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PubMed1998

Tumour necrosis factor alpha alters the expression of connexin43, connexin40, and connexin37 in human umbilical vein endothelial cells.

Tumour necrosis factor alpha (TNF-alpha) plays an important role in orchestrating inflammatory responses with the vascular endothelium as main target cell type, and was found to promote migration of endothelial cells, as occurs in wound healing processes. Substantial evidence exists that endothelial cell migration in wound healing is related to changes in cell coupling by means of gap junctions. Gap junctions are agglomerates of cell-to-cell channels that allow direct electrical and metabolic communication between cells. The authors have investigated whether TNF-alpha alters the expression of gap junction proteins (connexins, Cx) between human umbilical vein endothelial cells (HUVEC), thereby changing the extent of intercellular communication, as measured by dye coupling. Under control conditions, Cx43, Cx40, and Cx37 protein and mRNA were present in HUVEC. After exposure to 0.5 nM TNF-alpha for 48 h, however, the authors were no longer able to detect Cx37 and Cx40 protein, whereas Cx43 levels seemed unaltered but showed more perinuclear staining. After 24 and 48 h exposure to TNF-alpha, levels of Cx37 and Cx40 mRNA, were reduced, while the level of Cx43 mRNA remained unaltered, suggesting transcriptional regulation. If TNF-alpha was removed from the medium, Cx37 and Cx40 expression was restored within 24 h. The modulation of connexin expression by TNF-alpha resulted in a decrease in dye coupling of 40%.

Cells, Cultured↗
PubMed2000

Irsogladine upregulates expressions of connexin32 and connexin26 in the rat liver.

A gap junction is the channel for cell-to-cell communication and plays an important role in the maintenance of tissue homeostasis, control of cell growth and differentiation, and prevention of experimental hepatocarcino-genesis. Irsogladine, an antiulcer drug, augments gap junctional intercellular communication in gastric mucosa, but the effect of irsogladine on the liver remains uncertain. In this study the effects of irsogladine on the liver were investigated from the viewpoints of gap junctional protein connexin (Cx)32 and Cx26 in rats. Twelve rats were divided into a control group (n=6) and the irsogladine group (n=6) in which irsogladine (20 mg/kg per day) was administered orally for 3 days before sample collection, and the two groups were compared in regard to liver enzymes (serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH)), serum- and tissue-calcium concentrations, immunohistochemical expressions of Cx32 and Cx26, and RT-PCR analysis. In immunohistochemistry, analyzed using an image processor for analytical pathology (IPAP), the number of Cx32-positive spots was higher and the area of Cx26-positive spots were larger in the irsogladine group than those in the control group (P=0.036 and P=0.00032, respectively). In RT-PCR analysis, the mRNA of Cx32 or Cx26 in the irsogladine group showed a tendency to be higher than in the control group, but not significantly (Cx32, P=0.70; Cx26, P=0.07). Another 30 rats were used for measurements of cyclic-adenosine monophosphate (c-AMP) of the liver. c-AMP concentration was increased 1 h after the administration of irsogladine, which partially explained how the Cxs were upregulated. These findings may suggest that irsogladine upregulates Cx32 and Cx26 expressions in the liver of rats.

Journal Article↗
PubMed2000

Influence of mature adipocytes on osteoblast proliferation in human primary cocultures.

It has been shown that the bone loss occurring with aging in spongy bone is associated with a reduced osteoblastic bone formation and an increased volume of marrow adipose tissue. This observation suggests a relationship between cells from the osteoblastic and adipogenic lineages. The purpose of the present study was to evaluate the influence of mature adipocytes on osteoblastic proliferation and activity in a model of coculture. Human primary osteoblastic (hBOB) cells were derived from femoral bone explants collected in patients undergoing orthopedic surgery. Human stromal osteoblastic (hMSOB) cells were obtained from bone marrow samples collected by aspiration during orthopedic surgery. Extramedullary and medullary mature adipocytes (hAd) showing similar functions, except for their response to insulin, hAd were isolated from mammary adipose tissue collected in women undergoing tumorectomy. Cells were cocultured, with hAd being separated from osteoblastic cells (hBOB or hMSOB) by a porous membrane (0.4 microm). When hBOB cells were seeded on the upper side of the insert and hAd were floating on the lower side, cell contacts between the two cell types were possible through the pores of the membrane. At the end of the experiment, proliferation of the osteoblastic cells was evaluated by [(3)H]-thymidine incorporation and alkaline phosphatase (AP) activity was measured. After 20 h of coculture, proliferation of the hBOB cells was significantly decreased when compared with control hBOB (-40 +/- 6%, p < 0.05). To establish whether or not the influence of hAd on hBOB proliferation required intercellular communications, hAd and hBOB cells were cocultured far from the porous membrane. Six other independent experiments confirmed an inhibition of hBOB proliferation under both experimental conditions (p < 0.05): -35 +/- 7% with possible intercellular contacts, and -30 +/- 7% without any contact. In contrast, the proliferation of hMSOB cells was not significantly modified after coculture with hAd. In addition, the presence of hAd did not significantly modify the AP activity of hBOB (0.163 +/- 0.143 and 0.181 +/- 0.114 nmol/min per microgram of protein in controls and after coculture, respectively). No reproducible effect of hAd-conditioned medium was noted on hBOB- and hMSOB-cell proliferation or hBOB-cell activity. In conclusion, mature adipocytes induced an inhibition of hBOB-cells proliferation, probably mediated by a factor secreted by hAd. This effect may contribute to the age-related reduction of bone formation and bone loss.

Adipocytes↗
PubMed2001

Gap-junctional communication mediates parathyroid hormone stimulation of mineralization in osteoblastic cultures.

Previously we showed that physiological levels of parathyroid hormone (PTH) can increase the mineralization of extracellular matrix (ECM) by osteoblast-like cells in vitro. In this study, we assess the role of gap-junctional intercellular communication (GJC) in the PTH-enhanced mineralization of ECM in MC3T3-E1 cells, a murine culture model of osteoblastic differentiation. Messenger RNA and protein for connexin 43 (Cx43), the major component of MC3T3-E1 gap junctions, and GJC increased as the cells progressed toward a mature phenotype. Immunocytochemistry showed accumulation of Cx43 at the area of close contact between cells. The timing of the PTH treatment that increased matrix mineralization in these cells coincided with the highest expression of Cx43 and GJC. Administration of 18-alpha-glycyrrhetinic acid (AGA) promptly blocked GJC in cultures of MC3T3-E1 cells in a dose-dependent and reversible manner at all times tested during the culture period. Treatment with AGA, but not with an inactive analog, reversed the PTH-induced ECM mineralization. These data suggest that GJC mediates anabolic actions of PTH related to osteoblast-mediated mineralization.

Animals↗
PubMed1998

Rapid determination of gap junction formation using HeLa cells microinjected with cDNAs encoding wild-type and chimeric connexins.

A procedure for rapidly determining the functionality of gap junctions constructed of recombinant connexins in communication-deficient HeLa cells is described. Nuclear microinjection of cDNA encoding wild-type connexins (Cx) 26, 32, 43, and a range of connexin-aequorin (Cx-Aeq) chimerase resulted in generation of gap junction intercellular communication channels. Expression of recombinant protein was detected in > 95% of cells 18-72 h following nuclear microinjection, and the functionality of the channels generated was determined according to their ability to transfer the fluorescent dye tracers Lucifer yellow and propidium iodide. The dye transfer results obtained correlated closely with other published studies using stably transfected cells and yet are obtained as rapidly as 18 h following microinjection of cDNA. Expression of a truncated form of Cx43 (Cx43 delta 244) by this new method indicated diminished intercellular transfer of both dyes and supports a channel-gating mechanism that postulates interaction between the carboxyl tail and the intracellular loop.

Aequorin↗
PubMed1993

Specificity of gap junction communication among human mammary cells and connexin transfectants in culture.

In a previous paper (Lee et al., 1992), it was shown that normal human mammary epithelial cells (NMEC) express two connexin genes, Cx26 and Cx43, whereas neither gene is transcribed in a series of mammary tumor cell lines (TMEC). In this paper it is shown that normal human mammary fibroblasts (NMF) communicate and express Cx43 mRNA and protein. Transfection of either Cx26 or Cx43 genes into a tumor line, 21MT-2, induced the expression of the corresponding mRNAs and proteins as well as communication via gap junctions (GJs), although immunofluorescence demonstrated that the majority of Cx26 and Cx43 proteins present in transfected TMEC was largely cytoplasmic. Immunoblotting demonstrated that NMEC, NMF, and transfected TMEC each displayed a unique pattern of posttranslationally modified forms of Cx43 protein. The role of different connexins in regulating gap junction intercellular communication (GJIC) was examined using a novel two-dye method to assess homologous and heterologous communication quantitatively. The recipient cell population was prestained with a permanent non-toxic lipophilic dye that binds to membranes irreversibly (PKH26, Zynaxis); and the donor population is treated with a GJ-permeable dye Calcein, a derivative of fluorescein diacetate (Molecular Probes). After mixing the two cell populations under conditions promoting GJ formation, cells were analyzed by flow cytometry to determine the percentage of cells containing both dyes. It is shown here that Cx26 and Cx43 transfectants display strong homologous communication, as do NMEC and NMF. Furthermore, NMEC mixed with NMF communicate efficiently, Cx26 transfectants communicate with NMEC but not with NMF, and Cx43 transfectants communicate with NMF. Communication between Cx26 TMEC transfectants and NMEC was asymetrical with preferential movement of calcein from TMEC to NMEC. Despite the presence of Cx43 as well as Cx26 encoded proteins in the GJs of NMEC, few Cx43 transfectants communicated with NMEC. No heterologous GJIC was observed between Cx26- and Cx43-transfected TMEC suggesting that heterotypic GJs do not form or that Cx26/Cx43 channels do not permit dye transfer.

Blotting, Western↗
PubMed2004

Gap junctional communication is required to maintain mouse cortical neural progenitor cells in a proliferative state.

The mechanisms that determine whether neural stem cells remain in a proliferative state or differentiate into neurons or glia are largely unknown. Here we establish a pivotal role for gap junction-mediated intercellular communication in determining the proliferation and survival of mouse neural progenitor cells (NPCs). When cultured in the presence of basic fibroblast growth factor (bFGF), NPCs express the gap junction protein connexin 43 and are dye-coupled. Upon withdrawal of bFGF, levels of connexin 43 and dye coupling decrease, and the cells cease proliferating and differentiate into neurons; the induction of gap junctions by bFGF is mediated by p42/p44 mitogen-activated protein kinases. Inhibition of gap junctions abolishes the ability of bFGF to maintain NPCs in a proliferative state resulting in cell differentiation or cell death, while overexpression of connexin 43 promotes NPC self-renewal in the absence of bFGF. In addition to promoting their proliferation, gap junctions are required for the survival of NPCs. Gap junctional communication is therefore both necessary and sufficient to maintain NPCs in a self-renewing state.

Animals↗
PubMed1994

Vitamin D influences gap junctional communication in C3H/10T 1/2 murine fibroblast cells.

Vitamin D3, cholecalciferol, induces cell-cell communication via gap junctions in murine fibroblasts (C3H/10T 1/2 cells) at concentrations between 0.01 and 1.0 microM, as assayed by the dye transfer method using Lucifer yellow CH. The extent of induction is similar to that obtained with the positive controls, canthaxanthin or retinoic acid, applied at 10 and 1 microM, respectively. Vitamin D2 also induces cell-cell communication. At elevated concentrations of vitamin D3 (5 microM) there is a suppression of gap junctional communication, reversible upon exposure to all-trans retinoic acid (1 microM) after removal of vitamin D3 from the medium. Conversely, communication between cells prestimulated with retinoic acid (1 microM) rapidly decreases when the retinoid is replaced by vitamin D3 (5 microM). The data demonstrate a role for vitamin D in the regulation of intercellular communication. This novel property of vitamin D may contribute to the antiproliferative effects of vitamin D exhibited in some types of cancer.

Animals↗
PubMed1990

Vanadium compounds promote the induction of morphological transformation of hamster embryo cells with no effect on gap junctional cell communication.

Vanadium compounds were found to promote the induction of morphological transformation of hamster embryo cells. Exposure of the cells to Na-O-vanadate, vanadin (V) oxide or vanadin (IV) oxide sulfate following pre-exposure to a low concentration of benzo[a]pyrene, potentiated the induction of transformed colonies similar to 12-O-tetradecanoylphorbol-13-acetate. Unlike this phorbol ester, vanadium compounds did not inhibit intercellular communication, or active protein kinase C. Nor did vanadate influence the reoccurrence of communication after removal of a communication blocking phorbol ester. On the other hand, vanadate showed strong synergism with the phorbol ester on induction of transformed morphology in the phorbol ester sensitive cell line BPNi. This suggests that vanadium and tumor promoting phorbol esters mediate their effect on the induction of morphological transformation of hamster embryo cells through different mechanisms.

Animals↗
PubMed1993

A synthetic C22 carotenoid inhibits carcinogen-induced neoplastic transformation and enhances gap junctional communication.

In 10T1/2 cells several dietary carotenoids have previously been shown to be capable of inhibiting carcinogen-induced neoplastic transformation. Two synthetic novel compounds, a C22 carotenoid, C22-polyene-tetrone-diacetal, and a C28 carotenoid, C28-polyene-tetrone, have now been tested in this system. The C22 compound was active in completely inhibiting 3-methylcholanthrene-induced transformation at 10(-5) M when added during the post-initiation phase of carcinogenesis. Gap junctional intercellular communication was strongly upregulated at this concentration. This activity has previously been shown to be highly correlated with, and has been proposed to be mechanistically linked to, inhibition of transformation by carotenoids in 10T1/2 cells. In contrast, the C28 compound, previously reported to be more active as a singlet oxygen quencher than C22, did not demonstrate activity in 10T1/2 cells in either assay system. This lack of activity was not due to chemical instability or lack of cellular uptake: the C28 compound was more stable in cell culture medium over 7 days and achieved higher cellular levels than the C22 compound (5 x 10(-11) mol/10(6) cells versus 0.5 x 10(-11) mol/10(6) cells). The activity of the C22 compound was not due to toxicity, since transformation occurred in carcinogen-treated cultures after its removal; neither was it due to antiproliferative effects on transformed cells, since the C22 compound did not prevent focus formation by transformed cells in reconstruction experiments. The demonstration that synthetic carotenoids possess biological activities comparable to the most potent naturally occurring compounds suggest that rational synthesis of compounds with improved pharmacological properties should be possible.

Acetals↗
PubMed2000

A useful marker for evaluating tissue-engineered products: gap-junctional communication for assessment of the tumor-promoting action and disruption of cell differentiation in tissue-engineered products.

An in vitro system for evaluating the safety of tissue-engineered products is a convenient because of its rapidity and low cost. On the basis of recent studies, intercellular channels called gap-junctions are considered to play an important role on the tumor-promotion stage during the tumorigenesis induced by polyurethanes. Further, we also demonstrate the significance of the intercellular communication during neuronal cell differentiation. From these results, we propose a survey of the function of the gap-junctional communication as a probable useful marker for evaluating the safety of tissue-engineered products.

Animals↗
PubMed1983

Control of gap junction formation in early mouse embryos.

Intercellular communication via gap junctions begins in the eight-cell stage in early mouse embryos. We have studied the timing of this event in relation to compaction, and have begun to explore some of the possible control mechanisms underlying it. Gap junction formation was inferred by measuring ionic coupling as well as by observing the intercellular transfer of fluorescent dye. Embryos were obtained early on Day 3 of pregnancy by flushing the oviducts of HA/ICR mice that had been mated with CB6F1/J males. Gap junctions were detected only in those embryos which had achieved the fully compacted state. Inhibition of protein synthesis by cycloheximide treatment beginning as early as the late four-cell stage failed to block compaction or the acquisition of gap junctions, demonstrating that the necessary proteinaceous components are present in advance of these events. In order to test the possibility that gap junctions could be induced to form prematurely, fully compacted, communication-competent eight-cell embryos were aggregated with two- or four-cell embryos. Even after 10 hr of aggregation, no interembryonic gap junctions could be detected. Fully compacted eight-cell embryos when aggregated with each other, however, became ionically coupled within 3-5 hr. The number of interembryonic junctional channels was judged to be effectively small, since the aggregated embryos exhibited obvious ionic coupling but very weak dye coupling. In contrast to gap junction formation within embryos, junction formation between embryos was blocked by cycloheximide. These results demonstrate that gap junction formation in early mouse embryos is under precise temporal control, involving the assembly or mobilisation of preexisting components. This stockpile of components is either unavailable or insufficient to allow the formation of additional gap junctions between aggregated communication-competent embryos without new protein synthesis.

Animals↗
PubMed2005

Intercellular movement of transcription factors.

Intercellular communication by the direct trafficking of transcription factors has been reported in plant developmental events such as root radial or epidermal cell patterning and shoot organogenesis. Investigations of this novel communication system have just begun and have highlighted the structural requirements for and mechanisms of transcription factor movement. Early studies suggest that plants employ both targeted (selective) and non-targeted (non-selective) intercellular movement of transcription factors. Factors that affect the intercellular movement of transcription factors through plasmodesmata have been explored.

Arabidopsis↗
PubMed1997

PKC phosphorylation disrupts gap junctional communication at G0/S phase in clone 9 cells.

Gap junctional communication during the progression of cell cycle from quiescent G0 to S phase was examined in cultured clone 9 rat liver cells. The transfer of scrape-loaded fluorescent dye was suppressed immediately after the stimulation of cell cycle progression in a synchronized cell population. Northern blot analysis showed that the temporal disturbance of gap junctional communication in cells passing from G0 to S phase did not result from transcriptional down-regulation of connexin 43. It was also found that the PKC inhibitor, calphostin C, was able to restore intercellular communication in serum stimulated cells. Data suggest a control mechanism by PKC mediated phosphorylation in the regulation of gap junction function which is vulnerable to cell cycling. The loss of gap junctional communication correlated with the increased phosphorylation of connexin 43 on serine residues in clone 9 cells.

Animals↗
PubMed1979

Voltage dependence of junctional conductance in early amphibian embryos.

Isolated pairs of blastomeres from early amphibian embryos (Ambystoma, Rana, Xenopus) are electrontonically coupled. Junctional conductance and permeability to the dye Lucifer Yellow are markeldy and reversibly decreased by moderate transjunctional polarization in either direction. The relationship between junctional conductance and transjunctional voltage is sufficiently steep that a physiological role in regulation of intercellular communication is plausible.

Ambystoma↗
PubMed1993

Intercellular calcium signaling induced by extracellular adenosine 5'-triphosphate and mechanical stimulation in airway epithelial cells.

Airway epithelial cells in culture respond to extracellular adenosine 5'-triphosphate (ATP) by increasing their intracellular Ca2+ concentration ([Ca2+]i). The effective concentration of ATP that elicited a Ca2+ response equal to 50% of the maximal response (EC50) was 0.5 microM. Release of ATP from a pipette to form a local gradient of ATP increased [Ca2+]i of individual cells in a sequential manner. Cells closest to the pipette showed an immediate increase in [Ca2+]i while more distal cells displayed a delayed increase in [Ca2+]i. This response to the local release of ATP appeared as a wave of increasing [Ca2+]i that spread to several cells and, in this respect, was similar to the intercellularly communicated Ca2+ waves initiated by mechanical stimulation in airway epithelial cells (Sanderson et al., Cell Regul. 1, 585-596, 1990). In the presence of a unidirectional fluid flow, the Ca2+ response to a local release of ATP was biased such that virtually all the cells responding with an increase in [Ca2+]i were downstream of the release site. By contrast, an identical fluid flow did not bias the radial propagation of intercellular Ca2+ waves induced by mechanical stimulation. Suramin, a P2-purinergic receptor antagonist, did attenuate the Ca2+ response induced by ATP but did not block the propagation of mechanically induced Ca2+ waves. Cells from young cultures (3-5 days) or those at the leading edge of an outgrowth elevated their [Ca2+]i in response to ATP. However, these cells do not respond to mechanical stimulation by the propagation of a Ca2+ wave. From these results we conclude that the intercellular Ca2+ waves elicited by mechanical stimulation are not the result of ATP or another compound released from the stimulated cell, diffusing through the extracellular fluid. This conclusion is consistent with previous experimental evidence suggesting that intercellular Ca2+ signaling in epithelial cells is mediated by the movement of inositol trisphosphate through gap junctions.

Adenosine Triphosphate↗
PubMed1999

Interactions between growth factors and gap junctional communication in developing systems.

In the vertebrate limb bud fibroblast growth factor (FGF) 4 secreted by cells of the posterior apical ectodermal ridge controls digit pattern, which is directed by polarizing cells in the posterior mesenchyme at the tip of the bud. FGF4 also controls the expression of gap junctions in the limb. Both chick and mouse limb bud mesenchyme express connexin 32 (Cx32; beta 1) and Cx43 (alpha 1), although not in the same gap junction plaques. Quantitative analysis reveals two gradients of gap junctions: from posterior to anterior in the subapical mesenchyme and from distal to proximal along the bud. The highest gap junction density is associated with the polarizing region. Micromass cultures of chick and mouse posterior and anterior mesenchyme cells were used to assess the ability of FGF4 to modulate gap junctional communication. Posterior mesenchyme (polarizing region) cells express a population of gap junctions that are highly sensitive to FGF4, whereas gap junctions between anterior mesenchyme cells are completely insensitive to FGF4. FGF4 doubles gap junction density, intercellular communication and the polarizing capacity of posterior mesenchyme cells, restoring polarizing capacity to in vivo levels. We conclude that gap junctional communication and polarizing capacity are intimately linked. Interactions between signalling molecules and junctional communication may play an important role in controlling development.

Amphibians↗
PubMed1993

Neurotransmitters as growth regulatory signals: role of receptors and second messengers.

In the adult nervous system, neurotransmitters act as chemical mediators of intercellular communication by the activation of specific receptors and second messengers in postsynaptic cells. This specialized role may have evolved from more primitive functions in lower organisms where these substances were used as both intra- and intercellular signalling devices. This view derives from the finding that a number of 'classical' neurotransmitters are present in primitive organisms and early embryos in the absence of a nervous system, and pharmacological evidence that these substances regulate morphogenetic activities such as proliferation, differentiation, cell motility and metamorphosis. These phylogenetically old functions may be reiterated in the developing nervous system and in the humoral functions of neurotransmitters outside the nervous system. This review will provide evidence for this hypothesis based on the commonality of signal transduction mechanisms used in primitive organisms, early embryos and non-neuronal cells, and relate these relationships to the functions of neurotransmitters in the developing nervous system. This discussion has generally been limited to neurotransmitters where non-neuronal functions have been studied and information regarding the involvement of receptors and second messenger pathways is available.

Animals↗