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At least 937 records · Page 52Linked to original sources
PubMed2001

Mitogenic effects of neutrophins on a periodontal ligament cell line.

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) are three representative neurotrophins responsible for the differentiation and survival of neurons, and their high-affinity receptors are tropomyosin-receptor-kinase (TRK)A, TRKB, and TRKC, respectively. In this study, we investigated the expression of neurotrophins in a mouse periodontal ligament cell line (MPL), by reverse transcription-polymerase chain-reaction (RT-PCR) and enzyme-linked immunoabsorbent assay (ELISA). We also studied the expression of TRK receptors on MPL by immunostaining and the effects of neurotrophins on the proliferation of MPL, with a hypothesis of autocrine mechanism of neurotrophins. Each neurotrophin and TRK receptor was expressed, and neurotrophins enhanced the proliferation of MPL. These findings suggest that the MPL has functional neurotrophin receptors involved in an autocrine function of neurotrophins. The expression level of neurotrophins and TRKs showed the reverse pattern, and we propose an auto-regulatory mechanism of ligands and receptors in accordance with the level of synthesized neurotrophins.

Alkaline Phosphatase↗
PubMed1999

Migration inhibitory factor related protein-8 (MRP-8) is an autocrine chemotactic factor for periodontal ligament cells.

Previous studies have suggested that human periodontal ligament (PDL) cells secrete a chemotactic factor which stimulates motility in an autocrine manner. Here we report the partial amino acid sequence of a purified factor which shows 100% homology with human migration inhibitory factor related protein-8 (MRP-8). In addition, reverse-transcription polymerase chain-reaction (RT-PCR) analysis revealed that mRNA encoding MRP-8 was expressed in cultured human PDL cells. To confirm that MRP-8 is chemotactic for PDL cells, we synthesized 25 mer peptides overlapped by 5 amino acids covering the entire MRP-8 protein and tested them for their chemotactic activities. The data indicated that amino acid residues 21-45 showed chemotactic activity for cultured human PDL cells. The maximum chemotactic response was observed at the concentration of 10(-15) mol/mL for human PDL cells. The chemotactic activity was estimated to be approximately 1000-fold higher than that of platelet-derived growth factor (PDGF), insulin-like growth factors-I and -II (IGF-I, -II), and epidermal growth factor (EGF) when compared on a molar basis. Since MRP-8 is reported to be produced mainly by neutrophils and monocytes, the result of the current study may suggest another important role of MRP-8 in human PDL cells.

Amino Acid Sequence↗
PubMed2002

Stanniocalcin 1 (STC1) protein and mRNA are developmentally regulated during embryonic mouse osteogenesis: the potential of stc1 as an autocrine/paracrine factor for osteoblast development and bone formation.

STC1, a mammalian homologue of stanniocalcin (STC) which plays a major role in calcium/phosphate homeostasis in fish, has been recently isolated. We have characterized the spatiotemporal distribution of STC1 mRNA and protein during mouse embryonic development generally and osteogenesis specifically. Northern blotting analysis of whole embryos showed that STC1 mRNA is highly and differentially expressed during embryogenesis. By in situ hybridization, STC1 mRNA was detected early in mesenchymal condensations and was then found to be highly expressed in perichondrial cells, periosteal cells, and then osteoblasts during endochondral bone formation. In bones forming by intramembranous ossification, STC1 mRNA was not detected until osteogenic cells appeared. The cellular distribution of STC1 protein closely corresponded to that of its mRNA, but the protein was also detected in hypertrophic chondrocytes. In the MC3T3-E1 osteogenic cell model, STC1 protein and mRNA were detectable throughout proliferation and differentiation stages but levels were relatively higher late during nodule formation/mineralization phases. For comparison, STC1 mRNA was also found in epithelial cells of both embryonic and adult intestine that had not previously been described among tissues responsive to calcium/phosphate transport. These results suggest that STC1 is expressed in a time- and cell-specific manner and may play an autocrine/paracrine role during osteoblast development and bone formation.

Animals↗
PubMed2000

PAF, a putative mediator of oral inflammation.

PAF, or platelet-activating factor, is a family of structurally related phospholipids (1-O-alkyl/acyl/alkenyl-2-acetyl-sn-glycero-3-phosphocholine) which possesses a wide spectrum of potent pro-inflammatory actions. These phospholipids are synthesized by a diverse array of cells, including neutrophilic polymorphonuclear leukocytes (PMN), platelets, mast cells, monocytes/macrophages, vascular endothelial cells, and lymphocytes. PAF targets these and other cells via specific, G-protein-coupled receptors to initiate intracrine, autocrine, paracrine, and juxtacrine cell activation. Of importance, these unique acetylated phospholipids are frequently synthesized in concert with pro-inflammatory lipid mediators derived from arachidonic acid. Since PAF synergizes with these and other mediators to amplify the inflammatory response, it seems likely that PAF plays an integral, perhaps pivotal, role in acute and chronic inflammatory processes. PAF is present in the mixed saliva of dentate, but not edentulous, human subjects. The levels of PAF in mixed saliva or in gingival crevicular fluid and tissues are significantly increased during oral inflammatory conditions such as periodontitis and mucositis. Interestingly, the levels of salivary PAF correlate with the extent/severity of these oral diseases. These observations suggest that PAF may participate in pathophysiologic events during the course of oral inflammation. The availability of specific PAF receptor antagonists and human recombinant PAF-acetylhydrolase (PAF-AH), a plasma enzyme which rapidly destroys PAF, should provide clinical tools for the investigation of the role of PAF in these and other inflammatory disorders; and perhaps, ultimately, some of these reagents may prove to be therapeutically useful in the treatment and management of these conditions.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2002

TGF-beta1 is an autocrine mediator of renal tubular epithelial cell growth and collagen IV production.

Recent studies in cultured cells have provided evidence that a variety of pathobiologic stimuli, including high glucose, angiotensin II, and thromboxane A(2), trigger a signaling pathway leading to autocrine induction of TGF-beta1. TGF-beta1 production through this pathway may profoundly affect cell growth, matrix synthesis, and response to injury. This study examines the role of autocrine versus exogenously added TGF-beta1 in cellular proliferation and collagen IV production, critical targets of TGF-beta1 signaling, using renal cells derived from TGF-beta1 knockout (KO) animals or wild-type (WT) controls. Growth of WT and KO cells was assessed by cell counting and [(3)H]thymidine uptake. Basal and TGF-beta1-stimulated collagen production was assessed by Northern and Western blotting; transcriptional activity of the alpha1(IV) collagen gene was assessed by transient transfection analysis. KO cells grew at a faster rate than WT cells carefully matched for plating density and passage number. This increased growth rate was paralleled by increases in [(3)H]thymidine uptake. KO cells expressed lower levels of the cell cycle inhibitors p21 and p27 than WT cells. KO cells failed to express TGF-beta1, as expected. Basal TGF-beta3 mRNA levels were higher in KO cells than in WT cells. WT cells expressed higher basal levels of TGF-beta2 mRNA than KO cells. Basal alpha1(IV) and alpha2(IV) collagen mRNA and protein expression were significantly lower in KO cells than WT cells. Administration of exogenous TGF-beta1 induced collagen IV production in both KO and WT cells. Although basal transcriptional activity of an alpha1(IV) collagen-CAT construct was lower in KO cells than WT cells, administration of exogenous TGF-beta1 was associated with significant increases in transcriptional activity of this construct in both KO and WT cells. These studies provide evidence that autocrine production of TGF-beta1 may play a critical role in regulation of growth and basal collagen IV production by renal tubular epithelial cells.

Animals↗
PubMed2004

Dissecting autocrine effects on pulsatile release of gonadotropin-releasing hormone in cultured rat hypothalamic tissue.

The control of reproductive function is manifested centrally through the control of hypothalamic release of gonadotropin-releasing hormone (GnRH) in episodic events or pulses. For GnRH release to occur in pulses, GnRH neurons must coordinate release events periodically to elicit a bolus of GnRH. We used a perifusion culture system to examine the release of GnRH from both intact hypothalami and enzymatically dispersed hypothalamic cells after challenge with GnRH analogs to evaluate the role of anatomical neuronal connections on autocrine/paracrine signals by GnRH on GnRH neurons. The potent GnRH agonist des-Gly(10)-D-Ala(6)-GnRH N-ethylamide, potent GnRH antagonists D-Phe(2)-D-Ala(6)-GnRH and D-Phe(2,6)-Pro(3)-GnRH or vehicle were infused, whereas GnRH release from hypothalamic tissue and cells were measured. PULSAR analysis of GnRH release profiles was conducted to evaluate parameters of pulsatile GnRH release. Infusion of the GnRH agonist resulted in a decrease in mean GnRH (P < 0.001), pulse nadir (P < 0.01), and pulse frequency (P < 0.05) but no effect on pulse amplitude. Infusion of GnRH antagonists resulted in an increase in mean GnRH (P < 0.001), pulse nadir (P < 0.05), and pulse frequency (P < 0.05) and in GnRH pulse amplitude only in dispersed cells (P < 0.05). These results are consistent with the hypothesis that GnRH inhibits endogenous GnRH release by an ultrashort-loop feedback mechanism and that treatment of hypothalamic tissue or cells with GnRH agonist inhibits ultrashort-loop feedback, whereas treatment with antagonists disrupts normal feedback to GnRH neurons and elicits an increased GnRH signal.

Animals↗
PubMed2005

Possibility of autocrine beta-adrenergic signaling in C2C12 myotubes.

Levodopa reportedly inhibits insulin action in skeletal muscle. Here we show that C2C12 myotubes produce levodopa and that insulin-stimulated glucose transport is enhanced when endogenous levodopa is depleted. Exogenous levodopa prevented the stimulation of glucose transport by insulin (P < 0.05) and increased cAMP concentrations (P < 0.05). The decrease in insulin-stimulated glucose transport caused by levodopa was attenuated by propranolol (a beta-adrenergic antagonist) and prevented by NSD-1015 (NSD), an inhibitor of DOPA decarboxylase (DDC; converts levodopa to dopamine). Propranolol and NSD both prevented levodopa-related increases in [cAMP]. However, the effects of levodopa were unlikely to be dependent on the conversion of levodopa to catecholamines because we could detect neither DDC in myotubes nor catecholamines in media after incubation of myotubes with levodopa. The data suggest the possibility of novel autocrine beta-adrenergic action in C2C12 myotubes in which levodopa, produced by myotubes, could have hormone-like effects that impinge on glucose metabolism.

Adrenergic beta-Antagonists↗
PubMed2002

Tumor necrosis factor-alpha expressed constitutively in erythroid cells or induced by erythropoietin has negative and stimulatory roles in normal erythropoiesis and erythroleukemia.

Binding of erythropoietin (EPO) to its receptor (EPOR) on erythroid cells induces the activation of numerous signal transduction pathways, including the mitogen-activated protein kinase Jun-N-terminal kinase (JNK). In an effort to understand the regulation of EPO-induced proliferation and JNK activation, we have examined the role of potential autocrine factors in the proliferation of the murine erythroleukemia cell line HCD57. We report here that treatment of these cells with EPO induced the expression and secretion of tumor necrosis factor alpha (TNF-alpha). EPO-dependent proliferation was reduced by the addition of neutralizing antibodies to TNF-alpha, and exogenously added TNF-alpha induced proliferation of HCD57 cells. EPO also could induce TNF-alpha expression in BAF3 and DA3 myeloid cells ectopically expressing EPOR. Addition of TNF-alpha activated JNK in HCD57 cells, and the activity of JNK was partially inhibited by addition of a TNF-alpha neutralizing antibody. Primary human and murine erythroid progenitors expressed TNF-alpha in either an EPO-dependent or constitutive manner. However, TNF-alpha had an inhibitory effect on both immature primary human and murine cells, suggestive that the proliferative effects of TNF-alpha may be limited to erythroleukemic cells. This study suggests a novel role for autocrine TNF-alpha expression in the proliferation of erythroleukemia cells that is distinct from the effect of TNF-alpha in normal erythropoiesis.

Animals↗
PubMed2002

Interferon-gamma switches monocyte differentiation from dendritic cells to macrophages.

Human monocytes differentiate into dendritic cells (DCs) or macrophages according to the nature of environmental signals. Monocytes stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin 4 (IL-4) yield DCs. We tested here whether interferon-gamma (IFN-gamma), a potent activator of macrophages, may modulate monocyte differentiation. Addition of IFN-gamma to IL-4 plus GM-CSF-stimulated monocytes switches their differentiation from DCs to CD14(-)CD64(+) macrophages. IFN-gamma increases macrophage colony-stimulating factor (M-CSF) and IL-6 production by IL-4 plus GM-CSF-stimulated monocytes by acting at the transcriptional level and acts together with IL-4 to up-regulate M-CSF but not IL-6 production. IFN-gamma also increases M-CSF receptor internalization. Results from neutralizing experiments show that both M-CSF and IL-6 are involved in the ability of IFN-gamma to skew monocyte differentiation from DCs to macrophages. Finally, this effect of IFN-gamma is limited to early stages of differentiation. When added to immature DCs, IFN-gamma up-regulates IL-6 but not M-CSF production and does not convert them to macrophages, even in the presence of exogenous M-CSF. In conclusion, IFN-gamma shifts monocyte differentiation to macrophages rather than DCs through autocrine M-CSF and IL-6 production. These data show that IFN-gamma controls the differentiation of antigen-presenting cells and thereby reveals a new mechanism by which IFN-gamma orchestrates the outcome of specific immune responses.

Animals↗
PubMed2002

Primitive interleukin 3 null hematopoietic cells transduced with BCR-ABL show accelerated loss after culture of factor-independence in vitro and leukemogenic activity in vivo.

Primitive chronic myeloid leukemia cells display a unique autocrine interleukin 3 (IL-3)/granulocyte-colony-stimluating factor (G-CSF) mechanism that may explain their abnormal proliferation and differentiation control. Here we show that BCR-ABL transduction of primitive Sca-1(+) lin(-) mouse bone marrow (BM) cells causes immediate activation of IL-3, G-CSF, and granulocyte macrophage-colony-stimulating factor (GM-CSF) expression in these cells. Their autocrine IL-3-mediated growth dependence is thus demonstrable only in clonal cultures where paracrine effects are reduced. Interestingly, upon continued culture, these cells produce large populations of rapidly proliferating mast cells in which only the IL-3 autocrine mechanism is consistently maintained, together with evidence of hyperphosphorylation of p210(BCR-ABL) and STAT5 and retention of a multilineage but attenuated in vivo leukemogenic potential characterized by a prolonged latency. BCR-ABL transduction of IL-3(-/-) Sca-1(+) lin(-) BM cells initially activates GM-CSF and G-CSF production, factor independence, and the ability to generate phenotypically indistinguishable populations of mast cells. However, maintenance of factor independence, and p210(BCR-ABL) and STAT 5 activation beyond 4 to 6 weeks, requires rescue with an IL-3 transgene. The cultured BCR-ABL-transduced IL-3(-/-) cells also lack leukemogenic activity in vivo. These findings provide new evidence that IL-3 production is a rapid, sustained, and biologically relevant consequence of BCR-ABL expression in primitive hematopoietic cells with multilineage leukemogenic activity.

Animals↗
PubMed2002

Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML).

Although many acute myeloid leukemia (AML) colony-forming cells (CFCs) and long-term culture-initiating cells (LTC-ICs) directly isolated from patients are actively cycling, quiescent progenitors are present in most samples. In the current study, (3)H-thymidine ((3)H-Tdr) suicide assays demonstrated that most NOD/SCID mouse leukemia-initiating cells (NOD/SL-ICs) are quiescent in 6 of 7 AML samples. AML cells in G(0), G(1), and S/G(2)+M were isolated from 4 of these samples using Hoechst 33342/pyroninY staining and cell sorting. The progenitor content of each subpopulation was consistent with the (3)H-Tdr suicide results, with NOD/SL-ICs found almost exclusively among G(0) cells while the cycling status of AML CFCs and LTC-ICs was more heterogeneous. Interestingly, after 72 hours in serum-free culture with or without Steel factor (SF), Flt-3 ligand (FL), and interleukin-3 (IL-3), most G(0) AML cells entered active cell cycle (percentage of AML cells remaining in G(0) at 72 hours, 1.2% to 37%, and 0% to 7.6% in cultures without and with growth factors [GFs], respectively) while G(0) cells from normal lineage-depleted bone marrow remained quiescent in the absence of GF. All 4 AML samples showed evidence of autocrine production of 2 or more of SF, FL, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, 3 of 4 samples contained an internal tandem duplication of the FLT3 gene. In summary, quiescent leukemic cells, including NOD/SL-ICs, are present in most AML patients. Their spontaneous entry into active cell cycle in short-term culture might be explained by the deregulated GF signaling present in many AMLs.

Adult↗
PubMed2003

Gene expression profiling of plasma cells and plasmablasts: toward a better understanding of the late stages of B-cell differentiation.

Plasma cells (PCs), the end point of B-cell differentiation, are a heterogeneous cell compartment comprising several cell subsets from short-lived highly proliferative plasmablasts to long-lived nondividing fully mature PCs. Whereas the major transcription factors driving the differentiation of B cells to PCs were recently identified, the subtle genetic changes that underlie the transition from plasmablasts to mature PCs are poorly understood. We recently described an in vitro model making it possible to obtain a large number of cells with the morphologic, phenotypic, and functional characteristics of normal polyclonal plasmablastic cells (PPCs). Using Affymetrix microarrays we compared the gene expression profiles of these PPCs with those of mature PCs isolated from tonsils (TPCs) and bone marrow (BMPCs), and with those of B cells purified from peripheral blood (PBB cells) and tonsils (TBCs). Unsupervised principal component analysis clearly distinguished the 5 cell populations on the basis of their differentiation and proliferation status. Detailed statistical analysis allowed the identification of 85 PC genes and 40 B-cell genes, overexpressed, respectively, in the 3 PC subsets or in the 2 B-cell subsets. In addition, several signaling molecules and antiapoptotic proteins were found to be induced in BMPCs compared with PPCs and could be involved in the accumulation and prolonged survival of BMPCs in close contact with specialized stromal microenvironment. These data should help to better understand the molecular events that regulate commitment to a PC fate, mediate PC maintenance in survival niches, and could facilitate PC immortalization in plasma cell dyscrasias.

Autocrine Communication↗
PubMed2003

Endogenous CCL2 (monocyte chemotactic protein-1) modulates human immunodeficiency virus type-1 replication and affects cytoskeleton organization in human monocyte-derived macrophages.

CC chemokine ligand 2 (CCL2) is constitutively expressed at high levels in human peripheral blood monocytes, and its expression is further up-modulated during their differentiation into macrophages as well as in the course of HIV infection. To investigate the role of endogenous CCL2 on HIV replication and macrophage function, CCL2's activity was neutralized by specific antibodies. Infection of monocyte-derived macrophages with laboratory-adapted HIV-1 or primary viral isolates in the continuous presence of anti-CCL2 antibody resulted in significantly lower p24 Gag antigen release with respect to control cultures. Interestingly, CCL2 neutralization did not affect the early steps of the HIV life cycle but resulted in the intracellular accumulation of p24 Gag antigen. Simultaneously, remarkable changes in cell morphology and size occurred in cell cultures maintained in the presence of anti-CCL2 antibody. These results suggest that CCL2 may represent an autocrine factor important for enhancing virion production likely by affecting the macrophage cytoskeleton.

Autocrine Communication↗
PubMed2003

Fas ligation induces IL-1beta-dependent maturation and IL-1beta-independent survival of dendritic cells: different roles of ERK and NF-kappaB signaling pathways.

The mechanisms that underpin the intriguing capacity of Fas ligation on dendritic cells (DCs) to induce maturation and activation, rather than apoptosis, remain unclear. In the present study we confirm that Fas signaling induces both phenotypic and functional maturation of murine DCs, and we demonstrate that phenotypic maturation is associated with phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, activation of caspase-1, and secretion of interleukin-beta (IL-1beta). Specific inhibition of ERK1/2 diminished Fas ligation-induced caspase-1 activation, IL-1beta secretion, and ensuing up-regulation of developmental markers, whereas treatment with neutralizing anti-IL-1beta antibody abrogated phenotypic and functional maturation, indicating that IL-1beta mediates Fas ligation-induced DC maturation in an autocrine manner. NF-kappaB activation was responsible for maintaining DC viability after Fas ligation. Inhibiting NF-kappaB did not affect either IL-1beta secretion or phenotypic maturation but rather sensitized DCs to Fas-mediated apoptosis. In conclusion, positive signals originating from Fas are transduced through at least 2 different intracellular pathways in DCs, promoting not only survival but also an increase in maturation that correlates with increased antigen-presentation capability.

Animals↗
PubMed2003

The role of autocrine FGF-2 in the distinctive bone marrow fibrosis of hairy-cell leukemia (HCL).

Bone marrow (BM) fibrosis is a central diagnostic and pathogenetic feature of hairy-cell leukemia (HCL). It is known that fibronectin (FN) produced and assembled by the malignant hairy cells (HCs) themselves is a major component of this fibrosis. It is also known that FN production is greatly enhanced by adhesion of HCs to hyaluronan (HA) via CD44. The aim of the present study was to establish the roles of fibrogenic autocrine cytokines (fibroblast growth factor-2 [FGF-2] and transforming growth factor beta [TGFbeta]) and of different isoforms of CD44 in this FN production. We show that HC adhesion to HA stimulates FGF-2, but not TGFbeta, production and that HCs possess FGF-2 receptor. In a range of experiments, FN production was greatly reduced by blocking FGF-2 but not TGFbeta. Moreover FN, but not FGF-2, secretion was blocked by down-regulation of the v3 isoform of CD44 and by addition of heparitinase. These results show that autocrine FGF-2 secreted by HCs is the principal cytokine responsible for FN production by these cells when cultured on HA. The central role of FGF-2 in the pathogenesis of the BM fibrosis of HCL was supported by our immunohistochemical demonstration of large amounts of this cytokine in fibrotic BM but not in HCL spleen where there is no fibrosis. As regards CD44 isoforms, the present work demonstrates that CD44v3 is essential for providing the heparan sulfate necessary for HC stimulation by FGF-2, whereas the signal for production of the cytokine was provided by HA binding to CD44H, the standard hematopoietic form of the molecule.

Autocrine Communication↗
PubMed2004

Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways.

Besides being expressed on endothelial cells, vascular endothelial growth factor receptors (VEGFRs) are also functional on subsets of leukemias, resulting in autocrine loops that sustain leukemia migration and proliferation. While recent evidence suggests that VEGF supports hematopoietic stem cell survival via an internal loop, the molecular mechanisms whereby autocrine stimulation of VEGFR-2 (KDR) promotes leukemia growth are not well understood. Here we show on acute myeloid primary leukemias and cell lines that VEGF/KDR autocrine loops operate both internally and externally. First, we demonstrate that KDR is constitutively phosphorylated and located at the nucleus of VEGF-producing leukemias. Treatment with anti-VEGF antibody, which acts externally, blocked KDR nuclear translocation and inhibited nuclear factor kappa B (NF-kappaB; p65 and c-rel) activation. In contrast, a KDR-specific intracellular inhibitor failed to block KDR nuclear translocation, but inhibited the constitutive activation of mitogen activated protein kinase (MAPK)/Erk and the phosphatidylinositol 3-kinase/AKT pathways. Notably, treatment with the anti-VEGF antibody alone had little effect on cell survival, while the internal inhibitor induced leukemia apoptosis, and the 2 drugs produced synergistic effects, together and with chemotherapy, reducing cell survival to a larger extent than either agent alone. Our results demonstrate that internal and external VEGF/KDR autocrine loops regulate leukemia survival via different mechanisms, and suggest that blocking both may have therapeutic potential.

Active Transport, Cell Nucleus↗
PubMed2004

Selective recognition of fibroblast growth factor-2 by the long pentraxin PTX3 inhibits angiogenesis.

The long pentraxin PTX3 is a soluble pattern recognition receptor produced by monocytes and endothelial cells that plays a nonredundant role in inflammation. Several pathologic conditions are characterized by local production of both PTX3 and the angiogenic fibroblast growth factor-2 (FGF2). Here, solid-phase binding assays demonstrated that PTX3 binds with high affinity to FGF2 but not to a panel of cytokines and growth factors, including FGF1, FGF4, and FGF8. Accordingly, PTX3 prevented (125)I-FGF2 binding to endothelial cell receptors, leading to specific inhibition of FGF2-induced proliferation. PTX3 hampered also the motogenic activity exerted by endogenous FGF2 on a wounded endothelial cell monolayer. Moreover, PTX3 cDNA transduction in FGF2-transformed endothelial cells inhibited their autocrine FGF2-dependent proliferation and morphogenesis in vitro and their capacity to generate vascular lesions when injected in nude mice. Finally, PTX3 suppressed neovascularization triggered by FGF2 in the chick embryo chorioallantoic membrane with no effect on physiologic angiogenesis. In contrast, the short pentraxin C-reactive protein was a poor FGF2 ligand/antagonist. These results establish the selective binding of a member of the pentraxin superfamily to a growth factor. PTX3/FGF2 interaction may modulate angiogenesis in various physiopathologic conditions driven by inflammation, innate immunity, and/or neoplastic transformation.

Angiogenesis Inhibitors↗
PubMed2004

Neuromedin U: a Myb-regulated autocrine growth factor for human myeloid leukemias.

The c-myb proto-oncogene has been implicated in leukemogenesis, but possible mechanisms remain ill defined. To gain further insight to this process, we used transcript profiling in K562 cells expressing a dominant-negative Myb (MERT) protein. A total of 105 potential Myb gene targets were identified. Neuromedin U (NmU), a peptide affecting calcium transport, underwent the greatest expression change ( approximately 5-fold decrease). To verify a linkage between c-myb and NmU, their mRNA levels were quantitated using real-time polymerase chain reaction in primary acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), as well as normal hematopoietic cells. We found that c-myb was elevated in AML and ALL samples, but NmU expression was increased only in AML cells. Significantly, only AML cells expressed the cognate receptor of NmU, NMU1R, suggesting the presence of a novel autocrine loop. We examined this possibility in detail. Exogenous NmU "rescued" growth suppression in K562-MERT cells and stimulated the growth of primary AML cells. Short interfering RNA "knockdown" of NmU in K562 cells arrested cell growth. Exposing Indo-1-labeled K562 cells to NmU induced an intracellular Ca(++) flux consistent with engagement of the NMU1R. Combined, these results suggest that NmU expression is related to Myb and that the NmU/NMU1R axis constitutes a previously unknown growth-promoting autocrine loop in myeloid leukemia cells.

Autocrine Communication↗