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PubMed2001

Cripto-1 enhances migration and branching morphogenesis of mouse mammary epithelial cells.

Cripto-1 is an EGF-CFC protein that performs an important role during early vertebrate development and is overexpressed in several types of human cancer. In the present study mouse EpH4, NMuMG, and TAC-2 mammary epithelial cells that are negative for endogenous cripto-1 expression were transfected with the murine cripto-1 cDNA. Cripto-1-transfected cell lines exhibited functional and physiological differences from the original cell lines including enhanced anchorage-independent growth in soft agar (EpH4 cells), growth in serum-free medium, increased proliferation, and formation of branching, duct-like structures when grown in a three-dimensional collagen type I matrix. Furthermore, cripto-1-expressing cell lines showed elevated migration in vitro in Boyden chamber and wound-healing assays. These results indicate that cripto-1 can function through an autocrine pathway that enables mammary epithelial cells to undergo an epithelial to mesenchymal transition.

Animals↗
PubMed1989

Differences between adult and foetal fibroblasts in the regulation of hyaluronate synthesis: correlation with migratory activity.

We have previously reported that confluent foetal fibroblasts migrate into three-dimensional collagen gel matrices to a significantly greater extent than do adult cells. Hyaluronic acid (HA) is a major constituent of the extracellular matrix deposited by fibroblasts and has been demonstrated to stimulate the migration of a number of different cell types. Previous studies have indicated that the synthesis of HA by normal adult skin fibroblasts declines significantly when the cells achieve confluence. Data presented in this paper indicate that foetal fibroblasts differ from adult cells in this respect, in that they do not show an inverse relationship between cell density and HA synthesis, i.e. confluent foetal fibroblasts continue to produce approximately the same amount of HA as do subconfluent cells. These data suggest that the synthesis of relatively high levels of HA by foetal fibroblasts at confluence may be causally related to the elevated migration displayed by these cells. In this context, a close correlation was observed between the level of HA synthesized by confluent foetal and adult fibroblasts and the differential migratory activity displayed by these cells. Such differences in HA synthesis and migratory behaviour were only apparent at cell confluence, with subconfluent foetal and adult fibroblasts being indistinguishable in terms of these two criteria. Our data further reveal that: (1) cell density affects the size class of HA synthesized by both foetal and adult cells; and that (2) there is a considerable degree of heterogeneity amongst the nine different fibroblast lines examined in this study in terms of the size class of HA that they produce.

Adult↗
PubMed2006

EGF AND TGF-alpha motogenic activities are mediated by the EGF receptor via distinct matrix-dependent mechanisms.

EGF and TGF-alpha induce an equipotent stimulation of fibroblast migration and proliferation. In spite of their homologous structure and ligation by the same receptor (EGFR), we report that their respective motogenic activities are mediated by different signal transduction intermediates, with p70(S6K) participating in EGF signalling and phospholipase Cgamma in TGF-alpha signalling. We additionally demonstrate that EGF and TGF-alpha motogenic activities may be resolved into two stages: (a) cell "activation" by a transient exposure to either cytokine, and (b) the subsequent "manifestation" of an enhanced migratory phenotype in the absence of cytokine. The cell activation and manifestation stages for each cytokine are mediated by distinct matrix-dependent mechanisms: motogenetic activation by EGF requires the concomitant functionality of EGFR and the hyaluronan receptor CD44, whereas activation by TGF-alpha requires EGFR and integrin alphavbeta3. Manifestation of elevated migration no longer requires the continued presence of exogenous cytokine and functional EGFR but does require the above mentioned matrix receptors, as well as their respective ligands, i.e., hyaluronan in the case of EGF, and vitronectin in the case of TGF-alpha. In contrast, the mitogenic activities of EGF and TGF-alpha are independent of CD44 and alphavbeta3 functionality. These results demonstrate clear qualitative differences between EGF and TGF-alpha pathways and highlight the importance of the extracellular matrix in regulating cytokine bioactivity.

Cell Movement↗
PubMedDate not supplied

Hypoxia modulates expression of the 70-kD heat shock protein and reduces Leishmania infection in macrophages.

Hypoxia, a microenvironmental factor present in diseased tissues, has been recognized as a specific metabolic stimulus or a signal of cellular response. Experimental hypoxia has been reported to induce adaptation in macrophages such as differential migration, elevation of proinflammatory cytokines and glycolytic enzyme activities, and decreased phagocytosis of inert particles. In this study we demonstrate that although exposure to hypoxia (5% O2, 5% CO2, and balanced N2) did not change macrophage viability, or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cleavage and proliferation, it significantly reduced expression of the 70-kD heat shock protein (HSP70), which was restored to prehypoxia levels after reoxygenation. The influence of low oxygen tension on macrophage functional activity was also studied, i.e. the ability of these cells to maintain or resist infection by a microorganism. We demonstrate that macrophages from two different sources (a murine cell line and primary cells) exposed to hypoxia were efficiently infected with Leishmania amazonensis, but after 24 h showed a reduction in the percentage of infected cells and of the number of intracellular parasites per macrophage, indicating that hypoxia induced macrophages to kill the intracellular parasites. These results support the notion that hypoxia, a microenvironmental factor, can modulate macrophage protein expression and functional activity.

Animals↗
PubMed2007

Mitochondria contribute to LPS-induced MAPK activation via uncoupling protein UCP2 in macrophages.

The mitochondrion is a major organelle contributing to energy metabolism but also a main site of ROS (reactive oxygen species) production. LPS (lipopolysaccharide)-induced ROS signalling is a critical event in macrophage activation. In the present paper we report that part of LPS-mediated ROS signalling comes from mitochondria inside a signal amplification loop that enhances MAPK (mitogen-activated protein kinase) activation. More precisely, we have identified the inner mitochondrial membrane UCP2 (uncoupling protein 2) as a physiological brake on ROS signalling. Stimulation of murine bone marrow-derived macrophages by LPS quickly down-regulated UCP2 through the JNK (c-Jun N-terminal kinase) and p38 pathways. UCP2 down-regulation was shown to be necessary to increase mitochondrial ROS production in order to potentiate MAPK activation. Consistent with this, UCP2-deficient macrophages exhibit an enhanced inflammatory state characterized by increased nitric oxide production and elevated migration ability. Additionally, we found that the absence of UCP2 renders macrophages more resistant to nitric oxide-induced apoptosis.

Animals↗
PubMed1996

Intracellular Ca2+ fluctuations modulate the rate of neuronal migration.

Transient elevations of intracellular Ca2+ levels play critical roles in neuronal development, but such elevations have not been demonstrated in migrating neurons. Here, we show that the amplitude and frequency components of Ca2+ fluctuations are correlated positively with the rate of granule cell movement in cerebellar microexplant cultures. Moreover, depression of the amplitude and frequency components of Ca2+ fluctuations by blockade of Ca2+ influx across the plasma membrane results in a reversible retardation of cell movement. These results indicate that the combination of amplitude and frequency components of intracellular Ca2+ fluctuations may provide an intracellular signal controlling the rate of neuronal cell migration.

Animals↗
PubMed2001

Integrins alphavbeta3 and alphavbeta5 mediate VSMC migration and are elevated during neointima formation in the rat aorta.

Neointima formation involves tissue expression of matrix proteins and growth factors. The role of alphavbeta3, but not alphavbeta5 integrin in vascular cells has been sufficiently investigated. The aim of the present study was to determine and compare the function of alphavbeta3 and alphavbeta5 integrins in rat aortic (RASMC) and human coronary vascular smooth muscle cells (HCSMC) and to characterize their expression accompanying neointima formation in vivo. RASMC and HCSMC express alphavbeta3 and alphavbeta5 integrin subunits. The alphavbeta5 integrin predominantly mediated adhesion of RASMCs to vitronectin and spreading on vitronectin via RGD-binding sequences. In contrast, the alphavbeta3 integrin did not contribute to the adhesion and spreading on fibronectin, vitronectin, gelatin or collagen I coated layers. PDGF-directed migration through gelatin coated membranes involved both alphavbeta3 and alphavbeta5 integrins. Selective blocking antibodies for alphavbeta3 and alphavbeta5 inhibited migration of RASMC and HCSMC by more than 60 % (p < 0.01). Integrin expression was studied in vivo in thoracic aorta of Sprague Dawley rats before and after balloon injury. In situ hybridization demonstrated low signals for alphav, beta3 and beta5 mRNA in uninjured aorta, which increased significantly at 14 days, localized predominantly in the neointima. Northern analysis of aorta after 14 days of injury also demonstrated an upregulation of alphav, beta3 and beta5 mRNA compared to uninjured aorta. Consistent with the increase in message levels, increased integrin protein expression was seen in the neointima after 7 and 14 days. This study provides evidence that alphavbeta3 and alphavbeta5 are elevated during neointima formation in the rat and indicates a novel role for alphavbeta5 participating in mechanisms regulating smooth muscle cell migration.

Animals↗
PubMed2003

Endothelin-1 promotes migration and induces elevation of [Ca2+]i and phosphorylation of MAP kinase of a human extravillous trophoblast cell line.

A highly proliferative, migratory and invasive subpopulation of human placental trophoblasts, known as extravillous trophoblasts (EVT), invades the uterus and its vasculature, to establish an adequate exchange of key molecules between the maternal and fetal circulation. Our earlier studies provided evidence for a positive regulation of migration/invasion of EVT by an autocrine factor IGFII and a paracrine, decidua-derived factor IGFBP1. The present study examined the role played by endothelin (ET)-1, also produced at the fetal-maternal interface, and its receptor subtypes ET(A) and ET(B) in the regulation of human EVT cell functions. We utilized an in vitro propagated EVT cell line (HTR-8/SVneo) which exhibits the phenotypic and functional characteristics of EVT in situ. Reverse transcription-PCR with primers specific for prepro-ET-1, ET(A) and ET(B) cDNAs demonstrated the expression of all these genes in HTR-8/SVneo cells. While proliferation was not influenced, migration of these cells through porous Transwell membranes was stimulated by exogenous ET-1. ET-1 also induced biphasic elevation of cytosolic free Ca(2+) concentrations ([Ca(2+)](i)) consisting of an initial transient followed by a sustained plateau, as measured by spectrofluorimetry. The dependence of the Ca(2+) response on phospholipase C (PLC) was demonstrated by its abrogation in the presence of PLC inhibitor U73122. Furthermore, ET-1 treatment of EVT cells rapidly stimulated phosphorylation of MAP kinase (ERK1/2). By using ET receptor antagonists and agonists, it was shown that both ET(A) and ET(B) receptors were responsible for the effects of ET-1 on migration, [Ca(2+)](i) and MAPK phosphorylation. Thus, ET-1 may represent an autocrine/paracrine mediator of invasive trophoblast function.

Adenylyl Cyclases↗
PubMed2002

Marked elevation of macrophage migration inhibitory factor in the peritoneal fluid of women with endometriosis.

OBJECTIVE: To evaluate the presence of macrophage migration inhibitory factor (MIF) in the peritoneal fluid of normal fertile women and patients with endometriosis and its growth-promoting activity toward human endothelial cells. DESIGN: Retrospective study using ELISA to measure peritoneal fluid MIF, and [3H]-thymidine incorporation into the DNA of human endothelial cells to assess its mitogenic activity. SETTING: Gynecology clinic and human reproduction research laboratory. PATIENT(S): Thirty-six healthy women and 57 women with endometriosis. INTERVENTION(S): Peritoneal fluid samples were obtained at laparoscopy. MAIN OUTCOME MEASURE(S): Macrophage migration inhibitory factor concentrations in the peritoneal fluid samples and [3H]-thymidine incorporation into the DNA of human microvascular endothelial cells to assess proliferation. RESULT(S): This study demonstrated the presence of MIF in the peritoneal fluid and a 238% increase of MIF levels in women with endometriosis as compared with healthy women. Both fertile and infertile women with endometriosis had significantly higher MIF concentrations than did fertile women with normal gynecological status, but the difference was more significant in infertile endometriosis patients. Anti-MIF antibody significantly inhibited proliferation of human microvascular endothelial cells in response to peritoneal fluids from healthy women and women with endometriosis stages I-II and III-IV, as assessed by [3H]-thymidine incorporation. CONCLUSION(S): This study revealed the presence of MIF in the peritoneal fluid and its increased levels in endometriosis and suggests that MIF may be involved in endometriosis-associated infertility and angiogenesis.

Adult↗
PubMed1998

The effect of elevated extracellular glucose on migration, adhesion and proliferation of SV40 transformed human corneal epithelial cells.

PURPOSE: To examine the effect of elevated extracellular glucose, thus simulating diabetes, on migration, adhesion and proliferation of SV40 transformed human corneal epithelial (HCE) cells. METHODS: HCE cells were maintained in serum supplemented media containing 5 mM, 17.5 mM or 38 mM D-glucose. Cell migration was determined using Blind well chambers fitted with fibronectin/collagen I coated filters. In adhesion experiments, cells were allowed to adhere to extracellular matrix protein-coated wells for 90 min at 37 degrees C. Non-adherent cells were removed by washing, then the fluorochrome calcein-AM was added to quantitate the number of attached cells. Proliferation was determined by plating the cells at low density, then quantitating viable cells with calcein-AM 5 to 7 days later. RESULTS: Raising extracellular glucose from 5 mM to 17.5 mM significantly increased cell migration by 42%. When glucose was further raised to 38 mM, migration was not significantly different from that in 5 mM glucose. Adhesion to fibronectin and collagen I (but not IV) was significantly increased (62% and 32% respectively) when cells were cultured in 17.5 mM glucose. Similarly, proliferation was increased by 44%. Adhesion and proliferation tended to be decreased at 38 mM compared to 17.5 mM glucose, but not significantly so. In the presence of 5 mM glucose and mannitol (12.5 mM or 33 mM), neither migration, adhesion nor proliferation were significantly different from that in 5 mM glucose alone. CONCLUSION: Elevated extracellular glucose modulates migration, adhesion and proliferation of HCE cells. The effects are dependent on the concentration of glucose and are not due to changes in osmolality since mannitol failed to produce similar results. Our in vitro findings suggest that high-glucose effects may directly contribute to the etiology of impaired corneal wound healing in diabetes.

Cell Adhesion↗
PubMed2005

Macrophage migration inhibition factor is elevated in pregnancy, but not to a greater extent in preeclampsia.

BACKGROUND: Maternal serum concentrations of macrophage migration inhibitory factor (MIF) have recently been reported to be elevated in cases with preeclampsia. These findings may be important in increasing our understanding of the underlying events leading to the development of preeclampsia, as this cytokine is also expressed in the placenta, where it has been shown to possess immunemodulatory activities. For this reason we attempted to independently verify this report. METHODS: Plasma levels of MIF were assessed by ELISA in plasma samples collected from normal healthy male and female blood donors (n=20 per group), as well as healthy normal pregnant women in all three trimesters of pregnancy (n=60). In addition, MIF levels were examined from cases with mild and severe preeclampsia (n=20 per study cohort) and matched normotensive pregnancies (n=20). RESULTS: MIF levels were found to be elevated in pregnancy (median=10.1 ng/ml) when compared to non-pregnant controls (median=1.7 ng/ml). A moderate, but not significant, elevation was found to occur from the first to the third trimester of pregnancy. No significant difference was found to occur between the two preeclampsia study groups when compared to the normotensive control group. CONCLUSIONS: Our data suggest that circulatory MIF concentrations are elevated throughout pregnancy, but are not further increased in preeclampsia.

Blood Donors↗
PubMed2001

Plasma levels of macrophage migration inhibitory factor are elevated in patients with severe sepsis.

OBJECTIVE: To investigate the role of macrophage migration inhibitory factor (MIF) as a marker of severity of systemic inflammation in patients with severe sepsis and critically ill postsurgical patients. DESIGN: Prospective observational study in consecutive patients with severe sepsis, critically ill nonseptic postsurgical patients, and healthy blood donors. SETTING: A surgical intensive care unit of a university hospital. PATIENTS AND PARTICIPANTS: 19 patients with severe sepsis, 18 critically ill nonseptic postsurgical patients, and 10 healthy blood donors. MEASUREMENTS AND RESULTS: MIF plasma levels of patients and participants were measured. Interleukin 6 plasma levels were monitored as a control marker of inflammation. The median MIF plasma level was four to five times higher in patients with severe sepsis (2.70 ng/ml, range 0.31-19.59) and in critically ill nonseptic postsurgical patients (2.43 ng/ml, range 0.49-4.31) than in healthy blood donors (0.56 ng/ml, range 0.16-1.68). MIF plasma levels did not differ between the patient groups. CONCLUSIONS: MIF serves as a general marker for systemic inflammation in septic and nonseptic acute critical illness, but MIF does not discriminate for severity or differentiate between infectious and noninfectious origins of an acute critical illness.

Adolescent↗
PubMed2005

Obesity, macrophage migration inhibitory factor, and weight loss.

OBJECTIVE: Elevated macrophage migration inhibitory factor (MIF) has been implicated as a causal mechanism in a number of disease conditions including cardiovascular disease (CVD), diabetes, and cancer. Excess body fat is associated with an increased risk of numerous health conditions including CVD, diabetes, and cancer. To our knowledge, the association between MIF and obesity status and the effect of weight loss on serum MIF concentrations have not been reported. In this study, we examined the effects of participation in a behavior-based weight loss program on MIF concentrations in obese individuals. SUBJECTS: Study participants were 71 men and women enrolled in The Cooper Institute Weight Management Program. Participants were predominantly female (68%, n=48), middle-aged (46.5+/-9.8 y), and severely obese (BMI=43.0+/-8.6). METHOD: Plasma MIF concentrations and other standard risk factors were measured before and after participation in a diet and physical activity based weight management program. RESULTS: The mean follow-up was 8.5+/-3.0 months with an average weight loss of 14.4 kg (P<0.001). The majority of clinical risk factors significantly improved at follow-up. Median levels of plasma MIF concentration were significantly lower at follow-up (median [IQR]; 5.1[3.6-10.3]) compared to baseline (8.4 [4.3-48.8]; P=0.0005). The percentage of participants with plasma MIF concentration > or =19.5 mg/nl (highest tertile at baseline) decreased from 33.8 to 5.6% (P<0.001). Further, elevated baseline plasma MIF concentration was associated with markers of beta-cell dysfunction and reductions in MIF were associated with improvements in beta-cell function. CONCLUSIONS: Circulating MIF concentrations are elevated in obese but otherwise healthy individuals; however, this elevation in MIF is not uniform across individuals. In obese individuals with elevated circulating MIF concentrations, participation in physical activity and a dietary-focused weight management program resulted in substantial reduction in MIF.

Adult↗
PubMed2004

Elevations in peritoneal fluid macrophage migration inhibitory factor are independent of the depth of invasion or stage of endometriosis.

OBJECTIVE: To quantify levels of macrophage migration inhibitory factor (MIF) in the peritoneal fluid (PF) of women with endometriosis, and to correlate these levels with the extent of disease. DESIGN: Controlled clinical study. SETTING: Academic medical center. PATIENT(S): Peritoneal fluid samples were collected during laparoscopic surgery in 60 women with endometriosis and 16 controls undergoing tubal ligation; 52 of the women with endometriosis had received no hormonal treatment in the 6 months prior to surgery, while 8 were using gonadotropin-releasing hormone (GnRH) agonists. MAIN OUTCOME MEASURE(S): Peritoneal fluid migration inhibitory factor (PF MIF) levels. RESULT(S): Women with endometriosis had significantly higher PF MIF levels (10.8 +/- 0.9 ng/mL) than controls (3.0 +/- 0.7 ng/mL). However, no correlation existed between MIF levels and the stage of disease (r = 0.05) or the depth of endometriotic invasion (r = 0.08). Moreover, treatment with a GnRH agonist did not suppress PF MIF levels. Peritoneal fluid MIF levels did not vary significantly between the proliferative and secretory phases of the cycle, and did not distinguish women with endometriosis-associated infertility from women with endometriosis-associated pain. CONCLUSION(S): Peritoneal fluid migration inhibitory factor levels are markedly elevated in women with endometriosis but are independent of the extent of disease.

Ascitic Fluid↗
PubMed1991

Postoperative proximal migration in total shoulder arthroplasty. Incidence and significance.

A retrospective review of 131 Neer total shoulder arthroplasties in 111 patients performed between 1974 and 1986 was undertaken to identify factors associated with proximal humeral migration. The influence of proximal migration on results was evaluated to clarify the indications for prosthetic constraint. The average follow-up period was 55 months (range: 24-124 mo). The results showed proximal migration in 22% of patients (29 shoulders). The migration was progressive in all cases, without corresponding increases in pain. Major rotator cuff tears were present in 21% of patients with a normal glenohumeral relationship and in 24% of the patients with proximal migration. Limited elevation was noted in patients with proximal migration, but all patients had improved range of motion and decreased postoperative pain. The cause of postoperative proximal migration is believed to be secondary to a combination of factors and not rotator cuff disruption alone. These data do not support the routine use of a constrained prosthesis for irreparable rotator cuff tears.

Humans↗
PubMed2002

Effect of elevated homocysteine on cardiac neural crest migration in vitro.

A positive correlation between elevated maternal homocysteine (Hcys) and an increased risk of neural tube, craniofacial, and cardiac defects is well known. Studies suggest Hcys perturbs neural crest (NC) development and may involve N-methyl-D-aspartate (NMDA) receptors (Rosenquist et al., 1999). However, there is no direct evidence that Hcys alters NC cell behavior. Here, we evaluated the effect of Hcys on cardiac NC cell migratory behavior in vitro. Neural tube segments from chick embryos treated in ovo with or without Hcys were placed in culture and the migratory behavior of emigrating NC cells was monitored. Hcys significantly increased in vitro NC cell motility at all embryonic stages examined. NC cell surface area and perimeter were also increased. However, the relative distance NC cells migrated from their original starting point only increased in NC cells treated in ovo at stage 6 or at the time neural tube segments were cultured. Cysteine had no effect. NMDA mimicked Hcys' effect on NC motility and migration distance but had no effect on cell area or perimeter. The noncompetitive inhibitor of NMDA receptors, MK801+, significantly inhibited NC cell motility, reduced migration distance, and also blocked the effects of NMDA and Hcys on NC motility and migratory distance in vitro. A monoclonal antibody directed against the NMDA receptor immunostained NC cells in vitro and, in western blots, bound a single protein with the appropriate molecular weight for the NMDA receptor in NC cell lysates. These data are consistent with the hypothesis that a Hcys-sensitive NMDA-like receptor is expressed by early emigrating NC cells or their precursors, which is important in mediating their migratory behavior. Perturbation of this receptor may be related to some of the teratogenic effects observed with elevated Hcys.

Animals↗
PubMed2005

Elevated levels of macrophage migration inhibitory factor in the peripheral blood of women with endometriosis.

OBJECTIVE: To evaluate the concentrations of macrophage migration inhibitory factor (MIF) in the peripheral blood of normal women and patients with endometriosis. DESIGN: Retrospective study using ELISA to measure peripheral blood MIF. SETTING: Gynecology clinic and human reproduction research laboratory. PATIENT(S): Thirty-eight normal women and 55 women with endometriosis. INTERVENTION(S): Peripheral blood samples were obtained a few days before laparoscopy. MAIN OUTCOME MEASURE(S): The MIF concentrations in blood serum. RESULT(S): This current study showed a 364% increase in MIF concentrations in women with endometriosis as compared to normal women. A significant increase was seen in endometriosis stages I-II, but a more marked increase was observed in the more advanced stages of the disease (III-IV). Both fertile and infertile women with endometriosis had higher levels of MIF than normal controls, but the difference was more significant in infertile women with endometriosis. Women with endometriosis with no pelvic pain had higher levels of MIF than normal controls, but a more significant increase in MIF levels was observed in women with endometriosis reporting pelvic pain. CONCLUSION(S): This study showed a marked increase in MIF concentrations in the peripheral blood of women with endometriosis and a relationship with disease progress, and suggests that MIF may be involved in endometriosis-related pain and infertility.

Adult↗