SEARCH · Search PubMed

Results for “Migration”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 541 records · Page 30Linked to original sources

PubMed1999

Migration Reactivities of sigma-Bonded Ligands of Organoiron and Organocobalt Porphyrins Depending on Different High Oxidation States.

Migration reactivities of sigma-bonded organo-iron and -cobalt porphyrins were examined as a function of the compound oxidation state. Migration rates were determined for both the one-electron and two-electron oxidized species produced in the electron-transfer oxidation with different oxidants in acetonitrile at 298 K. The investigated compounds are represented as [(OETPP)Fe(R)](n)()(+), where n = 1 or 2, OETPP = the dianion of 2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetraphenylporphyrin, and R = C(6)H(5), 3,5-C(6)F(2)H(3), or C(6)F(5), and as [(TPP)Co(R)](n)()(+), where n = 1 or 2, TPP = the dianion of 5,10,15,20-tetraphenylporphyrin, and R = CH(3) or C(6)H(5). The rapid two-electron oxidation of (OETPP)Fe(III)(R) occurs with [Ru(bpy)(3)](3+) (bpy = 2,2'-bipyridine) to produce [(OETPP)Fe(IV)(R)](2+). The formation of this species is followed by a slow migration of the sigma-bonded R group to a nitrogen of the porphyrin ring to give [(N-ROETPP)Fe(II)](2+) and then by a rapid electron-transfer oxidation of the migrated product with [Ru(bpy)(3)](3+) to yield [(N-ROETPP)Fe(III)](3+) as a final product. When [Ru(bpy)(3)](3+) is replaced by a much weaker oxidant such as ferricenium ion, only the one-electron oxidation of (OETPP)Fe(R) occurs to produce [(OETPP)Fe(IV)(R)](+). A migration of the R group also occurs in the one-electron oxidized porphyrin species, [(OETPP)Fe(IV)(R)](+), to produce [(N-ROETPP)Fe(II)](+), which is rapidly oxidized by ferricenium ion to yield [(N-ROETPP)Fe(III)](2+). The migration rate of the R group in [(OETPP)Fe(IV)(R)](+) is about 10(4) times slower than the migration rate of the corresponding two-electron oxidized species, [(OETPP)Fe(IV)(R)](2+). The migration rate of the sigma-bonded ligand of [(TPP)Co(IV)(R)](+), produced by the one-electron oxidation of (TPP)Co(III)(R) with [Fe(phen)(3)](3+) (phen = 1,10-phenanthroline) is also about 10(4) times slower than the migration rate of the R group in the corresponding two-electron oxidized species, [(TPP)Co(IV)(R)](2+), which is produced by the two-electron oxidation with [Ru(bpy)(3)](3+). A comparison of the migration rates with the oxidation states of the porphyrins indicates that the migration occurs via an intramolecular electron transfer from the R group to the Fe(IV) or Co(IV) metal of the organometallic porphyrin.

Journal Article↗

PubMed1996

Inhibition of the transendothelial migration of human lymphocytes but not monocytes by phosphodiesterase inhibitors.

This study describes an in vitro model of peripheral blood mononuclear cell (PBMC) migration through human endothelial cells, held on polycarbonate inserts, which allows automatic differential counting of migrated cells as lymphocytes and monocytes. Using this system it was found that treatment of PBMC with the phosphodiesterase (PDE) inhibitors theophylline (at 1 and 10 micrograms/ml) and RO-20-1724 (at 1 microM) inhibited the migration of the lymphocyte component to 64.2+/-16.4%, 48.9+/-3.0% and 47.5+/-5.8% of the control values, respectively, while the migration of the monocytes component was largely unaffected. The PDE inhibitors needed to be present during the assay to inhibit migration, whereas pre-treatment of either the endothelium or the PBMC did not consistently effect lymphocyte migration. The drugs also inhibited the migration of lymphocytes through control inserts, either uncoated or coated with fibronectin, suggesting that some of the inhibition is an effect on lymphocyte motility rather than lymphocyte-endothelial interactions. Lymphocyte migration through fibronectin-coated filters was significantly enhanced compared with uncoated filters. Activation of the PBMC by anti-CD3 MoAb increased motility and migration by up to 300%. This migration appeared to be greatly inhibited by the PDE inhibitors, although the effect was complicated by problems of lymphocyte aggregation. This study provides a novel method of measuring mononuclear cell transendothelial migration, and suggests a possible role of PDE inhibitors in reducing this progress.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗

PubMed1997

Beta 2 (CD18) and beta 1 (CD29) integrin mechanisms in migration of human polymorphonuclear leucocytes and monocytes through lung fibroblast barriers: shared and distinct mechanisms.

Accumulation of leucocytes in inflamed lung tissue and alveolar space involves their migration through vascular endothelium and then lung connective tissue. As a model of this process, we investigated human polymorphonuclear leucocyte (PMNL) and monocyte migration through a biological barrier of human lung fibroblasts (HLF) grown on polycarbonate filters. Very few PMNL (1-2%) or monocytes (3-8%) migrated through the HLF barriers spontaneously. Migration increased to 48-53% of added PMNL and 17-24% of added monocytes, when a C5a chemotactic gradient was present. The monocyte migration induced by C5a was not inhibited by monoclonal antibodies (mAb) to CD18 (beta 2 integrins). This CD18-independent migration was partially inhibited (35%) by mAb to gamma 5 of VLA-5 and completely inhibited by the combination of mAb to gamma 4 of VLA-4 with mAb to VLA-5, in the presence of mAb to CD18. In contrast, PMNL migration across HLF induced by C5a was partially inhibited by mAb to CD18 alone, but even with the addition of mAb to VLA-4, VLA-5 beta 1 and VLA-6, the greatest degree of inhibition was only 60%. Blocking the function of CD18 was not required to observe the inhibition by mAb to VLA-4, although the inhibitory effect of mAb to VLA-5 and VLA-6 alone or in combination was only observed when CD18 mechanisms were also blocked with anti-CD18 mAb. These results demonstrate that (a) both monocytes and PMNL can use either CD11/CD18 (beta 2 integrin) or beta 1 (CD49/CD29) integrins to migrate through HLF barriers; (b) in the case of monocytes, the VLA-4 and VLA-5 integrins account for essentially all the CD11/CD18-independent migration mechanisms; and (c) in contrast to monocytes, PMNL CD18-independent migration is mediated not only by VLA-4 and VLA-5, but also by VLA-6, and up to 40% of the migration appears to be via yet to be defined PMNL surface molecules.

CD11 Antigens↗

PubMed1998

Migration of human keratinocytes in electric fields requires growth factors and extracellular calcium.

Currents that leak out of wounds generate electric fields lateral to the wound. These fields induce directional locomotion of human keratinocytes in vitro and may promote wound healing in vivo. We have examined the effects of growth factors and calcium, normally present in culture medium and the wound fluid, on the directional migration of human keratinocytes in culture. In electric fields of physiologic strength (100 mV per mm), keratinocytes migrated directionally towards the cathode at a rate of about 1 microm per min. This directional migration requires several growth factors. In the absence of these growth factors, the cell migration rate decreased but directionality was maintained. Epidermal growth factor alone restored cell migration rates at concentrations as low as 0.2 ng per ml. Insulin at 5-100 microg per ml or bovine pituitary extract at 0.2%-2% vol/vol also stimulated keratinocyte motility but was not sufficient to fully restore the migration rate. Keratinocyte migration in electric fields requires extracellular calcium. Changes in calcium concentrations from 3 microM to 3.3 mM did not significantly change keratinocyte migration rate nor directionality in electric fields; however, addition of the chelator ethyleneglycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid to migration medium reduced, and eventually abolished, keratinocyte motility. Our results show that (i) growth factors and extracellular calcium are required for electric field-induced directional migration of human keratinocytes, and (ii) keratinocytes migrate equally well in low and high calcium media.

Animals↗

PubMed2005

G protein-coupled receptor signaling through Gq and JNK negatively regulates neural progenitor cell migration.

In the early development of the central nervous system, neural progenitor cells divide in an asymmetric manner and migrate along the radial glia cells. The radial migration is an important process for the proper lamination of the cerebral cortex. Recently, a new mode of the radial migration was found at the intermediate zone where the neural progenitor cells become multipolar and reduce the migration rate. However, the regulatory signals for the radial migration are unknown. Using the migration assay in vitro, we examined how neural progenitor cell migration is regulated. Neural progenitor cells derived from embryonic mouse telencephalon migrated on laminin-coated dishes. Endothelin (ET)-1 inhibited the neural progenitor cell migration. This ET-1 effect was blocked by BQ788, a specific inhibitor of the ETB receptor, and by the expression of a carboxyl-terminal peptide of Galpha q but not Galpha i. The expression of constitutively active mutant of Galpha q, Galpha qR183C, inhibited the migration of neural progenitor cells. Moreover, the inhibitory effect of ET-1 was suppressed by the c-Jun N-terminal kinase (JNK) inhibitor SP600125 and the expression of the JNK-binding domain of JNK-interacting protein-1, a specific inhibitor of the JNK pathway. Using the slice culture system of embryonic brain, we demonstrated that ET-1 and the constitutively active mutant of Galpha q caused the retention of the neural progenitor cells in the intermediate zone and JNK-binding domain of JNK-interacting protein-1 abrogated the effect of ET-1. These results indicated that G protein-coupled receptor signaling negatively regulates neural progenitor cell migration through Gq and JNK.

Animals↗

PubMed1996

Ligand occupancy of the alpha-V-beta3 integrin is necessary for smooth muscle cells to migrate in response to insulin-like growth factor.

Smooth muscle cells (SMCs) have been shown to migrate in response to insulin-like growth factor I (IGF-I). However, the mechanism mediating this response has not been determined. The migration rates of porcine and human vascular SMCs were assessed in a monolayer wounding assay. IGF-I and IGF-II induced increases of 141% and 97%, respectively, in the number of cells that migrated in 4 days. The presence of 0.2% fetal bovine serum in the culture medium was necessary for the IGFs to stimulate migration over uncoated plastic surfaces. However, if vitronectin was used as the substratum, IGF-I stimulated migration by 162% even in the absence of serum. To determine the role of integrins in mediating this migration, SMC surface proteins were labeled with 125I and immunoprecipitated with specific anti-integrin antibodies. Integrins containing alpha-V (vitronectin receptor), alpha5 (fibronectin receptor), and alpha3 (collagen/laminin receptor) subunits were the most abundant. IGF-I treatment caused a 73% reduction in alpha5-integrin subunit protein and a 25% increase in alpha-V subunit. More importantly, ligand binding of alpha-V-beta3 was increased by 2.4-fold. We therefore examined whether the function of the alpha-V-beta3 integrin was important for IGF-I-mediated migration. The disintegrin kistrin was shown by affinity crosslinking to specifically bind with high affinity to alpha-V-beta3 and not to alpha5-beta1 or other abundant integrins. The related disintegrin echistatin specifically inhibited 125I-labeled kistrin binding to alpha-V-beta3, while a structurally distinct disintegrin, decorsin, had 1000-fold lower affinity. The addition of increasing concentrations of either kistrin or echistatin inhibited IGF-I-induced migration, whereas decorsin had a minimal effect. The potency of these disintegrins in inhibiting IGF-I-induced migration paralleled their apparent affinity for the alpha-V integrin. Furthermore, an alpha-V-beta3 blocking antibody inhibited SMC migration by 80%. In summary, vitronectin receptor activation is a necessary component of IGF-I-mediated stimulation of smooth muscle migration, and alpha-V-beta3 integrin antagonists appear to be important reagents for modulating this process.

Animals↗

PubMed1997

Embryonic fibroblasts that are genetically deficient in low density lipoprotein receptor-related protein demonstrate increased activity of the urokinase receptor system and accelerated migration on vitronectin.

Low density lipoprotein receptor-related protein (LRP) mediates the endocytosis of diverse ligands, including urokinase plasminogen activator (uPA) and its receptor, uPAR, which have been implicated in cellular migration. The purpose of this study was to determine whether LRP affects cellular migration. Murine embryonic fibroblasts (MEF) that are LRP-deficient due to targeted gene disruption and exotoxin selection (MEF-2), heterozygous fibroblasts (PEA-10), and wild-type fibroblasts (MEF-1) were compared. When cultures were denuded of cells in a 1-mm-wide strip, all three cell types migrated into the denuded area. The MEF-2 cells migrated nearly twice as rapidly as the MEF-1 cells or PEA-10 cells. The difference in migration velocity was duplicated in culture wells that were precoated with serum or vitronectin and partially duplicated in wells coated with fibronectin but not in wells coated with type I collagen or Matrigel. uPA was detected in MEF-2 conditioned medium (CM) at a concentration of 0.30 +/- 0.02 nM, which was 13-fold higher than the level detected in MEF-1 CM or PEA-10 CM, suggesting one potential mechanism for the enhanced migration of MEF-2 cells. uPAR was also increased on MEF-2 cells by 4-5-fold, as determined by PI-PLC release, and by 2.5-fold, as determined by a uPA/uPAR activity assay. Mannosamine treatment, which down-regulates cell-surface uPAR, decreased MEF-2 migration by 40% without significantly affecting MEF-1 migration. MEF-2 CM, which is uPA-rich, increased the rate of MEF-1 migration, and MEF-1 CM did not. These studies demonstrate alterations in cellular migration and in the activity of the uPA/uPAR system which accompany complete deficiency of LRP expression in fibroblasts. We propose that uPA and uPAR form an autocrine loop for promoting fibroblast migration and that LRP counteracts the activity of this system.

Animals↗

PubMed2004

Influence of polymer matrix and adsorption onto silica materials on the migration of alpha-tocopherol into 95% ethanol from active packaging.

In this study, the effect of polymer materials with different polarity, namely low density polyethylene (LDPE) and ethylene vinyl acetate (EVA), on the migration behaviour of alpha-tocopherol from active packaging was investigated. The antioxidant was also adsorbed onto silica materials, namely SBA-15 (Santa Barbara-15) and Syloblock, in order to protect the antioxidant during extrusion and to ensure a controlled and sufficient release during the shelf-life of the food product. Migration experiments were performed at 7.0 +/- 0.5 degrees C and 95% ethanol was used as fatty food simulant. All films contained a high concentration of alpha-tocopherol, approximately 2000 mg kg(-1), to obtain an active packaging. Polymer matrix had a small influence on the migration profile. The migration of 80% of total migrated amount of antioxidant was retarded for 2.4 days by using LDPE instead of EVA. When alpha-tocopherol was adsorbed onto both silica materials, the migration of 80% of total migrated amount of antioxidant was retarded for 3.4 days in comparison to pure alpha-tocopherol. No difference was seen between the migration profiles of alpha-tocopherol adsorbed onto both silica materials. In the case of pure alpha-tocopherol, 82% of the initial amount of alpha-tocopherol in the film migrated into the food simulant at a rather fast migration rate. In the case of adsorption on silica materials, a total migration was observed. These antioxidative films can have positive food applications.

Adsorption↗

PubMed2004

CD200 maintains microglial potential to migrate in adult human retinal explant model.

PURPOSE: Retinal microglia (MG) migrate in response to injury, degeneration and inflammation dependent upon both soluble and cognate signals they receive. Previously we found that lipopolysaccharide/interferon-gamma (LPS/IFNgamma) stimulation induces a paradoxical IL-10 mediated suppression of MG migration from retinal explants. Given the high expression of neuronal CD200, which can induce down regulation of CD200 receptor-positive MG activation and neuronal fractalkine expression potentially stimulating MG migration, we wished to further examine their respective roles in the maintenance of MG activation and migration. METHODS: A human retinal explant model of MG migration was used. CD200 receptor and fractalkine receptor stimulation was achieved by addition to explants of CD200:Fc fusion protein and recombinant cytokine respectively, with or without LPS-IFNgamma stimulation that is known to suppress migration. Cell migration and cell activation (iNOS expression) was counted and assessed by numbers of CD45+ cells by immunofluorescence and standardised flow cytometric bead array analysis was performed for cytokine production. RESULTS: Retinal explants expressed fractalkine and CX3CR1 immunohistochemically and by PCR. Addition of Fractalkine and not CD200:Fc induced MG migration from retinal explants. However LPS/IFNgamma-induced suppression of MG migration could only be restored in the presence of CD200:Fc, whilst MG remained iNOS-negative and generated IL-10. CONCLUSIONS: Microglial responses are tightly governed within retina. Although MG do not classically activate following LPS/IFNgamma stimulation, their migration is sustained via CD200R stimulation maintaining their potential to migrate in response to injury.

Antigens, CD↗

PubMed1991

Attachment to fibronectin or vitronectin makes human neutrophil migration sensitive to alterations in cytosolic free calcium concentration.

Transient increases in cytosolic free calcium concentration, [Ca2+]i, appear to be required for the migration of human neutrophils on poly-D-lysine-coated glass in the presence of dilute serum (Marks, P. W., and F. R. Maxfield. 1990. J. Cell Biol. 110:43-52). In contrast, no requirement for [Ca2+]i transients exists when neutrophils migrate on albumin-coated glass in the absence of serum. To determine the mechanism that necessitates [Ca2+]i transients on poly-D-lysine in the presence of serum, migration was examined on substrates consisting of purified adhesive glycoproteins. In the absence of external Ca2+, a treatment which causes the cessation of [Ca2+]i transients, migration on fibronectin (fn) and vitronectin (vn) was significantly inhibited. Migration was also inhibited in Ca2(+)-buffered cells on these substrates, indicating that this effect was the result of an alteration of [Ca2+]i. In the absence of external Ca2+, the inhibition of migration on fn or vn was more pronounced when soluble fn or vn was added to cells migrating on these substrates. This effect of soluble adhesive glycoprotein was specific: in the absence of external Ca2+, soluble fn did not affect the migration of cells on vn, and soluble vn did not affect the migration on fn. No additional inhibition of migration was observed in Ca2(+)-buffered cells with the addition of soluble adhesive glycoprotein. These data indicate that [Ca2+]i transients are involved in continued migration of human neutrophils on fn or vn, proteins which are part of the extracellular matrix that neutrophils encounter in vivo.

Blood Proteins↗

PubMed1993

Maximal migration of human smooth muscle cells on fibronectin and type IV collagen occurs at an intermediate attachment strength.

Although a biphasic dependence of cell migration speed on cell-substratum adhesiveness has been predicted theoretically, experimental data directly demonstrating a relationship between these two phenomena have been lacking. To determine whether an optimal strength of cell-substratum adhesive interactions exists for cell migration, we measured quantitatively both the initial attachment strength and migration speed of human smooth muscle cells (HSMCs) on a range of surface concentrations of fibronectin (Fn) and type IV collagen (CnIV). Initial attachment strength was measured in order to characterize short time-scale cell-substratum interactions, which may be representative of dynamic interactions involved in cell migration. The critical fluid shear stress for cell detachment, determined in a radial-flow detachment assay, increased linearly with the surface concentrations of adsorbed Fn and CnIV. The detachment stress required for cells on Fn, 3.6 +/- 0.2 x 10(-3) mu dynes/absorbed molecule, was much greater than that on CnIV, 5.0 +/- 1.4 x 10(-5) mu dynes/absorbed molecule. Time-lapse videomicroscopy of individual cell movement paths showed that the migration behavior of HSMCs on these substrates varied with the absorbed concentration of each matrix protein, exhibiting biphasic dependence. Cell speed reached a maximum at intermediate concentrations of both proteins, with optimal concentrations for migration at 1 x 10(3) molecules/micron2 and 1 x 10(4) molecules/micron2 on Fn and CnIV, respectively. These optimal protein concentrations represent optimal initial attachment strengths corresponding to detachment shear stresses of 3.8 mu dyne/micron2 on Fn and 1.5 mu dyne/micron2 on CnIV. Thus, while the optimal absorbed protein concentrations for migration on Fn and CnIV differed by an order of magnitude, the optimal initial attachment strengths for migration on these two proteins were very similar. Further, the same minimum strength of initial attachment, corresponding to a detachment shear stress of approximately 1 mu dyne/micron2, was required for movement on either protein. These results suggest that initial cell-substratum attachment strength is a central variable governing cell migration speed, able to correlate observations of motility on substrata differing in adhesiveness. They also demonstrate that migration speed depends in biphasic manner on attachment strength, with maximal migration at an intermediate level of cell-substratum adhesiveness.

Cell Adhesion↗

PubMed2000

Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5.

Laminin-5 (Ln-5) is an extracellular matrix substrate for cell adhesion and migration, which is found in many epithelial basement membranes. Mechanisms eliciting migration on Ln-5 need to be elucidated because of their relevance to tissue remodeling and cancer metastasis. We showed that exogenous addition of activated matrix metalloprotease (MMP) 2 stimulates migration onto Ln-5 in breast epithelial cells via cleavage of the gamma2 subunit. To investigate the biological scope of this proteolytic mechanism, we tested a panel of cells, including colon and breast carcinomas, hepatomas, and immortalized hepatocytes, selected because they migrated or scattered constitutively in the presence of Ln-5. We found that constitutive migration was inhibited by BB94 or TIMPs, known inhibitors of MMPs. Limited profiling by gelatin zymography and Western blotting indicated that the ability to constitutively migrate on Ln-5 correlated with expression of plasma membrane bound MT1-MMP metalloprotease, rather than secretion of MMP2, since MMP2 was not produced by three cell lines (one breast and two colon carcinomas) that constitutively migrated on Ln-5. Moreover, migration on Ln-5 was reduced by MT1-MMP antisense oligonucleotides both in MMP2+ and MMP2- cell lines. MT1-MMP directly cleaved Ln-5, with a pattern similar to that of MMP2. The hemopexin-like domain of MMP2, which interferes with MMP2 activation, reduced Ln-5 migration in MT1-MMP+, MMP2+ cells, but not in MT1-MMP+, MMP2- cells. These results suggest a model whereby expression of MT1-MMP is the primary trigger for migration over Ln-5, whereas MMP2, which is activated by MT1-MMP, may play an ancillary role, perhaps by amplifying the MT1-MMP effects. Codistribution of MT1-MMP with Ln-5 in colon and breast cancer tissue specimens suggested a role for this mechanism in invasion. Thus, Ln-5 cleavage by MMPs may be a widespread mechanism that triggers migration in cells contacting epithelial basement membranes.

Animals↗

PubMed1955

The acceleration and inhibition of migration of human leucocytes in vitro by plasma protein fractions.

A new method is described for the quantitative study of leucocyte migration. Blood drawn into a capillary tube is centrifuged, forming a buffy coat. The migration of the leucocytes from the buffy coat into the plasma is measured by means of an ocular micrometer. While there is a great deal of variation from one normal individual to another in the migration rates of leucocytes those of each individual show relatively little variation in migration from day to day (Table I). In all cases of illness studied, the average migration rates fall within the normal range, but there was a wider variation in the day to day migration rate than obtains in normal healthy individuals (Tables II and III). From experiments in which the cells with typically "slow" and "fast" migration rates were tested in both the "slow" and "fast" plasmas, it could be concluded that while the cells invariably have some influence on the migration rate, the major factors influencing leucocyte migration reside in the plasma (Table V). Experiments in which the plasma proteins were fractionated according to the method of Lever et al. indicated the presence of a system of proteins which regulate leucocyte migration. A heat-labile (56 degrees C. for 30 minutes) component of fraction II was able to accelerate leucocyte migration, while fraction III acted as an inhibitor (Tables IX and X).

Blood Proteins↗

PubMed1995

Monocyte migration to arthritis in the rat utilizes both CD11/CD18 and very late activation antigen 4 integrin mechanisms.

In human and experimental models of arthritis, blood monocytes migrate into the inflamed synovium and joint space. The mechanisms required for monocyte migration across the vascular endothelium in joints is poorly defined. Radiolabeled rat blood monocytes were used to measure monocyte migration to the inflamed joints of rats with adjuvant arthritis, and the role of monocyte adhesion molecules was analyzed. Monocyte accumulation in the inflamed joints was maximal 14-21 d after immunization with adjuvant, when arthritis had fully developed. Blocking mAbs to lymphocyte function-associated antigen 1 (LFA-1), Mac-1, and very late activation antigen 4 (VLA-4) were used to evaluate the role of these integrins in the migration. Migration to the joints was not inhibited by treatment of the animals with mAb to LFA-1, Mac-1, or VLA-4 alone, and was partially (50%) inhibited in only the most arthritic joint, the talar joint, by the combination of mAb to LFA-1 plus Mac-1. In contrast, this combination inhibited migration to dermal inflammation induced by C5ades Arg, endotoxin, tumor necrosis factor alpha, and polyinosine-cytosine by 60-70%. When mAbs to LFA-1 and VLA-4 were combined, migration to all the inflamed joints was strongly inhibited (80-98%, depending on the joint). Treatment with the combination of the three mAbs to LFA-1, Mac-1, and VLA-4 completely eliminated monocyte migration to all joints and dermal inflammation. The results show that 51Cr blood monocytes can be used to quantify monocyte migration to arthritic joints in the rat. LFA-1 alone or VLA-4 alone is sufficient to mediate most of this migration, and either LFA-1 or VLA-4 is required for monocyte migration to joint inflammation. These results indicate that both the VLA-4 and LFA-1 integrins should be therapeutic targets for suppression of monocyte infiltration of joints in arthritis.

Animals↗

PubMed1997

Alpha 6 integrins are required for Langerhans cell migration from the epidermis.

Topical exposure of mice to chemical allergens results in the migration of epidermal Langerhans cells (LCs) from the skin and their accumulation as immunostimulatory dendritic cells (DCs) in draining lymph nodes. Epidermal cell-derived cytokines have been implicated in the maturation and migration of LCs, but the adhesion molecules that regulate LC migration have not been studied. We hypothesized that integrin-mediated interactions with extracellular matrix components of the skin and lymph node may regulate LC/DC migration. We found that alpha 6 integrins and alpha 4 integrins were differentially expressed by epidermal LCs and lymph node DCs. A majority of LCs (70%) expressed the alpha 6 integrin subunit, whereas DCs did not express alpha 6 integrins. In contrast, the alpha 4 integrin subunit was expressed at high levels on DCs but at much lower levels on LCs. The anti-alpha 6 integrin antibody, GoH3, which blocks binding to laminin, completely prevented the spontaneous migration of LCs from skin explants in vitro and the rapid migration of LCs from mouse ear skin induced after intradermal administration of TNF-alpha in vivo. GoH3 also reduced the accumulation of DCs in draining lymph nodes by a maximum of 70% after topical administration of the chemical allergen oxazolone. LCs remaining in the epidermis in the presence of GoH3 adopted a rounded morphology, rather than the interdigitating appearance typical of LCs in naive skin, suggesting that the cells had detached from neighboring keratinocytes and withdrawn cellular processes in preparation for migration, but were unable to leave the epidermis. The anti-alpha 4 integrin antibody PS/2, which blocks binding to fibronectin, had no effect on LC migration from the epidermis either in vitro or in vivo, or on the accumulation of DCs in draining lymph nodes after oxazolone application. RGD-containing peptides were also without effect on LC migration from skin explants. These results identify an important role for alpha 6 integrins in the migration of LC from the epidermis to the draining lymph node by regulating access across the epidermal basement membrane. In contrast, alpha 4 integrins, or other integrin-dependent interactions with fibronectin that are mediated by the RGD recognition sequence, did not influence LC migration from the epidermis. In addition, alpha 4 integrins did not affect the accumulation of LCs as DCs in draining lymph nodes.

Animals↗

PubMed1999

Mutations affecting symmetrical migration of distal tip cells in Caenorhabditis elegans.

The rotational symmetry of the Caenorhabditis elegans gonad arms is generated by the symmetrical migration of two distal tip cells (DTCs), located on the anterior and posterior ends of the gonad primordium. Mutations that cause asymmetrical migration of the two DTCs were isolated. All seven mutations were recessive and assigned to six different complementation groups. vab-3(k121) and vab-3(k143) affected anterior DTC migration more frequently than posterior, although null mutants showed no bias. The other five mutations, mig-14(k124), mig-17(k113), mig-18(k140), mig-19(k142), and mig-20(k148), affected posterior DTC migration more frequently than anterior. These observations imply that the migration of each DTC is regulated differently. mig-14 and mig-19 also affected the migration of other cells in the posterior body region. Four distinct types of DTC migration abnormalities were defined on the basis of the mutant phenotypes. vab-3; mig-14 double mutants exhibited the types of DTC migration defects seen for vab-3 single mutants. Combination of mig-17 and mig-18 or mig-19, which are characterized by the same types of posterior DTC migration defects, exhibited strong enhancement of anterior DTC migration defects, suggesting that they affect the same or parallel pathways regulating anterior DTC migration.

Animals↗

PubMed1994

Elucidation of the role of breathless, a Drosophila FGF receptor homolog, in tracheal cell migration.

DFGF-R1 (breathless), a Drosophila FGF receptor homolog, is required for the migration of tracheal cells and the posterior midline glial cells during embryonic development. To define the role of this receptor in cell migration, we have monitored the biological effects of a deregulated receptor containing the extracellular and transmembrane regions of the torso dominant allele and the cytoplasmic domain of DFGF-R1. Ubiquitous expression of the chimeric receptor at the time of tracheal cell migration did not disrupt migration in wild-type embryos. However, induction of the chimeric receptor corrected the tracheal defects of breathless (btl) mutant embryos, allowing the tracheal cells to migrate along their normal tracts. This result indicates that the normal activity of DFGF-R1 in promoting cell migration does not require spatially restricted cues. Late inductions of the chimeric construct, after the normal initiation of tracheal migration, allowed the definition of a broad time window during which the external signals guiding migration persist and the tracheal cells retain the capacity to respond to these cues. Rescue of tracheal migration in btl mutant embryos by the chimeric construct provides a sensitive biological assay for the activity of other Drosophila receptor tyrosine kinases (RTKs). Deregulated receptors containing the cytoplasmic domains of DFGF-R2, DER, torso, and sevenless were all able to partially rescue the migration defects. Consistent with the notion that these RTKs share a common signaling pathway, constructs containing the activated downstream elements Dras1 and Draf were also able to rescue tracheal migration, demonstrating that these two proteins are key players in the DFGF-R1 signaling pathway.

Animals↗

PubMed1995

Interleukin-1 alpha stimulates keratinocyte migration through an epidermal growth factor/transforming growth factor-alpha-independent pathway.

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) stimulate keratinocyte migration on collagen by up-regulating the alpha 2 subunit of the collagen integrin, alpha 2 beta 1. Interleukin-1 (IL-1) is an autocrine factor, produced by keratinocytes themselves, that is modulated by ultraviolet light and increases the proliferative potential of keratinocytes in culture. The autocrine nature of keratinocyte-derived IL-1 alpha is emphasized by the fact that it induces the keratinocyte to synthesize IL-1 alpha and TGF-alpha, a cytokine known to induce keratinocyte motility. Further, topical application of IL-1 alpha has been shown to promote wound healing in animals. In this study, we used a well-defined keratinocyte migration assay to assess the effect of IL-1 alpha on keratinocyte motility and to examine whether the IL-1 alpha/TGF alpha pathway is involved. The addition of recombinant human IL-1 alpha to keratinocytes produced a statistically significant and concentration-dependent increase in migration on matrices of collagen types I and IV, but not on laminin. Maximal levels of keratinocyte migration obtained on these matrices with IL-1 alpha were comparable to those obtained with stimulation by EGF and TGF-alpha. The effects of TGF-alpha and IL-1 alpha on keratinocyte migration are additive; however, the maximal level of migration achieved by using IL-1 alpha and TGF-alpha in combination never exceeds the maximal level of migration found by using either cytokine alone. The time course of keratinocyte migration induced by IL-1 alpha is delayed (onset of migration 9-12 h after addition) as compared with that induced by TGF-alpha (onset of migration 6-9 h after addition) even if the cells are preincubated in IL-1 alpha. Flow cytometry analysis demonstrated no change in surface expression of integrin subunits, specifically that of integrin subunit alpha 2, previously shown to be up-regulated by EGF/TGF-alpha. These results suggest that IL-1 alpha stimulates keratinocyte migration on collagen via a mechanism distinct from that of EGF/TGF-alpha.

Cell Movement↗