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PubMed2004

CXCR3 marks CD4+ memory T lymphocytes that are competent to migrate across a human brain microvascular endothelial cell layer.

Chemokines and their receptors may be implicated in leukocyte ingress into brain during inflammation observed during the course of multiple sclerosis (MS). To address receptor modulation on CD4+ memory T lymphocytes during diapedesis, we used an in vitro model of the blood-brain barrier (BBB). We found that only memory (CD45RO+) cells transmigrated and type 3 CXC chemokine receptor (CXCR3) was enriched on transmigrated cells. CXCR3 depletion of the input population did not affect transmigration capability. CXCR3 reemerged on CXCR3 depleted cells independently of endothelial cell exposure, but was susceptible to incubation at 4 degrees C, indicating receptor recycling. We propose that CXCR3 serves as a surface marker for cells that have the capacity to cross the BBB, but does not play an essential role in extravasation.

Blotting, Western↗
PubMed2006

Determinants of CCL5-driven mononuclear cell migration across the blood-brain barrier. Implications for therapeutically modulating neuroinflammation.

Chemokine receptors and adhesion molecules are used selectively for the transmigration of leukocytes across the blood-brain barrier (BBB) during neuroinflammation. We established an activated in vitro BBB (aIVBBB) using physiological concentrations of cytokines. We studied CCL5-driven migration as a model to determine how chemokine receptors and adhesion molecules regulate T-cell and monocyte migration across the aIVBBB. Increased expression of CCL5 and its receptors, CCR1 and CCR5 have been described in the perivascular space of multiple sclerosis (MS) lesions. Elucidating the determinants of CCL5-mediated mononuclear cell migration may clarify appropriate targets for therapeutic modulation in neuroinflammatory conditions. In response to CCL5, there was a significant increase in total mononuclear cell migration across the aIVBBB. Neutralizing monoclonal antibodies to CCR1 and CCR5 abrogated CCL5-driven transmigration, suggestive of non-redundant receptor usage in mononuclear cell migration to this chemokine in vitro. CCL5-driven transmigration was also dependent on alpha(4)beta(1) integrin/fibronectin connecting segment-1 (FN CS-1) and alpha(L)beta(2) integrin/intercellular adhesion molecule (ICAM-1) interactions. Monocyte migration to CCL5 was solely dependent on alpha(4)beta(1) integrin/FN CS-1 while T-cell migration required both alpha(L)beta(2) integrin/ICAM-1 and alpha(4)beta(1) integrin/FN CS-1 interactions. These findings provide plausible molecular targets for the selective inhibition of mononuclear cell trafficking during the acute immune effector phases of MS and other neuroinflammatory diseases.

Blood-Brain Barrier↗
PubMed2005

Prolonged culture of endothelial cells and deposition of basement membrane modify the recruitment of neutrophils.

We tested whether endothelial cell conditioning during prolonged culture and deposition of basement membrane (BM) could modify neutrophil recruitment induced by the inflammatory cytokine, tumour necrosis factor-alpha (TNF). Confluent endothelial cells (EC) from human umbilical veins were cultured for 1 to 20 days and then stimulated with 1, 10 or 100 U/ml of TNF for 4 h. When isolated neutrophils were settled on EC stimulated with the lower doses of TNF, the levels of adhesion and the proportion of adherent cells that transmigrated increased markedly with time of culture. At 100 U/ml TNF, time of culture had little effect on recruitment, but the transmigrated neutrophils moved more slowly under the monolayer in longer-term cultures. The inhibitory effects of function-blocking antibodies against E-selectin and beta2-integrin, and studies in which neutrophils were perfused over short- or long-term cultures, suggested that increased adhesion and migration arose from increased efficiency of neutrophil activation by the EC. Prolonged culture was also associated with deposition of a distinct BM. When fresh EC were seeded on day 20 BM, transmigrated neutrophils moved more slowly under the EC than under control monolayers. Thus, EC change their pro-inflammatory phenotype during prolonged culture, and the deposited basement membrane influences neutrophil migration.

Basement Membrane↗
PubMed2003

Development and comparison of in vivo and in vitro models for endometritis in cows and mares.

In order to investigate pathogenic mechanisms of acute endometritis in cows and mares, we established an in vivo model in both species. Based on the results of an in vitro transmigration system, human recombinant interleukin-8 (rhIL-8; 1.25 microg per mare and 5 microg per cow in 50 ml phosphate-buffered saline) was used to attract polymorphonuclear neutrophil granulocytes (PMNs) into the uteri. Peak numbers of uterine neutrophils were attracted after 6h, in both cows and mares. On average, mares responded more sensitively than cows, with 15 times higher numbers of rhIL-8-attracted uterine neutrophils (72+/-8 x 10(7)cells). In contrast to in vitro studies, in vivo migrated neutrophils (uterine neutrophils) of both species displayed a significantly reduced MHC class I expression. Expression of the CD11a molecule was significantly enhanced on equine uterine neutrophils but downregulated on bovine cells. Compared with untreated autologous peripheral neutrophils, both uterine and in vitro migrated neutrophils showed no alteration of phagocytic capacity. The ability to generate reactive oxygen species (ROS) was significantly upregulated in bovine and equine uterine neutrophils. This was also observed after in vitro migration of equine neutrophils, whereas ROS generation by bovine neutrophils was significantly depressed. In summary, the concept of inducing endometritis directly by local application of human interleukin-8 has been reliably successful in cows and mares. The model permits the analysis of PMN migration into the uterus under defined and controlled conditions. The observed differences between cows and mares with respect to phenotypical and functional characteristics of in vivo attracted uterine cells point to species-related features of neutrophil migration. In vitro transmigrated bovine and equine cells partially differ in phenotype and function from uterine neutrophils. Therefore, the in vitro transmigration assay cannot completely represent the in vivo endometritis model described here.

Animals↗
PubMed2000

Modulation of epithelial and endothelial paracellular permeability by leukocytes.

The tight junction acts as a regulated barrier for diffusion of ions, larger solutes, and migration of leukocytes through the paracellular space. Barrier function varies with the tissue type, and positively correlates with the number and complexity of tight junction strand formation. Polarized epithelia and brain capillary endothelium display a high degree of barrier function and tight junction formation. Conversely, vascular endothelium in other tissues has fewer, loosely organized tight junctions strands and greater permeability. Through cytoskeletal association, the tight junction and the adherens junction form a functional unit termed the apical junction complex. The development and stabilization of the tight junction is dependent upon the adherens junction. It has become apparent that paracellular permeability is altered during the migration of leukocytes across the apical junction complex and that the apical junction complex plays an important role in the regulation of leukocyte transmigration (or extravasation) through the endothelium and epithelium. Evidence suggests that important cell-cell adhesive events between transmigrating leukocytes and the apical junction complex and subsequent signaling events result in the facilitation of the passage of cells through the paracellular space. Possible mechanisms for the regulation of barrier function pertaining to leukocyte transmigration are discussed.

Animals↗
PubMed1999

The synthetic somatostatin analogue, octreotide, ameliorates acute and delayed intestinal radiation injury.

PURPOSE: Reducing intraluminal proteolytic activity attenuates intestinal radiation toxicity. This study assessed whether pharmacological inhibition of exocrine pancreatic secretion protects against early and delayed radiation enteropathy in a preclinical rat model. METHODS AND MATERIALS: Rat ileum was sham-irradiated or exposed to 16 once-daily 4.2 Gy fractions of X-radiation. Vehicle or somatostatin analogue (octreotide, 2 microg/kg/hr) were administered from 2 days prior to 10 days after the end of irradiation. Mucosal injury was monitored noninvasively by assessment of granulocyte transmigration. Radiation injury was assessed at 2 weeks (early phase) and 26 weeks (chronic phase) using quantitative histopathology, immunohistochemistry, and morphometry. RESULTS: Octreotide decreased granulocyte transmigration (p<0.0006), reduced accumulation of myeloperoxidase-positive cells at 2 weeks (p = 0.0002), attenuated structural injury at 2 weeks (p = 0.04) and 26 weeks (p = 0.02), preserved mucosal surface area at 2 weeks (p = 0.0008) and 26 weeks p = 0.0008), and reduced intestinal wall thickening at 26 weeks (p = 0.002). Octreotide did not affect granulocyte transmigration, histology, or mucosal surface area in sham-irradiated controls. CONCLUSION: These results demonstrate the importance of consequential mechanisms in the pathogenesis of chronic radiation enteropathy. Short-term octreotide administration ameliorates acute radiation-induced mucosal injury, as well as chronic structural changes, and should be subject to further preclinical and clinical testing.

Animals↗
PubMed1998

On the phenomenon of intraosseous migration of nonerupting teeth.

Little is know about intraosseous migration of nonerupting teeth, a rare natural condition of horizontal tooth movement and impaction. It occurs only in the mandible and involves primarily the second premolar or the canine. When the second premolar is the affected tooth, it always is found distal to its normal position. The origins of the second premolar intraosseous migration phenomenon are obscure and usually no treatment is recommended. Intraosseous migration involving the canine is commonly called transmigration because the affected canine moves mesially across the mandibular symphysis to the opposite side of the mandible. Analysis of 50 published cases of canine transmigration indicated higher occurrence in women and no sidedness preference. In over 80% of the studied cases, the canine remained nonerupted and, of the 24 cases receiving some treatment, all but two underwent extraction of the anomalous canine. The canine transmigration phenomenon appears to show signs of having some genetic determinants.

Bicuspid↗
PubMed2002

Polymorphonuclear leukocyte migration across model intestinal epithelia enhances Salmonella typhimurium killing via the epithelial derived cytokine, IL-6.

The host response to Salmonella typhimurium involves movement of polymorphonuclear leukocytes (PMN) across the epithelium and into the intestinal lumen. Following their arrival in the lumen, the PMN attempt to combat bacterial infection by activating antimicrobial defenses such as granule release, oxidative burst, phagocytosis, and cell signaling. We sought to examine PMN-S. typhimurium interaction following PMN arrival in the lumenal compartment. Here, for the first time, we demonstrate that PMN that have transmigrated across model intestinal epithelia have an enhanced ability to kill S. typhimurium. Our data provide evidence to indicate that the extracellular release of the primary and secondary granules of PMN, myeloperoxidase and lactoferrin, respectively, is correlated with enhanced bacterial killing. Furthermore, epithelial cells, during PMN transmigration, release the cytokine IL-6. IL-6 is known to increase intracellular stores of Ca(2+), and we have determined that this epithelial released cytokine is not only responsible for priming the PMN to release their granules, but also stimulating the PMN to kill S. typhimurium. These results substantiate the pathway in which PMN transmigration activates the epithelial release of IL-6, which in turn increases intracellular Ca(2+) storage. Our results, herein, extend this pathway to include an enhanced PMN granule release and an enhanced killing of S. typhimurium.

Cell Movement↗
PubMed1998

Kinetics of leukocyte-induced changes in endothelial barrier function.

1. Extravasation of polymorphonuclear leukocytes (PMN) and associated plasma leakage are key events in the inflammatory process. The kinetics of PMN-induced changes in endothelial barrier function were studied by means of confluent monolayers of bovine aorta or human umbilical vein endothelial cells (EC), cultured on permeable membranes and mounted in a two-compartment diffusion chamber. The model permitted continuous measurement of transendothelial electrical resistance (TEER), and analysis of protein efflux and PMN migration across the EC monolayer. 2. Transendothelial chemotactic stimulation (fMLP or LTB4) of PMN resting on EC in the upper compartment induced a prompt decline in TEER, followed by an increase in protein flux and transmigration of PMN. Adding the chemoattractant together with PMN in the upper compartment provoked adhesion of PMN, fall in TEER and increase in protein permeability, but no transmigration of PMN, whereas inhibition of PMN adhesion to EC by pretreatment with anti-CD18 mAb prevented all responses to chemotactic stimulation. 3. Chemoattractant-induced adhesion of PMN to the EC monolayer induced a rapid rise in EC cytosolic free Ca2+, similar to that obtained by direct stimulation of EC with histamine, indicating an active response of EC to PMN activation and adhesion. 4. In summary, continuous recording of transendothelial electrical resistance in the in vitro model described permits rapid and sensitive analysis of leukocyte activation-induced effects on EC barrier function. The kinetics and specificity of the EC and PMN responses to chemoattractant stimulation suggest that activated PMN, via adhesion-dependent events, have a direct effect on EC junctional integrity independent of whether transmigration occurs or not.

Animals↗
PubMed2000

Effects of the chemokine stromal cell-derived factor-1 on the migration and localization of precursor-B acute lymphoblastic leukemia cells within bone marrow stromal layers.

Acute lymphoblastic leukemia (ALL) blasts undergo migration into layers of bone marrow fibroblasts (BMF) in vitro, utilizing the beta1 integrins VLA-4 and VL-5 as adhesion molecules. However, it has been unclear as to whether this is a selective process mediated by specific chemoattractant molecules, or simply a reflection of the highly motile nature of early B cell precursors. We further characterized this process using a transwell culture system, in which the two chambers were separated by an 8 microm diameter microporous membrane, through which leukemic cells could move. When a BMF layer was grown on the upper surface of the membrane there was an 84.1% reduction in transmigration of the human pre-B ALL cell line NALM-6 into the lower chamber, compared to control membrane with no BMF layer. Localization of leukemic cells under the BMF layer was confirmed ultrastructurally, suggesting the possibility that the migration of leukemic cells was directed by a chemotactic agent secreted by BMF. The involvement of the chemokine stromal cell-derived factor-1 (SDF-1) in this process was next investigated. BMF were shown to express m-RNA for SDF-1. Addition of SDF-1 at 100 ng/ml into the lower chamber increased transmigration of NALM-6 across the membrane by 2.2-fold, and also induced a 1.4- to 6.1-fold increase in movement of NALM-6 through a BMF layer into the lower chamber. The receptor for SDF-1, CXCR4, was demonstrated by flow cytometry on all 10 cases of precursor-B ALL analyzed, as well as on NALM-6, KM-3 and REH lines. An inhibitory antibody to CXCR4 was able to block the migration of NALM-6 cells into BMF monolayers grown on plastic by 51%, and in nine cases of ALL by 8-40%, as well as partially inhibit transmigration of leukemic cells through BMF layers along an SDF-1 concentration gradient. These results confirm that precursor-B ALL cells selectively localize within bone marrow stroma in vitro, and that this process is partially due to the stromal chemokine SDF-1 binding to its receptor CXCR4 on leukemic cells. SDF-1 may be important in influencing the localization of precursor-B ALL cells in marrow microenvironmental inches which regulate their survival and proliferation.

Bone Marrow↗
PubMed1996

Granulocyte colony-stimulating factor (G-CSF) increases neutrophil migration across vascular endothelium independent of an effect on adhesion: comparison with granulocyte-macrophage colony-stimulating factor (GM-CSF).

Granulocyte colony-stimulating factor (G-CSF) increases neutrophil counts, and enhances and primes many neutrophil functions, implicating a role for this growth factor in host defence. This study investigated whether G-CSF is able to directly influence the transendothelial migration of neutrophils, and how such effects might be related to other effects on neutrophil adhesive properties. G-CSF, like GM-CSF, increased surface levels of the adhesive receptor, CD11b/CD18, but down-regulated L-selectin expression on neutrophils. Unlike GM-CSF, however, G-CSF had no effect on neutrophil adhesion to endothelium. Despite the lack of effect on neutrophil adhesion, G-CSF was able to produce significant enhancement of neutrophil transmigration across unstimulated endothelium in vitro. When used at an optimal concentration of 100 ng/ml, G-CSF increased neutrophil migration to 217 +/- 19% of baseline levels (P < 0.001, n = 10). This effect was similar to that previously demonstrated for GM-CSF (which increased migration to 271 +/- 40%, P < 0.001, n = 12). G-CSF-induced transmigration, like GM-CSF induced migration, was independent of concentration gradients, suggesting that these are not simply chemotactic effects. G-CSF differs from GM-CSF, however, in that although GM-CSF inhibited neutrophil migration across IL-1-activated endothelium (33 +/- 8% inhibition, n = 6, P < 0.01), G-CSF had no effect on neutrophil migration across IL-1 activated endothelium. Hence G-CSF, despite having no effect on neutrophil adhesion to endothelium, is a powerful stimulator of transmigration, and, unlike GM-CSF, does not inhibit cell movement across inflamed endothelium. These results suggest that G-CSF is able to influence neutrophil recruitment into local infective sites, and, further, that G-CSF mobilized cells would be competent to migrate into tissues in response to inflammatory stimuli.

Cell Adhesion↗
PubMed2002

Influence of cell cycling and cell division on transendothelial migration of CD34+ cells.

The migration of haemopoietic stem and progenitor cells across endothelium lining bone marrow sinuses is a critical first step in the homing and successful engraftment of these cells. We have previously shown that freshly isolated mobilized peripheral blood CD34+ cells adhere to the endothelial surface but do not transmigrate unless activated by growth factors. The aim of this work was to examine the relationship between cell cycle progression, cell division and migration across endothelium. We now show that the enhanced migration of cytokine-activated cells is selective for cells which are in G0G1 phase of the cell cycle. Thus, the transmigrated population of CD34+ cells was enriched for cells in G0G1 phase, and sorted cells in G0G1 migrated more efficiently than those in S+G2M. Conversely, cells in S+G2M were more adherent to endothelium, a finding that may explain their reduced migration. Using the cytoplasmic dye, carboxyfluorescein diacetate succinimidyl ester, to track the divisional kinetics of CD34+ cells, we found that migration occurred preferentially in non-divided cells. Thus, although CD34+ cells require cytokine activation in order to migrate, cell division is not required for transmigration, which occurs optimally before cells enter S phase. The superior migratory ability of CD34+ cells in G0G1 phase of the cell cycle may have important implications for the homing and engraftment of ex vivo expanded cells.

Adult↗
PubMed2003

Transendothelial migration confers a survival advantage to activated T lymphocytes: role of LFA-1/ICAM-1 interactions.

The clearance of activated T lymphocytes by apoptosis is an essential component in the resolution of the immune response; however, certain signals received within inflamed tissue may result in the persistence of activated T cells. Our previous work has shown that, when compared with resting cells, effector cells migrate more efficiently across endothelium, thus such cells may be selectively recruited to sites of inflammation. We hypothesized that transmigration of T cells across endothelium might influence cell survival. We have generated T cell lines by culturing in IL-2 following PHA activation. These T cell lines die rapidly by apoptosis when deprived of IL-2 (53.7 +/- 4.0% survival after 24 h). In contrast, cells that have migrated across human umbilical vein endothelial cells (HUVEC) survived significantly better than control cells (80.3 +/- 3.6%, n= 18, P<0.001). Endothelial cell conditioned medium was also able to reduce apoptosis, but this effect was small when compared with the protective effect of transmigration. Culture of T lymphocytes on fibronectin, or RGD peptides, or in suspension with a range of chemokines active on T cells, including RANTES and lymphotactin had no effect on survival. In contrast, blocking LFA-l/ICAM-l interactions reduced the protective effect of transmigration (42.3 +/- 6.7% reduction). Culture of activated T cells on immobilized ICAM-l alone also increased survival. These results indicate that signals received by activated T cells during extravasation can influence their subsequent survival within tissue, and implicates the involvement of LF A-l/ICAM-l interactions.

Apoptosis↗
PubMed2001

Endothelial intracellular Ca2+ release following monocyte adhesion is required for the transendothelial migration of monocytes.

Although molecular changes accompanying leukocyte extravasation have been investigated intensively, the particular events following leukocyte adhesion and leading to the actual transendothelial migration process remain largely unknown. To characterize intraendothelial signals elicited by leukocyte adhesion and functionally required for their transmigration, we recorded endothelial free cytosolic intracellular Ca(2+)levels ([Ca(2+)]i) during the course of leukocyte adhesion. We show that monocyte and granulocyte adhesion induced Ca(2+)transients in either untreated or TNF-alpha-stimulated microvascular endothelial cells (HMEC-1). The functional significance of these [Ca(2+)]i rises was demonstrated by treating filter-grown endothelial monolayers with BAPTA/AM. This in traendothelial Ca(2+)chelation left monocyte adhesion basically unaffected, but caused a significant and dose-dependent reduction of the transendothelial migration of monocytes. Granulocyte diapedesis, on the other hand, was hardly modified. Thapsigargin-treatment of endothelial cells almost completely inhibited the transmigration of monocytes suggesting that the necessary Ca(2+)transients depended on a release from intracellular Ca(2+)stores. Our results thus show that the transmigration of monocytes through endothelial monolayers of microvascular origin is favoured by an increase of the intraendothelial [Ca(2+)]i induced by leukocyte adhesion to the endothelial cells.

Calcium↗
PubMedDate not supplied

[Cytomegalovirus infection as a possible factor in the progression of neuroblastoma].

BACKGROUND: There is evidence that the infection with human cytomegalovirus is clinically associated with enhanced metastasis and progression of neuroblastoma disease. An in vitro model with HCMV-infected neuroblastoma cells (NB) was used to investigate whether HCMV modulates the metastatic potential of NB. METHODS: The neuroblastoma cell line UKF-NB-4 and its productively and persistently HCMV-infected variant UKF-NB-4AD169 were cocultured with human endothelial cells (EC). The rate of NB adherent to the endothelial monolayer and the rate of transmigrating NB was determined by means of combined reflexion interference contrast/phase contrast microscopy. RESULTS: UKF-NB-4AD169 adhered to and transmigrated through cocultured EC monolayer to a significantly higher extent compared with the non-infected cell line UKF-NB-4. At the cell-to-cell contact sites between UKF-NB-4AD169 and EC the intercellular endothelial contacts loosened resulting in the formation of reversible focal openings in the monolayer. This phenomenon was not observed with UKF-NB-4. The transendothelial migration rate of UKF-NB-4AD169 was therefore significantly higher than that of UKF-NB-4. The formation of focal openings in the endothelial monolayer and the enhanced transmigration rate of UKF-NB-4AD169 was suppressed in the presence of phenantroline, suggesting that HCMV-induced proteinases might be responsible for this phenomenon. CONCLUSION: The results confirm our assumption that HCMV has the ability to modulate functional properties of NB which are essential for the interactions with endothelial cells and thus for metastasation. The clinical relevance of these findings has to be further defined yet by means of prospective studies with HCMV-infected neuroblastoma patients. Proteinase inhibitors could be valuable in the therapeutic treatment of these patients.

Cell Migration Inhibition↗
PubMed1995

Receptors involved in carbohydrate binding modulate intestinal epithelial-neutrophil interactions.

Neutrophil (polymorphonuclear neutrophil) migration across epithelial barriers is a common morphologic feature of many diseases. Previous studies show that PMN-epithelial interactions are dependent on the PMN beta 2-integrin CD11b/18; however, nothing is known about surface carbohydrates and PMN-epithelial interactions. Here we investigate the role of carbohydrates on PMN-epithelial interactions using PMN and cultured monolayers of the intestinal epithelial cell line T84. Addition of the carbohydrates mannose 6-phosphate (Man-6-P) and glucose 6-phosphate (Glu-6-P), but not fructose 1-phosphate (Fru-1-P) inhibited transmigration by > or = 70%. Likewise, more complex carbohydrates, such as fucoidin and the Man-6-P-rich polysaccharide PPME selectively inhibited PMN transepithelial migration. These carbohydrates were found to be inhibitory in the apical-to-basolateral direction as well as the basolateral-to-apical direction, indicating a lack of polarity. This panel of related carbohydrates, however, was not effective in modulating short-term adhesion of PMN to epithelial monolayers, indicating that carbohydrate ligands may modulate different steps in the transmigration cascade. Finally, addition of functionally inhibitory monoclonal antibodies specific for the selectins (CD62E, CD62L, and CD62P) revealed no observable effect on PMN transmigration. These studies suggest that cell surface carbohydrates may play a role in inflammatory processes of the intestine.

Carbohydrate Metabolism↗
PubMed2005

Interleukin-3, -5, and granulocyte macrophage colony-stimulating factor induce adhesion and chemotaxis of human eosinophils via p38 mitogen-activated protein kinase and nuclear factor kappaB.

Hematopoietic cytokines such as interleukin (IL)-3, IL-5, and granulocyte macrophage colony-stimulating factor (GM-CSF) play a fundamental role in eosinophil functions in allergic asthma. The intracellular signal transduction mechanisms of these cytokines regulating the activation of eosinophils have been potential therapeutic targets. We investigated the roles of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-kappaB) in IL-3, IL-5, and GM-CSF-induced adhesion, morphological changes, and subsequence transmigration of human eosinophils. IL-3, IL-5, and GM-CSF could augment the phosphorylation of p38 MAPK and nucleus translocation of NF-kappaB in eosinophils. cDNA expression arrays demonstrated that the gene expression levels of several adhesion molecules including intercellular adhesion molecule-1 (ICAM-1), alpha6, beta2 integrin (CD18), and CD44 were upregulated by these cytokines. Results from functional assays showed that adhesion of eosinophils onto airway epithelial cells was enhanced after IL-3 and IL-5 but not GM-CSF stimulation. These cytokines could markedly induce shape change and augment the transmigration of eosinophils. Moreover, administration of either p38 MAPK inhibitor, SB 203580, or proteasome inhibitor, N-cbz-Leu-Leu-leucinal (MG-132), could inhibit the cytokine-induced adhesion, shape change, and transmigration of eosinophils. Together, our findings suggest that IL-3, IL-5, and GM-CSF regulated the adhesion and chemotaxis of human eosinophils through shared signaling pathways involving both p38 MAPK and NF-kappaB. Our results therefore shed light on the further development of more effective agents for allergic and inflammatory diseases.

Bronchi↗
PubMed2000

Monocytes induce reversible focal changes in vascular endothelial cadherin complex during transendothelial migration under flow.

The vascular endothelial cell cadherin complex (VE-cadherin, alpha-, beta-, and gamma-catenin, and p120/p100) localizes to adherens junctions surrounding vascular endothelial cells and may play a critical role in the transendothelial migration of circulating blood leukocytes. Previously, we have reported that neutrophil adhesion to human umbilical vein endothelial cell (HUVEC) monolayers, under static conditions, results in a dramatic loss of the VE-cadherin complex. Subsequent studies by us and others (Moll, T., E. Dejana, and D. Vestweber. 1998. J. Cell Biol. 140:403-407) suggested that this phenomenon might reflect degradation by neutrophil proteases released during specimen preparation. We postulated that some form of disruption of the VE-cadherin complex might, nonetheless, be a physiological process during leukocyte transmigration. In the present study, the findings demonstrate a specific, localized effect of migrating leukocytes on the VE-cadherin complex in cytokine-activated HUVEC monolayers. Monocytes and in vitro differentiated U937 cells induce focal loss in the staining of VE-cadherin, alpha-catenin, beta-catenin, and plakoglobin during transendothelial migration under physiological flow conditions. These events are inhibited by antibodies that prevent transendothelial migration and are reversed following transmigration. Together, these data suggest that an endothelial-dependent step of transient and focal disruption of the VE-cadherin complex occurs during leukocyte transmigration.

Antigens, CD↗