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PubMed1994

Molecular analysis of cell surface beta-1,4-galactosyltransferase function during cell migration.

Despite the identification and characterization of cell surface receptors for the extracellular matrix, it is unknown how their relative expression and cytoskeletal association regulate cell migration. Previous studies have identified beta-1,4-galactosyltransferase (GalTase; EC 2.4.1.38) on the surface of migrating cells, where it mediates cell migration on basal lamina matrices by associating with the cytoskeleton and binding to N-linked oligosaccharides in the E8 domain of laminin. In this study, the function of GalTase during cell migration was examined directly by analyzing the migration rate of stably transfected cell lines in which the relative level of surface GalTase and its ability to associate with the cytoskeleton were altered. We show here that the cytoskeleton contains a limiting, saturable, number of binding sites for surface GalTase. Furthermore, the rate of cell migration was inversely related to the ability of surface GalTase to associate with the cytoskeleton. Elevating surface GalTase in excess of the number of cytoskeleton-binding sites reduced the rate of cell migration, whereas decreasing the amount of surface GalTase available to bind the cytoskeleton increased migration rates. These results show that the rate of cell migration on basal lamina is directly dependent upon the expression of surface GalTase and the ability of this protein to associate with a limiting number of cytoskeleton-binding sites.

3T3 Cells↗
PubMed2001

RhoA inactivation by p190RhoGAP regulates cell spreading and migration by promoting membrane protrusion and polarity.

The binding of extracellular matrix proteins to integrins triggers rearrangements in the actin cytoskeleton by regulating the Rho family of small GTPases. The signaling events that mediate changes in the activity of Rho proteins in response to the extracellular matrix remain largely unknown. We have demonstrated in previous studies that integrin signaling transiently suppresses RhoA activity through stimulation of p190RhoGAP. Here, we investigated the biological significance of adhesion-dependent RhoA inactivation by manipulating p190RhoGAP signaling in Rat1 fibroblasts. The inhibition of RhoA activity that is induced transiently by adhesion was antagonized by expression of dominant negative p190RhoGAP. This resulted in impaired cell spreading on a fibronectin substrate, reduced cell protrusion, and premature assembly of stress fibers. Conversely, overexpression of p190RhoGAP augmented cell spreading. Dominant negative p190RhoGAP elevated RhoA activity in cells on fibronectin and inhibited migration, whereas overexpression of the wild-type GAP decreased RhoA activity, promoted the formation of membrane protrusions, and enhanced motility. Cells expressing dominant negative p190RhoGAP, but not control cells or cells overexpressing the wild-type GAP, were unable to establish polarity in the direction of migration. Taken together, these data demonstrate that integrin-triggered RhoA inhibition by p190RhoGAP enhances spreading and migration by regulating cell protrusion and polarity.

Actins↗
PubMed2003

Human chymase stimulates Ca2+ signaling in human polymorphonuclear cells.

Human chymase is known to function as a chemoattractant for human leukocytes. To investigate the mechanism of the chymase-induced cell migration, change in intracellular calcium concentration ([Ca(2+)]i) was examined in human polymorphonuclear (PMN) cells using Fluo-3 as a fluorescent Ca(2+) indicator. Treatment of PMN cells with human chymase caused [Ca(2+)]i elevation in a concentration-dependent manner. Depletion of extracellular Ca(2+) from the medium partially attenuated the chymase-induced [Ca(2+)]i increase, showing that both Ca(2+) influx and Ca(2+) release from internal stores might be involved in the [Ca(2+)]i response. Pretreatment of the cells with pertussis toxin completely blocked the chymase-induced [Ca(2+)]i signal, suggesting an involvement of G protein in the chymase-mediated [Ca(2+)]i elevation. The data in the present study raise the possibility that the chymase-induced cell migration is mediated by the [Ca(2+)]i elevation, which might be caused by stimulation of a G-protein-coupled receptor such as protease-activated receptors (PARs).

Calcium↗
PubMed2004

Magnification and toxicity of PCBs, PCDDs, and PCDFs in upriver-migrating Pacific salmon.

The depletion of lipids associated with pre-spawning migration of Pacific salmon has the potential to magnify concentrations of hydrophobic organic contaminants (HOCs), which elevates risk of toxic effects. We present data from a field study of sockeye salmon (Oncorhynchus nerka) migrating to spawn in Great Central Lake, BC, which demonstrate that pre-spawning migration causes a magnification of PCB, PCDD, and PCDF concentrations in female gonads (1.9-2.5-fold), female soma (3.4-5.6-fold), and male soma (5.6-9.7-fold). We further develop a model of prespawning migration chemical magnification for sockeye salmon stocks as a function of migration distance. This model is shown to be consistent with available empirical data on pre-spawning magnification and predicts magnification factors ranging between 1.4 and 7.9 in gonad and between 1.6 and 10.4 in soma in seven Pacific salmon stocks in British Columbia. Post-migration (prespawning) toxic equivalent dioxin concentrations in roe were measured to be approximately 3 pg/g lipid in salmon from the Great Central Lake sockeye stock and estimated to range between 1.5 pg/g lipid for the shortest-migrating stocks and 7 pg/g lipid for the longest-migrating stocks. Concentrations in certain stocks approach or exceed the concentration of 3 pg/g lipid associated with 30% egg mortality in Oncorhynchus mykiss. This indicates the potential for population-level effects of current contaminant levels. It also suggests that historic contaminant concentrations, which were greater than current concentrations, may have contributed significantly to the decline of certain Pacific salmon stocks in British Columbia.

Animal Migration↗
PubMed2001

Predicting the risk of restenosis after angioplasty in patients with peripheral arterial disease.

Restenosis is a serious therapeutic problem after percutaneous transluminal angioplasty (PTA). Strategies for the prevention of late restenosis include the use of antiaggregatory and anticoagulant drugs, aggressive lipid-lowering, intravascular radiation and others. As some of these therapeutic options are not without side effects it is important to identify patients with an increased risk to develop restenosis. Major clinically recognizable risk factors for restenosis are advanced disease stage and female gender. Elevated plasma levels of fibrinogen, Lp(a), CRP, and migration-inducing activity appear to indicate an unfavorable clinical outcome, and so does post-interventional increase of vWF and PAI-1 antigen. For peripheral arterial disease, only one study has addressed the influence of homocysteine levels upon the restenosis rate after PTA. Although homocysteine levels were elevated in >50% of patients at entry, they were not associated with a higher restenosis rate. Currently the available data allow a rough approximation of a patient's individual risk.

Angioplasty, Balloon, Coronary↗
PubMed1977

Angiostrongylus cantonensis: phospholipase in nonsensitized and sensitized rats after challenge.

Rats given an initial infection with Angiostrongylus cantonensis had moderately elevated phospholipase B activity in the lungs at 8 and 15 days after challenge, and greatly elevated levels were evident at 35, 43, and 49 days. In the brain, the values were elevated at 15 through 35 days. These periods of increased activity in the lungs and brain coincided with the migration patterns of the third stage larvae and the adult worms in this host. The elevated enzyme levels also were were correlated with increased numbers of eosinophils in the bone marrow at 8 and 15 days and again at 36, 43, and 49 days after infection. Similarly infected rats exhibited leukocytosis at 1 through 10 weeks of observation after challenge, and striking eosinophilia at 1, 7, 8, and 9 weeks. Rats reinfected after removal of the worms of the initial infection by thiabendazole treatment showed an anamnestic response characterized by (i) elevated enzyme values in both the lungs and brain at 1 day after reinfection and (ii) eosinophilia in the bone marrow by day 4. These accelerated responses were accompanied by a significant reduction in the worm burden of the rats. The results, which support our hypothesis that inflammation, elevated phospholipase B activity, and reduction in worm burden are causally related, are discussed in light of similar findings reported earlier from our studies with Trichinella spiralis and Nippostrongylus brasiliensis.

Animals↗
PubMed1998

The potent lipid mitogen sphingosylphosphocholine activates the DNA binding activity of upstream stimulating factor (USF), a basic helix-loop-helix-zipper protein.

We previously demonstrated that the sphingolipid, sphingosylphosphocholine (SPC) increased DNA binding activity of AP-1 proteins accompanying cellular proliferation. Herein, the effects of SPC on DNA binding activity and transcription of the basic, helix-loop-helix, leucine zipper (bHLH-ZIP) proteins Myc, Max, and USF were investigated because they regulate genes involved in mitogenesis. E-box (CACGTG) DNA binding proteins were detected by electrophoretic mobility shift assays in nuclear extracts from Swiss 3T3 fibroblasts. The slowest migrating complex (complex I) increased within 1-3 min after treatment with SPC, remained elevated for 10 min, and increased again after 12 h. Complexes I and II contained USF-1 and USF-2 proteins, and complex I migrated similarly to recombinant USF-1 protein/DNA complex. Treatment of nuclear extracts with alkaline phosphatase decreased these complexes suggesting USF might be a phosphoprotein, post-translationally modified by SPC. max and usf-1 mRNA levels were unaffected by SPC treatment. In contrast, c-myc mRNA was rapidly elevated, reached maximum levels at 0.5-1 h, and showed an additional increase after 12 h, just preceding S phase. Thus, certain bHLH-ZIP transcription factors may be involved in cell growth regulation by SPC.

3T3 Cells↗
PubMedDate not supplied

Effects of heat on embryos and foetuses.

OBJECTIVES: This paper reviews the effects of elevated maternal temperature on embryo and foetal development in experimental animals and in humans. CONCLUSIONS: Hyperthermia during pregnancy can cause embryonic death, abortion, growth retardation and developmental defects. Processes critical to embryonic development, such as cell proliferation, migration, differentiation and programmed cell death (apoptosis) are adversely affected by elevated maternal temperatures, showing some similarity to the effects of ionizing radiation. The development of the central nervous system is especially susceptible: a 2.5 degrees C elevation for 1 h during early neural tube closure in rats resulted in an increased incidence of cranio-facial defects, and a 'spike' temperature elevation of 2-2.5 degrees C in an exposure of 1 h during early neurogenesis in guinea pigs caused an increase in the incidence of microencephaly. However, in general, thresholds and dose-response relationships vary between species and even between different strains of the same species, depending on genotype. This precludes rigorous quantitative extrapolation to humans, although some general principles can be inferred. In humans, epidemiological studies suggest that an elevation of maternal body temperature by 2 degrees C for at least 24 h during fever can cause a range of developmental defects, but there is little information on thresholds for shorter exposures. Further experimental and epidemiological studies are recommended, focusing on stage-specific developmental effects in the central nervous system using a variety of sensitive assays.

Animals↗
PubMed2002

Collective effects in grain boundary migration.

In situ high-resolution transmission electron microscopy is used to study grain boundary structure and kinetics in bicrystalline Au films at elevated temperature. We report the first direct evidence for the existence of cooperative atomic motion in grain boundary migration. Certain nanoregions at grain boundaries, typically involving up to several hundred atoms, are found to switch back and forth between neighboring grains. Reversible structural fluctuations at temperatures near 0.5T(m) and above have been discovered in [110] and [001] tilt, as well as in general grain boundaries.

Journal Article↗
PubMed2006

Role of macrophage migration inhibitory factor in acute lung injury in mice with acute pancreatitis complicated by endotoxemia.

Acute pancreatitis accompanied by a subsequent infectious attack can often lead to multisystem organ dysfunction, including acute lung injury (ALI), but the molecular mechanisms are poorly defined. In this study, we explored the role of the priming insult by induction of cerulein pancreatitis, which was followed by the second attack due to endotoxemia, in the development of ALI in mice. Experiments revealed that LPS injection in mice with acute pancreatitis caused the development of ALI, as indicated by blood-gas derangements, pulmonary vascular hyperpermeability, increased inflammatory cell counts in bronchoalveolar lavage, and histologic lung damage. This was associated with the pancreatitis-induced increase in expression of macrophage migration inhibitory factor (MIF) in the lungs, together with elevated expression of Toll-like receptor (TLR)-4, both of which were inhibited by administration of anti-protease-activated receptor (PAR)-2 antibody. Furthermore, anti-MIF antibody treatment suppressed the pancreatitis-induced elevation of TLR-4 pulmonary expression. Genetic removal of MIF from mice resulted in less development of ALI in the setting of acute pancreatitis complicated by endotoxemia. These findings demonstrate that activation of protease-activated receptor-2 with trypsin, which can be released after pancreatitis induction, positively regulates the transcript level of MIF, and increased MIF results in exaggerated pulmonary expression of TLR-4, leading to the development of ALI with a subsequent infectious attack. We thus suggest that interventions designed to modulate MIF may have therapeutic advantages in treating ALI in patients with acute pancreatitis complicated by bacterial infection.

Acute Disease↗
PubMed2006

Effect of methanol-induced oxidative stress on the neuroimmune system of experimental rats.

It is well known that the nervous system has increased susceptibility to methanol intoxication. The present study reveals the effect of methanol intoxication on antioxidant status, lipid peroxidation and DNA integrity in hypothalamic-pituitary-adrenal (HPA) axis organs and spleen. Non-specific and specific immune functions were analyzed. In addition, open field behavior, plasma corticosterone level and blood methanol level were estimated. Male Wistar albino rats were intoxicated with methanol (2.37 g/kg b.wt., i.p.) for 1 day, 15 and 30 days. Administration of methanol showed significant increase in enzymatic (superoxide dismutase, catalase, glutathione peroxidase), non-enzymatic (reduced glutathione and Vitamin C) antioxidants and lipid peroxidation (LPO) in hypothalamus and adrenal gland of day 1 group. However, decrease in enzymatic and non-enzymatic antioxidants with concomitant increase in LPO level were observed in 15 and 30 days groups. Plasma corticosterone level was significantly increased in day 1 and 15 days groups whereas, 30 days methanol intoxication group showed considerable decrease in corticosterone level compared with control animals. Cell-mediated immune response of footpad thickness was significantly decreased with an increased leukocyte migration inhibition. Humoral immune response of antibody titers was elevated in methanol-intoxicated groups. Neutrophil functions, adherence and phagocytic index (PI) were found to be significantly decreases. Furthermore, significant increase in the avidity index and nitro blue tetrozolium reduction was observed in the methanol exposed animals. Day 1 methanol exposed group showed increased PI compared to the control ones. Methanol exposure for 30 days showed an increased DNA fragmentation in the hypothalamus, adrenal glands, and spleen. In conclusion, exposure to methanol-induced oxidative stress disturbs the HPA-axis function altering the level of corticosterone, which lead to varied non-specific and specific immune response in experimental rats.

Animals↗
PubMed1994

Rat CINC/gro: a novel mediator for locomotive and secretagogue activation of neutrophils in vivo.

The effects of rat CINC/gro, a member of the interleukin-8 family, on the endothelium-neutrophil interaction and transendothelial macromolecular leakage were studied in rat mesenteric microcirculation. Thirty minutes after superfusion with 10 nM CINC/gro, the number of neutrophils adherent to the venular endothelium and those migrated across the venules were significantly increased with a concomitant elevation of luminol-dependent chemiluminescence at the site of adhesion. Transendothelial macromolecular leakage as assessed by the relative length of venular wall stained with monastral blue B was also increased at 30 min after the start of CINC/gro superfusion. Pretreatments with a CD18-directed monoclonal antibody, WT-3 (1 mg/kg), significantly attenuated the increase in number of adherent and migrated neutrophils, the increase in luminol-dependent chemiluminescence, and the venular macromolecular leakage after the application of CINC/gro. These data suggest that CINC/gro is a novel stimulator that evokes not only locomotive but also secretagogue activation of neutrophils via a CD18-dependent mechanism in vivo.

Animals↗
PubMed2003

Serine/threonine kinase Mirk/Dyrk1B is an inhibitor of epithelial cell migration and is negatively regulated by the Met adaptor Ran-binding protein M.

Minibrain-related kinase (Mirk)/Dyrk1B is an arginine-directed serine/threonine kinase that is active in skeletal muscle development but is also expressed in various carcinomas. In the current study, the Met adaptor protein Ran-binding protein M (RanBPM) was identified as a Mirk-binding protein by yeast two-hybrid analysis. The Mirk-RanBPM association was confirmed by glutathione S-transferase pull-down assays, co-immunoprecipitation studies, and in vivo cross-linking. Met plays an important role in tumor cell invasion and cell migration. RanBPM has been reported to bind to the tyrosine kinase domain of the hepatocyte growth factor (HGF) receptor Met, enhance Met downstream signaling, and enhance HGF-induced A704 kidney carcinoma cell invasion (Wang, D., Li, Z., Messing, E. M., and Wu, G. (2002) J. Biol. Chem. 277, 36216-36222). We made a stable Mirk-inducible subline from nontransformed Mv1Lu lung epithelial cells and now demonstrate that induction of Mirk inhibited the migration of these cells in wounding experiments and inhibited their invasion through polycarbonate Transwell filters. Furthermore the ability of Mirk to inhibit Mv1Lu cell migration was attenuated when cells were exposed to HGF or to elevated levels of transiently expressed RanBPM. RanBPM inhibited the kinase activity of Mirk/Dyrk1B and Dyrk1A. In addition, RanBPM and HGF inhibited the function of Mirk as a transcriptional coactivator. Our findings suggest that Mirk plays a role in modulating cell migration through opposing the action of the Met signaling cascade adaptor protein RanBPM.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Serum level of macrophage migration inhibitory factor as a useful parameter of clinical course in patients with Wegener's granulomatosis and relapsing polychondritis.

Novel biological activities of macrophage migration inhibitory factor (MIF) have been rediscovered. In addition, elevation of the serum MIF level has been reported in different types of disorders, including various inflammatory and autoimmune diseases. In the present study, serum MIF levels were analyzed in patients with Wegener's granulomatosis (WG) and relapsing polychondritis. It was shown that the serum MIF levels in these patients were significantly higher than those of normal healthy controls. In a WG patient, the MIF level showed a good correlation with clinical symptoms and C-ANCA titers. Thus, serum MIF levels will be a useful laboratory parameter for following the clinical course of WG patients and determining medical treatment. The immunopathologic roles of MIF in these diseases are discussed.

Adult↗
PubMed2003

Differential regulation of cell motility and invasion by FAK.

Cell migration and invasion are fundamental components of tumor cell metastasis. Increased focal adhesion kinase (FAK) expression and tyrosine phosphorylation are connected with elevated tumorigenesis. Null mutation of FAK results in embryonic lethality, and FAK-/- fibroblasts exhibit cell migration defects in culture. Here we show that viral Src (v-Src) transformation of FAK-/- cells promotes integrin-stimulated motility equal to stable FAK reexpression. However, FAK-/- v-Src cells were not invasive, and FAK reexpression, Tyr-397 phosphorylation, and FAK kinase activity were required for the generation of an invasive cell phenotype. Cell invasion was linked to transient FAK accumulation at lamellipodia, formation of a FAK-Src-p130Cas-Dock180 signaling complex, elevated Rac and c-Jun NH2-terminal kinase activation, and increased matrix metalloproteinase expression and activity. Our studies support a dual role for FAK in promoting cell motility and invasion through the activation of distinct signaling pathways.

Animals↗
PubMed2003

A novel laminin-induced LPA autocrine loop in the migration of ovarian cancer cells.

We have reported previously that levels of lysophosphatidic acid (LPA) are elevated in the blood and ascites from patients with ovarian cancer. LPA stimulates proliferation of ovarian cancer cells and has been proposed as an autocrine growth factor. Here, we show that a novel autocrine loop of LPA promotes the migration of ovarian cancer cells, which is a critical step of tumor metastasis. We report that laminin, but not other extracellular matrix proteins, induces LPA production in ovarian cancer cells. A neutralizing antibody against beta1 integrin and a calcium-independent phospholipase A2-specific inhibitor, HELSS, block both LPA production and the haptotactic activity of laminin. Exogenously added LPA restores the migratory ability of HEY ovarian cancer cells to laminin. These data suggest that laminin-induced cell migration is mediated by LPA. We further show that a specific receptor for LPA, LPA3, is required for mediating the chemotactic activity of LPA. In addition, we show that cytosolic PLA2 is required for cell migration and its activation is phosphatidylinositol-3 kinase-dependent. These findings have revealed a new mechanism of crosstalk between a beta1 integrin receptor and a G protein-coupled receptor.

Autocrine Communication↗
PubMed2001

Inhibition of PKA blocks fibroblast migration in response to growth factors.

Cell migration requires precise coordination of many signaling pathways to achieve directed motility. We report here that NIH3T3 fibroblasts expressing a dominant negative PKA subunit (dnPKA) show diminished migration in response to serum or growth factors. This effect is not a general effect on cell motility, but rather a decreased capacity to enhance migration in response to stimuli. Control (neo) and dnPKA cells show very similar haptotactic migration toward fibronectin, but dnPKA cells show reduced stimulation of migration in response to EGF/PDGF or serum. These effects were not due to alterations in cell growth or adhesion to fibronectin. Forskolin, which elevates cyclic adenosine monophosphate (cAMP) levels, dramatically inhibited neo cell motility in a scrape migration assay, although dnPKA cell migration was unaffected. The MEK selective inhibitor U0126 and the phosphatidyl-inositol-3 kinase (PI3K) inhibitor LY294002 inhibited migrating neo cells and were able to further inhibit residual dnPKA cell migration. Our data show that intermediate or well-controlled levels of PKA activity are required for optimal growth factor-stimulated migration in fibroblasts. PKA may play an important role in the signaling processes that lead to motility.

3T3 Cells↗
PubMed2001

Differential role of CD18 integrins in mediating lung neutrophil sequestration and increased microvascular permeability induced by Escherichia coli in mice.

The in vivo contributions of CD18 integrin-dependent and -independent mechanisms in mediating the increases in lung neutrophil (polymorphonuclear leukocyte; PMN) sequestration and microvascular permeability are not well understood. We determined the time course of these responses to Gram-negative sepsis in the mouse lung and addressed the specific contributions of CD18 integrins and ICAM-1. PMN sequestration in the lung was assessed by morphometric analysis, and transalveolar PMN migration was assessed by bronchoalveolar lavage. Lung tissue PMN number increased by 6-fold within 1 h after i.p. Escherichia coli challenge; this value peaked at 3 h (7-fold above control) and decreased at 12 h (3.5-fold above control). PMN migration into the airspace was delayed; the value peaked at 6 h and remained elevated up to 12 h. Saturating concentrations of anti-CD18 and anti-ICAM-1 mAbs reduced lung tissue PMN sequestration and migration; however, peak responses at 3 and 6 h were inhibited by 40%, indicating that only a small component of PMN sequestration and migration was CD18 dependent at these times. In contrast to the time-dependent decreased role of CD18 integrins in mediating PMN sequestration and migration, CD18 and ICAM-1 blockade prevented the increase in lung microvascular permeability and edema formation at all times after E. coli challenge. Thus, Gram-negative sepsis engages CD18/ICAM-1-independent mechanisms capable of the time-dependent amplification of lung PMN sequestration and migration. The increased pulmonary microvascular permeability induced by E. coli is solely the result of engagement of CD18 integrins even when PMN accumulation and migration responses are significantly CD18 independent.

Animals↗