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At least 19 recordsLinked to original sources
PubMed2000

Intercellular communication in spinal cord astrocytes: fine tuning between gap junctions and P2 nucleotide receptors in calcium wave propagation.

Electrophysiological properties of gap junction channels and mechanisms involved in the propagation of intercellular calcium waves were studied in cultured spinal cord astrocytes from sibling wild-type (WT) and connexin43 (Cx43) knock-out (KO) mice. Comparison of the strength of coupling between pairs of WT and Cx43 KO spinal cord astrocytes indicates that two-thirds of total coupling is attributable to channels formed by Cx43, with other connexins contributing the remaining one-third of junctional conductance. Although such a difference in junctional conductance was expected to result in the reduced diffusion of signaling molecules through the Cx43 KO spinal cord syncytium, intercellular calcium waves were found to propagate with the same velocity and amplitude and to the same number of cells as between WT astrocytes. Measurements of calcium wave propagation in the presence of purinoceptor blockers indicate that calcium waves in Cx43 KO spinal cord astrocytes are mediated primarily by extracellular diffusion of ATP; measurements of responses to purinoceptor agonists revealed that the functional P2Y receptor subtype is shifted in the Cx43 KO astrocytes, with a markedly potentiated response to ATP and UTP. Thus, the reduction in gap junctional communication in Cx43 KO astrocytes leads to an increase in autocrine communication, which is a consequence of a functional switch in the P2Y nucleotide receptor subtype. Intercellular communication via calcium waves therefore is sustained in Cx43 null mice by a finely tuned interaction between gap junction-dependent and independent mechanisms.

Adenosine Triphosphate↗
PubMed2003

Long-range signal transmission in autocrine relays.

Intracellular signaling induced by peptide growth factors can stimulate secretion of these molecules into the extracellular medium. In autocrine and paracrine networks, this can establish a positive feedback loop between ligand binding and ligand release. When coupled to intercellular communication by autocrine ligands, this positive feedback can generate constant-speed traveling waves. To demonstrate that, we propose a mechanistic model of autocrine relay systems. The model is relevant to the physiology of epithelial layers and to a number of in vitro experimental formats. Using asymptotic and numerical tools, we find that traveling waves in autocrine relays exist and have a number of unusual properties, such as an optimal ligand binding strength necessary for the maximal speed of propagation. We compare our results to recent observations of autocrine and paracrine systems and discuss the steps toward experimental tests of our predictions.

Autocrine Communication↗
PubMed2001

Human vomeronasal organ function: a critical review of best and worst cases.

The human vomeronasal organ (VNO) has been the subject of some interest in the scientific literature and of considerable speculation in the popular science literature. A function for the human VNO has been both dismissed with ridicule and averred with conviction. This question of VNO function has been needlessly tied to the separate question of whether there is any place for pheromone communication among humans, a topic that is itself bogged down in conflicting definitions. This review is an attempt to weigh the evidence for and against human VNO function, to deconvolve that question from the question of pheromone communication and finally to provide a working definition of 'pheromone'. Further experimental work is required to resolve the conflicting evidence for and against human VNO function but chemical communication does appear to occur among humans. However, several examples reported in the literature do not meet the proposed definition for communication by pheromones: 'chemical substances released by one member of a species as communication with another member, to their mutual benefit'.

Animals↗
PubMed1993

[The ovaries, the immune system, cytokines: physiology].

Sevellar cellular types are involved together in the cyclical functioning of the ovary. Regulating this co-operation between cells are intercellular systems of communication both autocrine and paracrine. The immune system that is present in the ovary seems to have an important role among the regulatory factors. Cytokines are the vectors of intercellular communication. The authors after studying the recent literature show how the immune system elements undergo cyclical variations corresponding to the ovulatory cycle. Reciprocal co-operation between the different cells is brought in to play at all stages of growth and of atrophy of the follicle. The knowledge of these networks for regulation make it possible to understand what is going on better and to work out a more appropriate treatment for certain pathologies such as premature menopause and unforeseen responses to certain forms of stimulation of ovulation.

Cytokines↗
PubMed2002

Insulin feedback action on pancreatic beta-cell function.

Pancreatic beta-cell function is essential for the regulation of glucose homeostasis and its impairment leads to diabetes mellitus. Besides glucose, the major nutrient factor, inputs from neural and humoral components and intraislet cell-cell communication act together to guarantee an appropriate pancreatic beta-cell function. Data obtained over the last 5 years in several laboratories have revitalized a controversial concept, namely the autocrine feedback action of secreted insulin on beta-cell function. While, historically, insulin was suggested to exert a negative effect on beta-cells, recent data provide evidence for a positive role of insulin in transcription, translation, ion flux, insulin secretion and beta-cell survival.

Animals↗
PubMed2002

Role of adenine nucleotides in insulin secretion from MIN6 pseudoislets.

Insulin secretion from MIN6 cells configured as cell aggregates by culture on a gelatin substrate (pseudoislets) is enhanced compared to that of MIN6 cells grown as monolayers on tissue culture plastic, indicating the importance of beta-cell-to-beta-cell proximity for insulin release. In this study we have shown that glucose induced a biphasic release of insulin from pseudoislets, whereas the amplitude and duration of the responses of equivalent monolayer cells were much reduced. Purinergic aqonists have been implicated in intercellular communication between beta-cells, so we investigated whether adenine nucleotides co-released with insulin are responsible for the enhanced secretory responses of pseudoislets. We have demonstrated that MIN6 cells express purinergic A(1) and P2Y receptors, and that adenine nucleotides increased [Ca(2+)](i) with an efficacy of agonists being ATP > ADP > AMP. However, neither suramin nor the more selective A(1) antagonist 1,3-dipropyl-8-cyclopentylxanthine reduced glucose-induced insulin secretion from pseudoislets, and stimulation of monolayer cells with a range of adenine nucleotides did not enhance glucose-induced secretion. These results suggest that enhanced secretion from MIN6 pseudoislets is not due to increased paracrine/autocrine action of adenine nucleotides.

Adenine Nucleotides↗
PubMed2002

Extracellular NAD+: a novel autocrine/paracrine signal in osteoblast physiology.

Intercellular communication allows co-ordination of cell metabolism and sensitivity to extracellular stimuli. In bone cells, paracrine stimulation and cell-to-cell coupling through gap junctions induce the formation of complex intercellular networks, which favours the intercellular exchange of nutrients and second messengers, ultimately controlling the process of bone remodelling. The importance of local factors in bone remodelling is known since many years. Bone cells secrete and respond to a variety signals, among which include prostaglandins, cytokines, growth factors, and ATP. We here report evidence that extracellular NAD(+) is a novel extracellular signal stimulating osteoblast differentiation. We found that HOBIT human osteoblastic cells, which are known to express ADP-ribosyl cyclase/CD38 activity, respond to micromolar concentrations of extracellular NAD(+) with oscillatory increases of the cytosolic Ca(2+) concentration. The initial Ca(2+) response was followed by a time-dependent inhibition of cell growth, the appearance of an epithelial morphology, and by an increase of alkaline phosphatase and osteocalcin expression. Under resting condition HOBIT cells release NAD(+) in the extracellular medium and the release is significantly potentiated by mechanical stimulation. Taken together these results point to NAD(+) as a novel autocrine/paracrine factor involved in stimulation and maintenance of the osteoblast differentiated phenotype.

Adult↗
PubMed1998

Expression of growth factors, growth inhibiting factors, and their receptors in invasive breast cancer. I: An inventory in search of autocrine and paracrine loops.

The aim of the present study was to investigate which growth factors, receptors, and growth inhibiting factors are expressed in invasive breast cancer. Five (angiogenic) growth factors and their receptors: platelet-derived growth factor A chain (PDGF-AA) and PDGF receptor alpha (PDGF alpha R), PDGF-BB and PDGF beta receptor, transforming growth factor alpha (TGF alpha) and its receptor epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) and its receptors vascular endothelial growth factor receptor I (Flt-1) and vascular endothelial growth factor receptor II (Flk-1/KDR); two growth inhibiting factors: transforming growth factor-beta-1 (TGF beta 1) and (TGF beta 2) and their receptor couple transforming growth factor beta receptor I (TGF beta R-I) and TGF beta R-II; and basic fibroblast growth factor (bFGF) were stained by standard immunohistochemistry on frozen sections in 45 cases of invasive carcinoma of the breast. Staining was scored as negative or positive in tumour epithelium, stroma, and blood vessels. TGF beta 1 and TGF beta 2 were expressed in the tumour cells in 67 per cent and 76 per cent of cases, respectively, whereas PDG beta R and TGF beta R-II were expressed in 0 per cent and 2 per cent, respectively. The other factors showed variable expression in tumour cells. All factors were expressed in the stroma in most cases, except Flt-1, Flk-1/KDR, TGF beta 2, and TGF beta R-II, which showed variable expression, and EGFR, which showed no expression. The endothelium was in most cases positive for bFGF, PDGF-AA, PDGF-BB, VEGF, PDGF alpha R, PDGF beta R, and TGF beta 1 but TGF beta/ was negative in most cases and TGF alpha, EGFR, Flt-1, Flk-1/KDR, TGF beta R-I, and TGF beta R-II were variably expressed. The most interesting possible auto/paracrine loops, as demonstrated on serial sections and by fluorescence double staining, were the TGF alpha/EGFR, TGF beta s/TGF beta R, VEGF/Flt-1, and the VEGF/Flk-1 combinations. In conclusion, growth factors, growth inhibiting factors, and their receptors are frequently expressed in invasive breast cancer. Indications for some possible auto- and paracrine loops have been found, which should encourage further study on the role of these factors in breast cancer proliferation and angiogenesis.

Autocrine Communication↗
PubMed1998

Expression of growth factors, growth-inhibiting factors, and their receptors in invasive breast cancer. II: Correlations with proliferation and angiogenesis.

Growth factors may play an important role in tumour growth and angiogenesis by their influence on tumour cell proliferation or their effect on neovascularization. The aim of the present study was to determine which of the growth factors, growth-inhibiting factors, and their receptors investigated in a previous study are correlated with proliferation and angiogenesis in invasive breast cancer, with emphasis on the impact of possible autocrine and paracrine loops. Five growth factors and their receptors: platelet-derived growth factor A chain (PDGF-AA) and PDGF alpha receptor (PDGF alpha R), PDGF-BB and PDGF beta receptor (PDGF beta R), transforming growth factor alpha (TGF alpha) and its receptor epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and Flk-1/KDR; two growth-inhibiting factors: transforming growth factor beta-1 (TGF beta 1) and TGF beta 2 and their receptor couple TGF beta R-I and TGF beta R-II; and basic fibroblast growth factor (bFGF) were stained in 45 cases of invasive breast cancer by standard immunohistochemistry on frozen sections. Staining in tumour cells, stromal cells, and endothelial cells was scored as negative or positive. Proliferation was determined by assessment of the mitotic activity index (MAI) and the degree of angiogenesis was measure by counting the number of microvessels (microvessel density: MVD) in the most vascularized area of the tumour. bFGF and EGFR showed positive correlations with the MAI, while TGF beta 2 showed a negative correlation. Expression of bFGF, TGF alpha, TGF beta 2, and EGFR correlated positively with the MVD. Co-expression of the TGF alpha/EGFR growth factor/receptor combination showed a stronger correlation with the MAI and the MVD than EGFR or TGF alpha alone, and the TGF beta 2/TGF beta R-I/TGE beta R-II combination showed a positive correlation with the MVD. In conclusion, the expression of several growth factors, growth factor receptors and growth-inhibiting factors showed correlations with the rate of proliferation and the degree of angiogenesis in invasive breast cancer. Some growth factor/receptor combinations showed stronger correlations with proliferation and angiogenesis than the growth factor or receptor alone, pointing to the importance of possible auto- and paracrine loops for stimulation of proliferation and angiogenesis by growth factors and their receptors.

Autocrine Communication↗
PubMed1997

Epithelial-mesenchymal interactions in the alteration of gene expression and morphology following lung injury.

Numerous studies using morphologic techniques have demonstrated the plasticity of pulmonary epithelial cells and the requirement for complex intercellular interactions for regeneration of normal epithelium following lung injury. Recent developments in the molecular characterization of genes expressed in the lung have generated additional tools for evaluation of lung cell phenotypes and interactions. This review discusses the relationship between molecular and morphologic changes in lung cells during injury and repair. Changes in epithelial morphology and their differentiated gene products may be mediated through alterations in expression of numerous factors acting through paracrine and autocrine mechanisms. Tumor necrosis factor alpha, transforming growth factor beta, and retinoic acid, whose roles in the regulation of epithelial cell differentiation have been well documented, will be discussed in the context of normal lung development and repair from injury.

Animals↗
PubMed1997

Role of heparin-binding EGF-related peptides in proliferation and apoptosis of activated ras-stimulated intestinal epithelial cells.

The ras mutation is a common and critical step in carcinogenesis. Autocrine growth factors are also known to play an important role in cancer cell growth and transformation. However, the contribution of autocrine growth factors in regulation of proliferation and apoptosis of activated ras-stimulated intestinal epithelium is not fully understood. Therefore, we constructed activated ras-transfected intestinal epithelial cell clones (IEC-ras) to examine the role of epidermal growth factor (EGF)-related peptides in the behavior of IEC-ras. Overexpression of EGF family growth factors (transforming growth factor alpha, heparin-binding EGF-like growth factor, amphiregulin and betacellulin) and stronger phosphorylation of the EGF receptor was observed in IEC-ras compared with control cells. IEC-ras proliferated more rapidly than control cells, and a specific EGF receptor kinase inhibitor, AG 1478, abolished the increased proliferation of IEC-ras. Heparitinase and chlorate also prevented increased proliferation of IEC-ras. Additionally, IEC-ras expressed more bcl-2 and was more resistant to apoptosis induction by UV radiation and mitomycin C. AG 1478 suppressed bcl-2 expression and inhibited resistance to apoptosis of IEC-ras. Heparitinase and chlorate had effects similar to those of AG 1478. Our data indicate that heparin-binding EGF family growth factors play an important role in both increased proliferation and resistance to apoptosis of ras-stimulated intestinal epithelial cells.

Amphiregulin↗
PubMed1998

Production of stem cell factor and expression of c-kit in human rhabdomyosarcoma cells: lack of autocrine growth modulation.

Human rhabdomyosarcoma cells produce autocrine and paracrine growth factors that can sustain their growth and malignancy. Here we report constitutive production of stem cell factor (SCF) by 5 of 5 human rhabdomyosarcoma cell lines both of alveolar and embryonal histotype. SCF production, ranging from 30 to 162 pg/ml, was independent from the degree of myogenic differentiation and was not modulated by exogenous addition of retinoic acid (RA) or tumor necrosis factor-alpha (TNF-alpha). Four of 5 rhabdomyosarcoma cell lines expressed the mRNA for SCF receptor c-kit, while the 5th cell line became weakly positive for c-kit mRNA only after stimulation with retinoic acid. On the cell surface, c-kit protein was detectable at very low levels in only 1 of 5 rhabdomyosarcoma cell lines and was not up-regulated by RA or TNF-alpha. Addition of anti-c-kit and anti-SCF blocking antibodies, or of exogenous SCF did not alter the in vitro growth ability of rhabdomyosarcoma cells. In conclusion, our data show that rhabdomyosarcoma cells produce consistent amounts of SCF but did not demonstrate autocrine growth modulation. SCF secretion may thus have a paracrine, rather than an autocrine activity in this tumor.

Autocrine Communication↗
PubMed1999

Redundancy of autocrine loops in human osteosarcoma cells.

With the aim of identifying innovative therapeutic strategies for osteosarcoma patients who are refractory to conventional chemotherapy, we analyzed the in vitro effects of the blockage of autocrine circuits. Since the insulin-like growth factor-I receptor (IGF-IR)-mediated loop is relevant to the growth of osteosarcoma, we analyzed the activity of the IGF-IR-blocking antibody alphaIR3 in both sensitive and multidrug-resistant osteosarcoma cell lines. Only limited effects, however, were observed, suggesting the simultaneous existence of other autocrine circuits. Indeed, in a representative panel of 12 human osteosarcoma cell lines, in addition to the IGF-IR-mediated circuit, we demonstrated also a loop mediated by epidermal growth factor receptor as well as the presence of nerve growth factor, low-affinity nerve growth factor receptor as well as tyrosine receptor kinase A in the great majority of osteosarcomas. Therapies based on the inhibition of single circuits may have only limited effects in osteosarcoma, whereas the use of suramin, a drug which, besides other activities, non-selectively interferes with the binding of growth factors to their receptors, appears as a promising alternative, in both sensitive and drug-resistant osteosarcoma cells.

Antineoplastic Agents↗
PubMed2000

Dependence of autocrine growth factor stimulation in platelet-derived growth factor-B-induced mouse brain tumor cells.

In human gliomas, platelet-derived growth factor (PDGF) ligand and receptor mRNA are often co-expressed, which suggests the presence of an autocrine loop. To further investigate the significance of PDGF stimulation in brain tumors, we used a previously developed mouse tumor model, in which malignant brain tumors of neuroepithelial origin were induced by injecting a murine retrovirus containing the human PDGF B-chain gene into the brains of neonatal mice. In the present investigation, we have characterized a cell line established from such an experimentally induced tumor in an INK4a-/- mouse. Cultured tumor cells expressed nestin and NG2 chondroitin sulfate proteoglycan and are thus most likely derived from an oligodendrocyte precursor cell. Tumor cells produced PDGF-B protein and displayed constitutively activated PDGF alpha receptors. Autocrine receptor activation could be blocked with the specific PDGF receptor tyrosine kinase inhibitor CGP 57148B, which led to almost complete inhibition of cell proliferation, which was much less affected by a PDGF B-chain aptamer that inhibits binding of PDGF-B to PDGF receptors and is unlikely to be able to pass through the plasma membrane. Our results imply an important role for PDGF autocrine stimulation in both initiation and progression of a subtype of gliomas.

Animals↗
PubMed1999

Interleukin-6 (IL-6) and its soluble receptor support survival of sensory neurons.

The cytokine interleukin-6 (IL-6) has multiple functions in the immune and hematopoietic systems. IL-6 is related to ciliary neurotrophic factor (CNTF), a trophic factor for motoneurons, sensory dorsal root ganglion (DRG) neurons, and other neuronal subpopulations. Both act via related receptor complexes, consisting of one ligand-specific alpha-receptor subunit (IL-6R and CNTFR, respectively) and two signal-transducing receptor components. Even though IL-6 is expressed by neurons and glia, the functions of IL-6 in the nervous system are poorly understood. Here, we report that exogenous human IL-6 promotes the survival of dissociated newborn rat DRG neurons in vitro if supplemented with soluble human IL-6-alpha-receptor. The dosages of human IL-6 and soluble human IL-6R necessary to achieve neurotrophic effects could be reduced markedly by linking ligand and alpha-receptor component in a designer cytokine. Furthermore, we show that newborn rat DRG neurons express and secrete bioactive IL-6. Endogenously secreted IL-6 does not enhance survival of these neurons in vitro, suggesting that DRG neurons do not sufficiently express cell surface IL-6R. Exogenously added soluble rat IL-6R rendered DRG neurons responsive to secreted IL-6. Our results indicate an autocrine function of IL-6 in DRG neuron survival which depends on membrane-bound or soluble IL-6R as a neurotrophic cofactor.

Animals↗
PubMed1999

Schwann cell development in embryonic mouse nerves.

Previously we proposed that Schwann cell development from the neural crest is a two-step process that involves the generation of one main intermediate cell type, the Schwann cell precursor. Until now Schwann cell precursors have only been identified in the rat, and much remains to be learned about these cells and how they generate Schwann cells. Here we identify this cell in the mouse and analyze its transition to form Schwann cells in terms of timing, molecular expression, and extracellular signals and intracellular pathways involved in survival, proliferation, and differentiation. In the mouse, the transition from precursors to Schwann cells takes place 2 days earlier than in the rat, i.e., between embryo days 12/13 and 15/16, and is accompanied by the appearance of the 04 antigen and the establishment of an autocrine survival circuit. Beta neuregulins block precursor apoptosis and support Schwann cell generation in vitro, a process that is accelerated by basic fibroblast growth factor 2. The development of Schwann cells from precursors also involves a change in the intracellular survival signals utilized by neuregulins: To block precursor death neuregulins need to signal through both the mitogen-activated protein kinase and the phosphoinositide-3-kinase pathways although neuregulins support Schwann cell survival by signaling through the phosphoinositide-3-kinase pathway alone. Last, we describe the generation of precursor cultures from single 12-day-old embryos, a prerequisite for culture studies of genetically altered precursors when embryos are non-identical with respect to the transgene in question.

Animals↗
PubMed2000

HGF is an autocrine growth factor for skeletal muscle satellite cells in vitro.

Muscle satellite cell activation following injury is essential for muscle repair, and hepatocyte growth factor/scatter factor (HGF) was the first growth factor shown to be able to stimulate activation and early division of adult satellite cells in culture and in muscle tissue. In addition, HGF was shown to be present in uninjured and injured skeletal muscle. Experiments in this report demonstrate that cultured satellite cells also synthesize and secrete HGF. Reverse transcription-polymerase chain reaction (RT-PCR) was used to demonstrate the presence of HGF mRNA in cultured adult satellite cells as early as 12 h from the time of plating. Message content was detectable at early times in culture and appeared to increase between 36 and 48 h. HGF protein expression was demonstrated during this time period by immunofluorescence localization; HGF was localized to mononucleated cells and multinucleated myotubes. HGF message was not detectable in muscle-derived fibroblast clones, and fibroblast-like cells in satellite cell cultures were negative for HGF by immunofluorescence analysis. Furthermore, Western blot analysis revealed the presence of HGF in satellite cell culture conditioned medium, associated with the cell surface and inside cells. Finally, the addition of neutralizing HGF antibodies during the proliferation phase in culture (42-90 h) significantly reduced cell proliferation. These experiments indicate that HGF is expressed by cultured satellite cells and that endogenous HGF from satellite cells can act in an autocrine fashion. Because HGF plays a central role in satellite cell activation, it is likely that direct administration of HGF into damaged muscle may represent a potentially useful approach for stimulating muscle repair. This approach may also be useful in enhancing the efficiency of myoblast transplantation in vivo.

Animals↗