordetella pertussis bacilli, airway challenge was carried out after 1 further week. Four or 24 h after challenge, rats were fixed by perfusion or instillation and processed for microscopy. Several periarterial capillaries and connective tissue characterized the tissue between small pulmonary arteries, bronchioles and alveolar septa. Additionally, a partly pronounced interstitial edema was seen independent of the kind of fixation. Not only small arteries but also arterioles and venules were partly surrounded by edematous fluid already visible by light microscopy. Within the connective tissue and within the periarterial fluid, numerous leukocytes, predominantly eosinophils, were found. However, leukocytes were detected only rarely in the vascular lumen. Only sporadically were eosinophils seen in the wall of small arteries or venules. Eosinophils transmigrating the endothelium of capillaries or arterioles were not visible 4 or 24 h after challenge. Thus, granulocytes transmigrate in the periarterial space very rapidly or even earlier than 4 h after challenge. The location of transmigration in the periarterial space needs further investigation.

Allergens↗
PubMed2006

Visualization of tumor cell extravasation.

In cancer the blood-borne spread of tumor cells leads to the formation of secondary tumors at distant loci, whereby the extravasation of tumor cells is a prerequisite step during hematogenous metastasis. In regard to the fate of endothelial cells located at the site of tumor cell infiltration, tumor cell-endothelial interactions were analyzed using an in vitro real-time model. This model shows the complete sequence of the transmigration process and gave new insights into the complex and dynamic cell-cell and cell-matrix interactions which occur during tumor cell transmigration across the endothelial barrier. An in vitro real-time apoptosis assay permits the distinction between apoptotic cell death from necrotic cell death. This model indicates that transmigration of tumor cell clusters derived from the invasive human bladder carcinoma cell line T24 irreversibly damages the endothelial cells by inducing apoptosis at the site of tumor cell infiltration. It is postulated here that apoptosis induction facilitates the removal of detached endothelial cells, thereby forestalling a local inflammatory response which might be detrimental to extravasating tumor cells.

Cell Communication↗
PubMed2002

Simvastatin inhibits inflammatory properties of Staphylococcus aureus alpha-toxin.

BACKGROUND: Simvastatin, a 3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, has been shown to lower serum cholesterol levels in clinical use. Moreover, statins exert beneficial effects in vascular diseases by inhibition of leukocyte rolling, adherence, and transmigration. The aim of this study was to determine if pretreatment with simvastatin attenuates Staphylococcus aureus alpha-toxin-induced increase in leukocyte-endothelial interactions during exotoxemia. METHODS AND RESULTS: The effects of simvastatin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation. Simvastatin (50 or 100 microg/kg) was administered 18 hours before the study. Activation of microcirculation was induced by bolus administration of 40 microg/kg S aureus alpha-toxin. Exotoxemia resulted in a significant and time-dependent increase in leukocyte rolling, adherence, and transmigration of leukocytes as well as P-selectin expression on the intestinal vascular endothelium. Pretreatment with simvastatin significantly inhibited exotoxin-induced leukocyte rolling from 71+/-10 to 14+/-4.7 cells/min (P<0.01) and adherence from 14+/-3.5 to 0.4+/-0.2 cells (P<0.01). In addition, simvastatin pretreatment significantly inhibited transmigration of leukocytes from 10.5+/-1.2 to 4.2+/-0.9 (P<0.05) cells. Immunohistochemical detection of endothelial cell adhesion molecule P-selectin showed a 50% decrease in endothelial cell surface expression after simvastatin treatment. Furthermore, simvastatin treatment resulted in enhanced expression of endothelial cell NO synthase III in the intestinal microcirculation. CONCLUSIONS: These results demonstrate that simvastatin interferes with exotoxin-induced leukocyte-endothelial cell interactions, which may be relevant in various infectious diseases. Statin treatment may offer a new therapeutic strategy for these clinical conditions.

Animals↗
PubMed1996

LFA-1 and L-selectin regulation of recirculating lymphocyte tethering and rolling on lung microvascular endothelium.

Recirculating lymphocytes migrate into areas of lung inflammation by binding to microvascular endothelium and transmigrating into extravascular tissue. In this report, we examined the multiple-step paradigm using a unique system: recirculating lymphocytes from sheep peripheral lymphatics adhering to activated lung microvascular endothelium in conditions of physiologic flow. Video microscopy demonstrated that recirculating lymphocytes formed abrupt adhesions, without requisite rolling, on the lung microvascular endothelial cells. Lymphocyte velocity was unchanged within 100 ms of the development of firm adhesions. To dissect the adhesion mechanism, the lymphocytes were pretreated with anti-LFA-1 or anti-L-selectin monoclonal antibody (mAb). Both mAb decreased the incidence of firm adhesions. The mechanism of this inhibition was investigated using time-lapse topographic reconstructions of cell movement after pretreatment with mAb. Time-lapse analysis of the movement of lymphocytes pretreated with anti-LFA-1 mAb suggested that abortive adhesion was manifested by a characteristic saltatory movement and a sustained reduction in cell velocity (rolling) to <25 microns/s. In contrast, abortive adhesions of lymphocytes pretreated with anti-L-selectin mAb demonstrated transient arrest (tethering) but minimal rolling before resumption of baseline velocity in the flow stream. These observations provide insights into selectin and integrin regulation of lymphocyte transmigration into the lung. Further, the results of mAb inhibition suggest that the mechanism of lymphocyte migration may have some unique features not observed in studies of neutrophil transmigration.

Animals↗
PubMed2004

Role for platelet-endothelial cell adhesion molecule-1 in macrophage Fcgamma receptor function.

Platelet-endothelial cell adhesion molecule-1 (PECAM-1) (CD31), a 130-kD transmembrane glycoprotein that functions in adhesion and signaling, is thought to play a role in some forms of leukocyte transmigration. In the lung, PECAM-1 is highly expressed, yet there have been few studies examining its role in pulmonary pathology. We therefore examined the inflammatory response (measured by bronchoalveolar lavage cell counts and protein content) after several types of lung injury in wild-type and PECAM-1 knockout mice. Consistent with studies in other organs, instillation of an endothelial stimulant (interleukin-1) was PECAM-1-dependent. In contrast, we noted that three other forms of acute lung injury (acid aspiration, adenoviral instillation, and tumor necrosis factor instillation) were completely PECAM-1-independent. Interestingly, in situ immune complex deposition injury, another complex lung disease, was also PECAM-1-dependent. This surprising finding was investigated in more detail and found to be due to a defect in macrophage activation, and not to a blockade of leukocyte transmigration. Experiments in bone marrow chimeric mice as well as ex vivo data demonstrated that Fcgamma receptor-dependent phagocytosis and tumor necrosis factor release were significantly reduced in macrophages derived from PECAM-1 knockout mice. Although PECAM-1 may not be required for transmigration of leukocytes into the alveolar space in many forms of complex lung inflammation, it is important in the function of Fcgamma receptors on alveolar macrophages.

Animals↗
PubMed1997

Leukocyte adhesion in angiogenic blood vessels. Role of E-selectin, P-selectin, and beta2 integrin in lymphotoxin-mediated leukocyte recruitment in tumor microvessels.

Interaction of circulating leukocytes with tumor microvasculature is a critical event in the recruitment of effector cells into the tumor stroma. We have examined the ability of lymphotoxin (TNF-beta), to stimulate rolling, adhesion, and transmigration of leukocytes in angiogenic blood vessels induced by tumor spheroids of Lewis lung carcinoma (LLC) implanted in dorsal skinfold chambers of nude mice. In the absence of cytokine stimulation, circulating leukocytes failed to appreciably interact with tumor microvessels (TMV), although significant rolling and adhesion was observed in normal vessels. However, stimulation with lymphotoxin (LT) resulted in a rapid increase in the number of fast and slow rolling leukocytes in TMV. Treatment with anti-P-selectin mAb 5H1 resulted in inhibition of fast rollers alone, while combination treatment with anti-P-selectin and anti-E-selectin (9A9) mAbs effectively blocked slow rolling of leukocytes. Superfusion of the lymphotoxin-stimulated neovasculature with leukotriene B4 (LTB4) resulted in stable cell adhesion followed by emigration of leukocytes into the tumor stroma. LTB4-mediated adhesion and transmigration was significantly inhibited by treatment with anti-beta2 mAb 2E6. These studies delineate a multistep cascade of leukocyte adhesion in TMV and demonstrate that stimulation of the neovasculature with cytokines and chemoattractants can result in P- and E-selectin-dependent rolling and beta2-dependent stable adhesion followed by transmigration into the tumor stroma.

Animals↗
PubMed2003

Migration of V delta 1 and V delta 2 T cells in response to CXCR3 and CXCR4 ligands in healthy donors and HIV-1-infected patients: competition by HIV-1 Tat.

We show that HIV-1-infected patients have increased concentrations of circulating V delta 1 T cells (2.2%-9.0% of T lymphocytes; healthy donors, 1.0%-2%) and, in some instances, V delta 2 T cells (3.5%-4.8% vs 2.0%-3.3%). In these patients, both V delta 1 and V delta 2 T cells are CXCR3+CXCR4+, whereas in healthy donors CXCR4 was preferentially expressed on V delta 1 T lymphocytes. gamma delta T cells transmigrated across endothelial monolayers, in response to interferon-gamma-inducing protein-10 (IP-10/CXCL10), stromal cell-derived factor-1 (SDF-1/CXCL12), or both, according to the expression of the specific receptors CXCR3 and CXCR4. Interestingly, 6Ckine/SLC/CCL21 was more effective than IP-10/CXCL10 on V delta 1 CXCR3+ cells, whereas V delta 2 CXCR3+ cells were driven more efficiently by IP-10/CXCL10. IP-10/CXCL10- and SDF-1/CXCL12-induced transmigration was dependent on phosphoinositide-3 kinase (PI-3K), as demonstrated by the use of the specific blockers wortmannin and LY294002 and by the activation of the downstream serine kinase Akt/PKB on ligation of CXCR3 and CXCR4. Occupancy of CXCR3, but not of CXCR4, led to CAMKII activation; accordingly, the CAMKII inhibitors KN62 and KN93 decreased IP-10/CXCL10- but not SDF-1/CXCL12-driven transmigration. Finally, HIV-1 Tat, which is present in the serum of HIV-1-infected patients, interferes with the chemotactic activity of these chemokines because of the cysteine-rich domain of the protein, which contains CXC and CC chemokine-like sequences.

Adult↗
PubMed2005

Membrane type 1-matrix metalloproteinase is involved in migration of human monocytes and is regulated through their interaction with fibronectin or endothelium.

Membrane type 1-matrix metalloproteinase (MT1-MMP) is involved in endothelial and tumor-cell migration, but its putative role in leukocyte migration has not been characterized yet. Here, we demonstrate that anti-MT1-MMP monoclonal antibody (mAb) impaired monocyte chemotactic protein-1 (MCP-1)-stimulated monocyte migration on fibronectin (FN), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1). In addition, monocyte transmigration through tumor necrosis factor-alpha (TNF-alpha)-activated endothelium is also inhibited by anti-MT1-MMP mAb. Therefore, regulation of MT1-MMP in human peripheral blood monocytes was investigated. First, MT1-MMP clustering was observed at motility-associated membrane protrusions of MCP-1-stimulated monocytes migrating on FN, VCAM-1, or ICAM-1 and at the leading edge, together with profilin, of monocytes transmigrating through activated endothelial cells. In addition, up-regulation of MT1-MMP expression was induced in human monocytes upon attachment to FN in a manner dependent on alpha4beta1 and alpha5beta1 integrins. Binding of monocytes to TNF-alpha-activated human endothelial cells as well as to VCAM-1 or ICAM-1 also resulted in an increase of MT1-MMP expression. These findings correlated with an enhancement of MT1-MMP fibrinolytic activity in monocytes bound to FN, VCAM-1, or ICAM-1. Our data show that MT1-MMP is required during human monocyte migration and endothelial transmigration and that MT1-MMP localization, expression, and activity are regulated in monocytes upon contact with FN or endothelial ligands, pointing to a key role of MT1-MMP in monocyte recruitment during inflammation.

Cell Movement↗
PubMed2005

Neutrophil recruitment by fetal porcine endothelial cells: implications in scarless fetal wound healing.

Fetal dermal wounds heal scarlessly and with a minimal inflammatory response. When a robust inflammatory response is induced at the site of fetal dermal wounds by the application of cytokines, healing results in fibrosis. To test the hypothesis that the reduced inflammatory response in fetal wounds is due to impaired fetal leukocyte-endothelial interactions, the contributions of fetal endothelial cells to the inflammatory response in the fetus were investigated. Endothelial cells isolated from blood vessels of adult and mid-gestational fetal pigs were cultured in media until confluent monolayers were established. Adult porcine neutrophils were isolated and resuspended at a concentration of 1 million cells/mL. Interactions between neutrophils and endothelial cells were observed under static and flow conditions. Endothelial monolayers were exposed to neutrophils with and without prior stimulation of the endothelial cells with tumor necrosis factor alpha (TNF-alpha) for 4 h. The neutrophil-endothelial interactions were observed and analyzed for neutrophil adhesion, rolling velocity, and transmigration. Endothelial P-selectin mRNA expression was determined by real-time polymerase chain reaction (PCR). A novel in vitro model of fetal inflammation is described. Both adult and fetal endothelial cells demonstrated a dose-dependent increase in neutrophil adhesion and transmigration with increasing doses of TNF-alpha. The fetal response was significantly lower than the adult. As expected, rolling velocity was lower at higher cytokine concentrations and had an inverse correlation with P-selectin mRNA expression. Fetal endothelial cells are less permissive to adhesion and transmigration of neutrophils than adult endothelial cells. This may contribute to the paucity of inflammation seen in the fetal response to dermal injury.

Animals↗
PubMed1995

Localization of multiple functional domains on human PECAM-1 (CD31) by monoclonal antibody epitope mapping.

PECAM-1, a cell adhesion molecule of the immunoglobulin gene (Ig) superfamily, has been implicated in white cell transmigration, integrin activation on lymphocytes, and cell-cell adhesion. The purpose of this investigation was to identify specific regions of the PECAM-1 extracellular domain mediating these functions by identifying the location of epitopes of bioactive anti-PECAM-1 monoclonal antibodies. The binding regions of mAbs important in PECAM-1-mediated leukocyte transmigration (Hec 7.2 and 3D2) were mapped to N-terminal Ig-like domains. The epitopes of monoclonal antibodies that activated integrin function on lymphocytes were dispersed over the entire extracellular region, but those that had the strongest activating effect were preferentially localized to the N-terminus of the molecule. The binding regions of mAbs that blocked PECAM-1-mediated heterophilic L-cell aggregation were located either in Ig-like domain 2 (NIH31.4) or Ig-like domain 6 (4G6 and 1.2). Site-directed mutagenesis further pinpointed the epitope of the 4G6 mAb to a hexapeptide, CAVNEG, within Ig-like domain 6. These results demonstrate that PECAM-1 contains multiple functional domains. Regions within N-terminal Ig-like domains appear to be required for transmigration. In contrast, two distinct regions were implicated in L-cell mediated heterophilic aggregation.

Amino Acid Sequence↗
PubMed2002

Pseudomonas aeruginosa activates human mast cells to induce neutrophil transendothelial migration via mast cell-derived IL-1 alpha and beta.

The mechanisms of neutrophil (PMN) recruitment to Pseudomonas aeruginosa infection remain incompletely defined. Mast cells (MC) involvement in this process has not been studied previously. In this study, we demonstrate that human cord blood-derived MC phagocytose P. aeruginosa and release mediators that activate HUVEC monolayers for supporting PMN transmigration. Pretreatment of supernatants from P. aeruginosa-MC cocultures with neutralizing anti-IL-1alpha plus anti-IL-1beta Abs, or IL-1R antagonist before addition to HUVEC for stimulation completely abrogated MC-induced PMN transmigration, while anti-TNF-alpha treatment had no effect. The expression of E-selectin and ICAM-1 on HUVEC, the latter a ligand for PMN CD11/CD18, was significantly up-regulated by P. aeruginosa-induced MC mediators. Pretreatment of human PMN with anti-CD18 mAb or pretreatment of HUVEC with a combination of three mAbs (against ICAM-1, ICAM-2, and E-selectin) inhibited by 85% the MC-dependent PMN transmigration. Moreover, P. aeruginosa-induced production of IL-1alpha and IL-1beta was down-regulated by IL-10 and dexamethasone. This study demonstrates for the first time that MC may mediate P. aeruginosa-induced PMN recruitment via production of IL-1alpha and beta. These findings have important implications for diseases involving P. aeruginosa infection and suggest novel targets for modulating P. aeruginosa-induced inflammation.

Cell Adhesion Molecules↗
PubMed2004

Neutrophil elastase (NE)-deficient mice demonstrate a nonredundant role for NE in neutrophil migration, generation of proinflammatory mediators, and phagocytosis in response to zymosan particles in vivo.

Neutrophil elastase (NE) remains a controversial player in the process of leukocyte transmigration and much of this controversy stems from conflicting reports on the effects of NE inhibitors. The availability of NE-deficient mice (NE(-/-)) provides a clean and elegant tool for the study of leukocyte migration in vivo. In this study, NE(-/-) mice were used to investigate the role of NE in leukocyte migration through cremasteric venules, as observed by intravital microscopy, induced by locally administered cytokines IL-1beta and TNF-alpha and the particulate stimulus, zymosan. Although no defects in leukocyte responses induced by the cytokines were observed, zymosan-induced leukocyte firm adhesion and transmigration was suppressed in NE(-/-) mice. These responses were also inhibited in wild-type mice when zymosan was coinjected with a specific NE inhibitor. Quantification of inflammatory mediator levels in homogenates of zymosan-stimulated tissues indicated reductions in levels of IL-1beta, KC, and macrophage inflammatory protein-1alpha in NE(-/-) mice. Furthermore, phagocytosis of fluorescent zymosan particles, as observed by intravital microscopy, was diminished in NE-deficient animals. Collectively, the findings of this study indicate a nonredundant role for NE in zymosan-induced leukocyte firm adhesion and transmigration, and that this defect is associated with impaired generation of proinflammatory mediators as well as phagocytosis of zymosan particles in vivo.

Animals↗
PubMed1991

Evidence for specific suppression of gametocytemia by Plasmodium falciparum in residents of hyperendemic Irian Jaya.

An epidemiologic study of hyperendemic malaria in Arso PIR, a village in northeastern Irian Jaya (Indonesian New Guinea), revealed evidence suggesting suppression of gametocytemia independent of immune control of the asexual parasitemia. A total of 240 people, representing ages between 2 and 60 years, were followed by biweekly blood film examination for 16 weeks beginning in November 1987. Two distinct subpopulations were represented--1) life-long residents of Irian Jaya, and 2) transmigrants from Java who arrived in Irian Jaya 20 months before the surveillance effort began. Twenty-five percent of blood films from natives and 31% from Javanese were positive for falciparum malaria; of these, the rate of gametocytemia was 21% for natives, and 42% for the Javanese transmigrants (P less than 0.001). This difference could not be explained by differences in the frequency or grade of parasitemia, illness, or by known patterns of antimalarial consumption. Similarly, in Wor, a village near Arso PIR, the gametocyte rate for P. falciparum diminished from 83% to 25% in transmigrants from Java between their eleventh and twenty-fifth month of residence in Irian Jaya, a period during which the falciparum malaria rate remained stable between 30% and 50%. An immunofluorescent antibody test using whole, acetone-fixed gametocytes as substrate revealed correlation between antibody titer and protection from gametocytemia among the semi-immune natives of Arso PIR, but not among the Javanese. Specific immune suppression of gametocytes, independent of immune control of asexual parasites, can explain all of these observations.

Adolescent↗
PubMed1999

Neutrophil F-actin and myosin but not microtubules functionally regulate transepithelial migration induced by interleukin 8 across a cultured intestinal epithelial monolayer.

The role of the polymorphonuclear leukocyte (PMN) cytoskeleton during the transmigration across colonic epithelial cells is not very well understood. In order to study the role of different components of the PMN cytoskeleton during transepithelial migration across a colonic epithelial cell monolayer (T84), PMN were preincubated with drugs affecting either the actin cytoskeleton (cytochalasin B, iota toxin of Clostridium perfringens, and phalloidin) or the microtubules (colchicine and taxol). The role of PMN myosin during transepithelial migration was investigated using the inhibitor 2,3-butanedione monoxime (BDM) and DC3B toxin. PMN intracellular Ca2+, during neutrophil adhesion and translocation across the epithelium, was assessed by the Ca2+ chelator 1, 2bis-(2-aminophenoxy)-ethane-N,N,N', N'-tetra-acetic acid tetrakis (acetoxymethyl) ester (BAPTA-AM). Transmigration of PMN was initiated by applying either interleukin-8 or formyl-met-leu-phe (fMLP). While colchicine and taxol preexposure did not influence PMN transepithelial migration, treatment with cytochalasin B, iota toxin, phalloidin, BDM, DC3B toxin and BAPTA-AM greatly diminished migration of PMN across T84 monolayers. Similarly, cell-cell contacts established between PMN and epithelial cells during the transmigration were diminished after treatment of PMN with iota toxin or cytochalasin B. These data show that the neutrophil actin cytokeleton and myosin, but not the microtubules, evoke a Ca2+ -dependent motility that facilitates migration across the colonic epithelial barrier.

ADP Ribose Transferases↗
PubMed1999

Regulation of human eosinophil migration across lung epithelial monolayers by distinct calcium signaling mechanisms in the two cell types.

In asthmatic patients, eosinophils massively infiltrate the lung tissues and migrate through lung epithelium into the airways. The regulatory mechanisms involved are obscure. We studied the role of calcium in the migration of human eosinophils across monolayers of human lung epithelial H292 cell line cells induced by combined chemotactic solutions of platelet-activating factor and C5a. The transepithelial migration of eosinophils was attenuated by depletion of the external Ca2+ in the migration system, whereas the eosinophil migration itself was unaffected as evidenced by measuring eosinophil chemotaxis in the Boyden chamber in the absence of epithelial cells. Buffering of intracellular Ca2+ in eosinophils with 1, 2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA/AM) inhibited both eosinophil transepithelial migration and eosinophil chemotaxis in the Boyden chamber, suggesting the importance of intracellular Ca2+ in eosinophil transmigration. Although loading of BAPTA/AM or addition of thapsigargin to the epithelial cells effectively changed their cytoplasmic free Ca2+ concentrations, neither of these treatments affected transepithelial migration of eosinophils. Interestingly, addition of La3+ (0.2 mM) to epithelial cells suppressed eosinophil transmigration whereas addition of La3+ to eosinophils did not. Taken together, these results show the importance of Ca2+ in eosinophil migration across lung epithelium and support a distinctive regulatory role of intracellular and extracellular Ca2+ for the two cell types involved in this process; i.e., the transmigration of human eosinophils across a monolayer of lung epithelial cells is regulated by the intracellular Ca2+ in eosinophils, whereas the ability of the lung epithelial cell monolayer to allow eosinophil passage is dependent on the extracellular Ca2+.

Buffers↗