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At least 667 records · Page 37Linked to original sources
PubMed2006

Chemokine CXCL16, a scavenger receptor, induces proliferation and invasion of first-trimester human trophoblast cells in an autocrine manner.

BACKGROUND: The aim of this study was to investigate whether CXCL16/CXCR6, a newly identified chemokine pair, is expressed in first-trimester human placenta and whether they affect the trophoblast cell biology, since we have found CXCR6 highly transcribed in first-trimester human trophoblast cells previously. METHODS: We analysed the transcription and translation of CXCR6 and CXCL16 in purified first-trimester human trophoblast cells by real-time RT-PCR and immunochemical staining. We then examined the kinetic secretion of CXCL16 in the supernatant of primary-cultured trophoblast by enzyme-linked immunosorbent assay. We further investigated effects of CXCL16 on the proliferation and invasion of trophoblast cells in vitro. RESULTS: We found the chemokine pair CXCL16/CXCR6 was transcribed and translated in first-trimester trophoblast cells and JAR line. In addition, the primary-cultured trophoblasts secreted CXCL16 spontaneously and continuously in 100-h culture. Treating trophoblasts with CXCL16 induced marked proliferation and invasion in vitro. CONCLUSION: The findings from this study have demonstrated for the first time that CXCR6 and CXCL16 are co-expressed by first-trimester human trophoblast cells and stimulate their proliferation and invasion in an autocrine/paracrine manner. It suggests that CXCL16 plays important roles in human extravillous cytotrophoblast invasion and placentation.

Autocrine Communication↗
PubMed2000

Secretory, endocrine and autocrine/paracrine function of the adipocyte.

Obesity is a major public health problem in Western countries, and >55% of adult Americans are overweight or obese. A major contributor to the epidemic of obesity is the current environment, which is characterized by increased availability of high energy foods and decreased physical activity. Several studies also demonstrated that genetic susceptibility contributes to obesity in some populations. Obesity research has focused primarily on the role of the hypothalamus in neuroendocrine regulation of food intake. However, a growing number of studies support a potential contribution of adipose tissue, via its newly discovered secretory function, to the pathogenesis of obesity and co-morbid conditions including cardiovascular disease, diabetes and hypertension. This paper will review the role of four factors secreted by adipose tissue (leptin, agouti, angiotensin II and prostaglandins) and their functions in the regulation of energy balance and whole-body homeostasis. Several other peptide and nonpeptide substances are secreted from adipose tissue; their function and regulation have been documented extensively.

Adipocytes↗
PubMed2001

Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells.

BACKGROUND: Most (70%-100%) ovarian carcinomas express high levels of the epidermal growth factor receptor (EGFR). To examine the relationship between EGFR and the invasive phenotype, we assessed integrin expression, adhesion, matrix metalloproteinase (MMP) activity, and migration in ovarian cancer cells in which EGFR expression was modified. METHODS: NIH:OVCAR-8 human ovarian carcinoma cells were transfected with an expression vector containing the human EGFR complementary DNA in an antisense orientation (EGFR-antisense cells) or the vector alone (vector control cells). We compared vector control and EGFR-antisense cells for cell morphology and adhesion by light microscopy, expression of alpha(6)- and alpha(3)-integrin subunits by flow cytometry, MMP and tissue inhibitor of MMP (TIMP) activity by zymography, and migration by a wound migration assay. In some experiments, EGFR kinase activity in parental cells was inhibited by treatment with PD153035. All statistical tests were two-sided. RESULTS: EGFR-antisense cells were morphologically distinct from vector control cells and had a selective decrease in adhesion to laminin-1 that was not observed with vector control cells (P = .008) or on other extracellular matrix substrates. Compared with vector control cells, cell surface alpha(6)-integrin expression decreased by approximately 80% (difference = 78.7%; 95% confidence interval [CI] = 77.8% to 79.6), MMP-9 activity decreased by approximately 50%, and TIMP activity increased by approximately 50% in EGFR-antisense cells. Vector control cells were highly motile (5.51 arbitrary distance unit; 95% CI = 4.98 to 6.04), whereas the EGFR-antisense cells were not (0.99 arbitrary distance units; 95% CI = 0.38 to 1.60). The morphology and integrin profile of NIH:OVCAR-8 parental cells treated with PD153035 were similar to those of the EGFR-antisense cells. CONCLUSIONS: Reduced EGFR expression in ovarian carcinoma cells decreased their adhesion to laminin-1, expression of the alpha(6)-integrin subunit (a well-characterized laminin-1 receptor), and MMP-9 activity. These data support the hypothesis that EGFR overexpression in ovarian cancer cells results in multiple phenotypic changes that enhance the invasive phenotype.

Antigens, CD↗
PubMed2002

Gastrin-releasing peptide receptor-mediated autocrine growth in squamous cell carcinoma of the head and neck.

BACKGROUND: Gastrin-releasing peptide receptor (GRPR)-mediated autocrine growth appears to be an early marker of susceptibility to tobacco-related lung cancers. Because expression of GRPR, however, has not been reported in squamous cell carcinoma of the head and neck (SCCHN), we investigated its expression and that of its ligand GRP in normal mucosa and SCCHN tissues and the involvement of these proteins in the proliferation of SCCHN cells. METHODS: We assessed GRPR messenger RNA (mRNA) expression in specimens from 25 patients with SCCHN, six control noncancer patients, and 14 SCCHN cell lines by use of quantitative reverse transcriptase-polymerase chain reaction. We used neutralizing GRP monoclonal antibody 2A11 to block the GRP-GRPR interaction in SCCHN cell lines and xenografts and assessed the antibody's effect on proliferation by counting cultured cells or measuring xenograft tumor volume in vivo. All statistical tests were two-sided. RESULTS: Tumor and mucosa tissues, respectively, from SCCHN patients expressed sixfold and fourfold higher levels of GRPR mRNA than normal mucosa tissue from noncancer patients (P<.001). The levels of GRPR expression in the tumor and adjacent normal epithelium of individual patients with SCCHN were correlated (r =.652; P =.001), suggesting that increased GRPR expression is an early event in SCCHN formation. SCCHN cells expressed fivefold higher levels of GRPR mRNA than did cultured normal mucosal epithelial cells (P =.005). GRP stimulated proliferation of SCCHN cells in a dose-dependent fashion (P =.006). Neutralizing GRP monoclonal antibody 2A11 inhibited SCCHN cell proliferation in vitro and in vivo. Median survival was 54 months in patients with higher levels of GRPR mRNA and was not reached in those with lower levels. CONCLUSIONS: GRP and GRPR appear to participate in an autocrine regulatory pathway in SCCHN. Thus, strategies that specifically target GRP and/or GRPR may be effective therapeutic approaches for this disease.

Adult↗
PubMed2002

Autocrine signaling through Ras regulates cell survival activity in human glioma cells: potential cross-talk between Ras and the phosphatidylinositol 3-kinase-Akt pathway.

Autocrine fibroblast growth factor (FGF) signaling mediates an uncontrollable growth of human gliomas. We investigated the intracellular signaling of FGF on cell survival activity. U251MG human glioma cells were infected with adenovirus vectors expressing dominant negative type I FGF receptor (DNFR), constitutive active Ras (RasL61), or dominant negative Ras (RasN17). DNFR reduced glioma cell accumulation with apoptosis and this reduction was alleviated with exogenous epidermal growth factor (EGF), which can activate Ras independent of FGFR but not with bFGF. RasL61 prevented but RasN17-enhanced DNFR-induced apoptosis. Reportedly, cell survival signaling through Akt was constitutively active in U251MG cells and this effect may be dependent on autocrine signaling and dysfunction of PTEN, a tumor suppressor gene limiting phosphatidylinositol 3-kinase (PI3K) activity. DNFR dose-dependently inhibited Akt activity and this inhibition was recovered by RasL61, whereas RasN17 inhibited Akt activity. Wortmannin (a PI3K inhibitor) inhibited Akt activity and mildly promoted apoptosis. RasL61 prevented the down-regulation of Akt activity and apoptosis induced by wortmannin, but RasN17 plus wortmannin strongly inhibited Akt activity and promoted marked apoptosis. Our data suggested that the cell survival activity of human gliomas is largely dependent on cross-talk between Ras and the PI3K-Akt pathway, and this cross-talk could be a potential target for molecular-based therapeutics.

Apoptosis↗
PubMed2001

In-vitro evidence of autocrine secretion of vascular endothelial growth factor by endothelial cells from human placental blood vessels.

Vascular endothelial growth factor (VEGF), a highly specific mitogen for vascular endothelial cells, is involved in placental vascular growth and remodelling. The aim of this study was to investigate whether placental endothelial cells secrete VEGF in an autocrine manner and if this secretion is correlated with endothelial cell growth. Blood vessels, excised from the apical surface of three human placentae, were sectioned into 40 fragments per placenta and cultured in fibrin gel matrix for 27 days. Immunohistochemical detection of placental endothelial cells was performed by positive staining with anti-human factor VIII-associated antigen and negative staining with anti-human alpha-actin and desmin. To investigate the production and autocrine action of VEGF, VEGF concentrations in culture media were measured and the effect of an anti-VEGF neutralizing antibody on endothelial cell growth was observed. The results demonstrate that soluble VEGF is secreted by placental endothelial cells reaching a plateau from day 24 (68.74 +/- 7.52 pg/ml) to day 27 (67.20 +/- 6.28 pg/ml). Furthermore, VEGF concentrations in media collected on days 6, 12, 18, 21 and 27 of culture were found to be directly correlated to the sprouting parameter of endothelial cells, as calculated by image analysis on the same day ( P < 0.001, r (2) = 0.95 ). The use of 10 and 100 ng/ml of a neutralizing antibody against human VEGF suppressed cell proliferation, compared to that observed in the untreated controls, by 74.8 +/- 7.3 and 89.4 +/- 3.9% respectively. In conclusion, this study reports the first evidence of autocrine secretion of VEGF by human placental endothelial cells and demonstrates the involvement of VEGF in endothelial cell growth within a fibrin gel culture.

Autocrine Communication↗
PubMed1999

Autocrine induction of gliostatin/platelet-derived endothelial cell growth factor (GLS/PD-ECGF) and GLS-induced expression of matrix metalloproteinases in rheumatoid arthritis synoviocytes.

OBJECTIVE: The purpose of this study was to examine how gliostatin/platelet-derived endothelial cell growth factor (GLS/PD-ECGF) is involved in the molecular mechanism of cartilage degradation in rheumatoid arthritis (RA) with special reference to the GLS-induced gene expression and protein synthesis of matrix metalloproteinase (MMP)-1 (collagenase-1) and MMP-3 (stromelysin-1). METHODS: Fibroblast-like synoviocytes (FLSs) obtained from RA patients were cultured and stimulated by GLS. Changes in the expression levels of GLS, MMP-1 and MMP-3 were assessed by Northern blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) for GLS, and by RT-PCR and enzyme-linked immunosorbent assay for MMPs and tissue inhibitor of metalloproteinase 1. RESULTS: GLS demonstrated a self-induction of mRNA in cultured RA FLSs. GLS evoked a dose-dependent induction of MMP-1 and MMP-3 mRNAs, and subsequently their extracellular secretion. CONCLUSION: These findings suggest that GLS is a plausible pathogenic factor causing the extensive joint destruction in RA mediated via MMPs.

Arthritis, Rheumatoid↗
PubMed2004

Secretin controls anion secretion in the rat epididymis in an autocrine/paracrine fashion.

There is growing evidence that secretin, the first hormone discovered in our history, has functions in the brain other than in the gastrointestinal tract. This article reports for the first time that secretin and its receptor mRNAs are produced in distinct cell types within the epididymis. To test if secretin affects electrolyte transport in the epididymis, we measured short-circuit current (Isc) in cultured epididymal epithelia and found secretin dose-dependently stimulated Isc. Ion substitution experiments and use of pharmacological agents inferred that the stimulated Isc is a result of concurrent electrogenic chloride and bicarbonate secretion. It is further shown that secretin and pituitary adenylate cyclase-activating polypeptide (PACAP) function via totally different mechanisms: 1) PACAP works only from the apical side of the epithelium to stimulate chloride and not bicarbonate secretion, while secretin acts on the apical and basolateral sides to stimulate chloride and bicarbonate secretion. 2) the stimulation by PACAP but not secretin requires local prostaglandin synthesis. By immunocytochemical staining, secretin is localized in the principal cells of the initial segment and caput epididymidis, whereas secretin receptor is present in the principal cells of the proximal as well as the distal part of the epididymis. This pattern of distribution appears to be consistent with the idea that secretin is secreted by the proximal epididymis and acts on the proximal and distal epididymis in an autocrine and paracrine fashion. Its function is to control secretion of electrolytes and water.

Adenylyl Cyclase Inhibitors↗
PubMed1998

Autocrine mediators are required to act on the embryo by the 2-cell stage to promote normal development and survival of mouse preimplantation embryos in vitro.

Autocrine mediators released by the early embryo are implicated in the support of embryo development. Their mechanisms and timing of action, however, are uncertain. This study shows that their action is necessary during the 2-cell stage of development, at which time they do not act as classical growth factors, having no impact on the rate of cell-cycle progression. Rather, they act as survival factors, protecting embryos from subsequent cell death. Culture of zygotes for the first 48 h after insemination (but not the first 24 h only) at a high concentration of 1 embryo/microl before transfer to a concentration of 1 embryo/100 microl significantly improved development compared with culture at the lower concentration for 120 h. By contrast, if the initial 48 h of culture was at 1 embryo/100 microl, subsequent culture at 1 embryo/microl caused no improvement. Platelet-activating factor (PAF) supplementation (0.186 microM) of media for the 48-h period after insemination (but not 24 h only) improved the development of embryos cultured at low embryo concentrations (1 embryo/10 microl) even when transferred to PAF-free media for the subsequent 72-h culture period. The ability of PAF to mimic the effects of higher embryo density implicates embryo-derived PAF as one of the autocrine mediators stimulating early embryo development. The cell death that occurred at low embryo concentration had a mixed phenotype: some cells had lost membrane integrity whereas others had intact membranes but punctate or fragmented chromatin. It is concluded that the action of autocrine diffusible factors, including PAF, are necessary during the 2-cell stage for subsequent survival and normal development of embryos to the blastocyst stage.

Animals↗
PubMed2000

Activin A in JEG-3 cells: potential role as an autocrine regulator of steroidogenesis in humans.

Activin A has been shown to exert several regulatory functions on human placenta. In the present study, we tested the hypothesis that activin A is an autocrine regulator of trophoblast using a choriocarcinoma cell line, JEG-3, as a model. Messenger RNAs for activin beta(A) subunit, activin binding protein (follistatin), and various activin receptors, including ActR-IA, ActR-IB, ActR-IIA, and ActR-IIB, were detected in JEG-3 cells by reverse transcription-polymerase chain reaction. The expression of activin A in JEG-3 cells was further confirmed by Western blot analysis using an antibody against activin beta(A) subunit. Using Northern blot analysis, Smad-2 and Smad-4 mRNAs were also observed in JEG-3 cells. These data suggest that JEG-3 cells produce activin A and express activin binding proteins and receptors, as well as potential downstream signals. In cultured JEG-3 cells, basal progesterone production was stimulated by activin A but inhibited by follistatin-288. Similarly, in the presence of androstenedione, estradiol production was enhanced by activin A but decreased by follistatin-288. On the other hand, neither activin A nor follistatin affected JEG-3 cell growth. Taken together, these findings strongly suggest that activin A is an autocrine factor that is involved in the regulation of progesterone and estradiol production in JEG-3 cells.

Activin Receptors↗
PubMed1998

Activation of EGF receptor by oxidized LDL.

Oxidized low density lipoproteins (oxLDL) are thought to play a major role in atherosclerosis. OxLDL exhibit a wide variety of biological effects resulting from their ability to interfere with intracellular signaling. The cellular targets and primary signaling events of oxLDL are unknown. We report that oxLDL elicit, in intact cells, tyrosine phosphorylation of the epithelial growth factor receptor (EGFR) and activation of its signaling pathway. This activation triggered by oxLDL was associated with derivatization of reactive amino groups of EGFR and was mimicked by 4-hydroxynonenal (4-HNE, a major lipid peroxidation product of oxLDL). Immunopurified EGFR was derivatized and activated in vitro by oxLDL lipid extracts and 4-HNE, thus indicating that 1) EGFR may be a primary target of oxidized lipids and 2) EGFR derivatization may be associated with activation. The reported data suggest that EGFR acts as a sensor for oxidized lipids. We therefore propose a novel concept of the mechanism by which oxidized lipids (contained in oxLDL or more generally produced during oxidative stress) are able to activate receptor tyrosine kinase and subsequent signaling pathways, resulting finally in a gain of function.

Aldehydes↗
PubMed2000

TGF-beta autocrine loop regulates cell growth and myogenic differentiation in human rhabdomyosarcoma cells.

Transforming growth factor beta (TGF) is a well-known inhibitor of myogenic differentiation as well as an autocrine product of rhabdomyosarcoma cells. We studied the role of the TGF-beta autocrine loop in regulating growth and myogenic differentiation in the human rhabdomyosarcoma cell line, RD. We previously reported that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induces growth arrest and myogenic differentiation in these cells, which constitutively express muscle regulatory factors. We show that TPA inhibits the activation of secreted latent TGF-beta, thus decreasing the concentration of active TGF-beta to which the cells are exposed. This event is mediated by the TPA-induced alteration of the uPA/PAI serine-protease system. Complete removal of TGF-beta, mediated by the ectopic expression of a soluble type II TGF-beta receptor dominant negative cDNA, induces growth arrest, but does not trigger differentiation. In contrast, a reduction in the TGF-beta concentration, to a range of 0.14-0.20 x 10(-2) ng/ml (which is similar to that measured in TPA-treated cells), mimics TPA-induced differentiation. Taken together, these data demonstrate that cell growth and suppression of differentiation in rhabdomyosarcoma cells require overproduction of active TGF-beta; furthermore, they show that a 'critical' concentration of TGF-beta is necessary for myogenic differentiation to occur, whereas myogenesis is abolished below and above this concentration. By impairing the TGF-beta autocrine loop, TPA stabilizes the factor concentration within the range compatible for differentiation to occur. In contrast, in human primary muscle cells a much higher concentration of exogenous TGF-beta is required for the differentiation inhibitory effect and TPA inhibits differentiation in these cells probably through a TGF-beta independent mechanism. These data thus clarify the mechanism underlying the multiple roles of TGF-beta in the regulation of both the transformed and differentiated phenotype.

Animals↗
PubMed2001

Mechanical signaling through connective tissue: a mechanism for the therapeutic effect of acupuncture.

The mechanism of action of acupuncture remains largely unknown. The reaction to acupuncture needling known as 'de qi', widely viewed as essential to the therapeutic effect of acupuncture, may be a key to understanding its mechanism of action. De qi includes a characteristic needling sensation, perceived by the patient, and 'needle grasp' perceived by the acupuncturist. During needle grasp, the acupuncturist feels pulling and increased resistance to further movement of the inserted needle. We hypothesize that 1) needle grasp is due to mechanical coupling between the needle and connective tissue with winding of tissue around the needle during needle rotation and 2) needle manipulation transmits a mechanical signal to connective tissue cells via mechanotransduction. Such a mechanism may explain local and remote, as well as long-term effects of acupuncture.

Acupuncture Therapy↗
PubMed2002

Nerve growth factor-endothelial cell interaction leads to angiogenesis in vitro and in vivo.

Nerve growth factor (NGF) has important functions during embryonic development and on various tissues and organs under normal and pathological conditions during the extrauterine life. RT-PCR analysis and immunological methods demonstrate that human umbilical vein endothelial cells (HUVECs) express the NGF receptors trkA(NGFR) and p75NTR. NGF treatment caused a rapid phosphorylation of trkA(NGFR) in HUVECs, determining a parallel increase of phosphorylated ERK1/2. Accordingly, NGF induced a significant increase in HUVEC proliferation that was abolished by the trkA(NGFR) inhibitor K252a. Also, HUVECs express significant levels of NGF under standard culture conditions that were up-regulated during serum starvation. Endogenous NGF was responsible for the basal levels of trkA(NGFR) and ERK1/2 phosphorylation observed in untreated HUVEC cultures. Finally, NGF exerted a potent, direct, angiogenic activity in vivo when delivered onto the chorioallantoic membrane of the chicken embryo. The data indicate that NGF may play an important role in blood vessel formation in the nervous system and in several pathological processes, including tumors and inflammatory diseases. Unraveling mechanisms of NGF-dependent angiogenesis could provide valuable tools for novel therapeutic approaches in antiangiogenic therapy.

Animals↗
PubMed2003

The terminal complement complex inhibits apoptosis in vascular smooth muscle cells by activating an autocrine IGF-1 loop.

Two counteracting processes determine accumulation of human vascular smooth muscle cells (SMCs) in atherosclerotic lesions: cell proliferation and apoptosis. SMCs synthesize insulin-like growth factor-1 (IGF-1), which potently inhibits apoptosis. The terminal complement complex C5b-9 interacts with SMCs in early human atherogenesis. In this study, we investigated whether C5b-9 may activate the IGF-1 system in SMCs, resulting in the inhibition of SMC apoptosis. C5b-9 generation on SMCs in vitro markedly reduced CD95-mediated apoptosis as assessed by flowcytometric analysis of annexin V binding and in caspase 3 assays. C5b-9 induced both significant IGF-1 release and up-regulation of IGF-1 binding sites in SMCs. Immunoneutralization of IGF-1 with a monoclonal IGF-1 antibody abolished the antiapoptotic effects of C5b-9. We conclude that C5b-9 inhibits apoptosis in SMCs by inducing an autocrine IGF-1 loop. This mechanism may contribute to the accumulation of SMCs in early human atherosclerotic lesions.

Apoptosis↗
PubMed2003

VEGF differentially activates STAT3 in microvascular endothelial cells.

Increased VEGF expression is found in several pathologies characterized by abnormal angiogenesis. Previous studies have shown that the transcription factor STAT3 mediates VEGF gene transcription and its activation. In this study, Western analysis and confocal immunocytochemistry were used to examine STAT3 activation in retinal microvascular endothelial cells (BREC). We found that VEGF rapidly induces STAT3 tyrosine phosphorylation and nuclear translocation. Immunoprecipitation studies also showed that VEGF forms a complex with VEGFR2 only in BREC and not in aortic macrovascular endothelial cells (BAEC). In addition, quantitative real-time RT-PCR analysis of VEGF-induced VEGF expression showed a significant increase in specific mRNA formation only in BREC and not in BAEC, and this effect was significantly reduced by antisense-mediated reduction of STAT3 expression. Furthermore, studies conducted in human dermal microvascular endothelial cells (HDMEC) showed that, in this endothelial cell type, VEGF autocrine expression is also accompanied by STAT3 activation as in BREC. In this study we showed that VEGF can differentially induce STAT3 activation in micro- versus macro-vascular endothelial cells and that this effect is linked to VEGFR2/STAT3 complex formation, which correlates with VEGF autocrine ability to stimulate its own gene expression.

Active Transport, Cell Nucleus↗