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PubMed1982

Direct communication of homologous and heterologous endocrine islet cells in culture.

The transfer of 6-carboxyfluorescein between islet cells in monolayer culture was observed by fluorescence microscopy, and the endocrine cells involved in this transfer were identified by immunohistochemistry and electron microscopy. The results show that carboxyfluorescein was directly exchanged between homologous B-cells and also between B- and A- or D-cells. Successive microinjections of the probe into different cells of the same cluster showed the existence of separate territories, each formed by 2-8 communicating cells. Intercellular communication was not observed after every dye microinjection, and communicating and noncommunicating islet cells were found to coexist within the same cluster. The data indicate that the exchange of exogenous cytoplasmic molecules occurs between different types of endocrine islet cells. However, within a single cluster, all islet cells are not metabolically coupled to one another, at a given time.

Animals↗
PubMed1997

Cytokine signal networks and a new era in biomedical research.

Elucidation of the biochemical nature of the signal transduction pathway that regulate transcription and replication is the focus of attention in molecular biology. This research may make feasible manipulation of growth and differentiation of mammalian cells, which in turn would have profound implication in biomedical research on cell and gene therapy, and development of pharmaceutical products. Cytokines control growth, differentiation, death, and function of cells of lymphocytic, hemopoietic systems, and together with nerve cells provide a pertinent model to study intercellular communications and intercellular signal networks. This review outlines general features of signal transduction and several aspects of cytokine networks are discussed with emphasis on: transcriptional regulation of Th1 and Th2-specific cytokine genes in T cells, the roles of cytokines and their receptors in growth and differentiation of hemopoietic cells, and the manipulation of cytokine networks.

Animals↗
PubMed1997

[Cytokines and their receptors].

Cytokines control growth, differentiation, and function of cells of lymphocytic, hemopoietic systems and provide a pertinent model to study intercellular communications and intercellular signal networks. Cytokines have key properties that shape the nature of the network. 1) A single cytokine has multiple biological activities (pleiotropy). 2) Multiple cytokines have overlapping activities(redundancy). 3) A single cell interacts with multiple cytokines with seemingly identical responses(cross-talk). Gene cloning of cytokines and their receptors provide knowledge to understand molecular mechanisms of these phenomena. Within recent studies of modification of the cytoplasmic region of the cytokine receptor or the signaling molecules, it will become possible to apply these molecules for therapeutic purposes.

Animals↗
PubMed1993

An improved long-term culture of rat hepatocytes to detect liver tumour-promoting agents: results with phenobarbital.

Among various cocultures of hepatocytes with other cell types, we found that mouse embryonal cells (BALB/c 3T3) are more effective in maintaining rat hepatocytes in vitro. Because most human cancers are epithelial in origin, we thought that such a hepatocyte culture system could be used for the detection of tumour-promoting agents, most of which are inhibitors of gap-junctional intercellular communication. We, therefore, have examined the effect of the strong rat liver tumour promoter, phenobarbital, on the gap-junctional intercellular communication capacity of hepatocytes in long-term cultures. A single application of phenobarbital drastically inhibited the gap-junctional intercellular communication between hepatocytes in a coculture for only several hours, but treatment for 3 weeks provoked a constant decrease of gap-junctional intercellular communication (50%) throughout the treatment period. This type of long-term culture of rat hepatocytes may be usable in a rapid in vitro assay to detect tumour-promoting agents.

Albumins↗
PubMed1988

Loss of intercellular junctional communication correlates with metastatic potential in mammary adenocarcinoma cells.

A series of rat 13762NF mammary adenocarcinoma cell sublines and clones of various spontaneous pulmonary metastatic potentials from the mammary fat pads of syngeneic rats were examined for their intercellular junctional communication. Using the scrape-loading dye-transfer technique to introduce Lucifer yellow (Mr 457) into cells, we measured the abilities of 13762NF cells to transfer dye to adjacent cells. There was an excellent correlation between loss of Lucifer yellow dye transfer and spontaneous metastatic potential (average total volume of lung metastases inversely correlated to % cells coupled, r = 0.93; average total number of lung metastases inversely correlated to % cells coupled, r = 0.91). The data suggest that high metastatic potentials are closely correlated with loss of intercellular junctional communication in these malignant mammary tumor cells.

Adenocarcinoma↗
PubMed2005

In vitro response of tumour cells to non-uniform irradiation.

This study examines differences in tumour cellular response using clonogenic cell survival between uniform and non-uniform irradiation. Cells were irradiated with a 6 MV x-ray intensity-modulated beam, in a single large flask (i.e. intercellular communication is possible) or in three small flasks (i.e. intercellular communication is inhibited across the dose gradient). For non-small-cell lung cancer and melanoma cell lines, the dose response over the entire cell culture was significantly different between freely communicating cell cultures and those with inhibited communication across the dose non-uniformity. Communicating cells exhibited poorer survival in the low dose region of the field but improved survival in the high dose region. In general, the response to non-uniform irradiation appeared to 'average out' over the entire cell culture. This was not seen when intercellular communication was inhibited. The results add strength to the body of evidence regarding bystander effects and the inter-dependence of cellular response.

Carcinoma, Large Cell↗
PubMed1999

Cell-to-cell communication and expression of gap junctional proteins in human diabetic and nondiabetic skin fibroblasts: effects of basic fibroblast growth factor.

Wound healing involves the interactions of many cell types, and is controlled in part by growth factors. Intercellular communication mediated by gap junctions is considered to play an important role in the coordination of cellular metabolism duringthe growth and development of tissues and organs. Basic fibroblast growth factor (bFGF), known to be important in wound healing, has been found to increase Cx43 expression and intercellular communication in endothelial cells and cardiac fibroblasts. It has been proposed that an increased coupling is necessary for the coordination of these cells in wound healing and angiogenesis, and that one of the actions of bFGF is to modulate intercellular communication. The aim of our study was to evaluate the effects of bFGF on gap junctional intercellular communication (GJIC) in vitro, and the presence of gap junctional proteins connexin (Cx) 26, Cx32, and Cx43 in fibroblasts of diabetic and nondiabetic individuals. Fibroblast cell lines (n = 10) were cultured for 3 d in serum-free media with or without bFGF (3 ng/mL). Cells were evaluated for the rate of GJIC by using laser cytometry, and for the presence of Cx26, Cx32, and Cx43 by immunohistochemical and Western analyses. All cell types communicated via contact-dependent mechanisms. The rate of GJIC was greater (p < 0.01) for diabetic than for nondiabetic fibroblasts (4.1 +/- 0.01 vs 3.3 +/- 0.01%/min). bFGF increased (p < 0.01) the rate of GJIC for diabetic (4.9 +/- 0.01 vs 4.1 +/- 0.01%) and nondiabetic (4.1 +/- 0.01 vs 3.3 +/- 0.01%) fibroblasts. Immunohistochemistry identified Cx26 in the cytoplasm, Cx32 was not detected, and Cx43 was present on the cellular borders in all cultures. Image analysis of immunofluorescent staining demonstrated that bFGF increased (p < 0.05) Cx43 expression in diabetic and nondiabetic fibroblasts. Western immunoblot analysis revealed bands at 43-46 kD that were similar in volume for diabetic and nondiabetic fibroblasts. Thus, gap junctions involving Cx43 and GJIC among fibroblasts appear to be targets for bFGF. Fibroblasts of diabetic individuals appear to have an increased rate of cell-cell coupling, correlating with a decreased rate of proliferation.

Adult↗
PubMed1991

Aberrant expression and function of gap junctions during carcinogenesis.

Gap junctional intercellular communication plays a key role in the maintenance of homeostasis in multicellular organisms. Reflecting deranged homeostasis in cancer cells, most transformed or cancerous cells show aberrant gap junctional intercellular communication; they have decreased junctional communication between each other and/or with surrounding normal cells. Studies with in vitro cell transformation and animal carcinogenesis models suggest an involvement of blocked intercellular communication in later stages of carcinogenesis. Analysis of expression of gap junction proteins (connexins) and corresponding mRNA indicates that a number of regulation sites are involved in aberrant function of gap junctions during carcinogenesis. Suppression of transformed phenotypes is often seen when transformed cells are physically in contact with their normal counterparts. Some studies suggest that gap junctional intercellular communication is involved in such tumor suppression.

3T3 Cells↗
PubMed2002

Downregulation of connexin 43 expression by high glucose reduces gap junction activity in microvascular endothelial cells.

Impairment of retinal vascular homeostasis is associated with the development and progression of diabetic retinopathy involving gap junction intercellular communication (GJIC) activity. The principal gap junction protein of intercellular communication, connexin, was investigated to determine the effects of high glucose concentrations on the expression of endothelial-specific connexins (Cx37, Cx40, and Cx43), connexin phosphorylation pattern, and GJIC activity. Rat microvascular endothelial (RME) cells grown in high (30 mmol/l)-glucose medium for 9 days had reduced Cx43 expression: Cx43 mRNA (68 +/- 13% of control; P = 0.019, n = 5) and protein (55.6 +/- 16% of control; P = 0.003, n = 5) levels were reduced; however, Cx37 and Cx40 expression was not affected. Using alkaline phosphatase and Western blot analyses, we identified three forms of Cx43: a nonphosphorylated form (P0) and two phosphorylated forms (P1 and P2). Expression of all three forms was decreased in cells grown in high-glucose medium: PO, 73 +/- 15% of control (P = 0.04); P1, 57 +/- 16% of control (P = 0.01); and P2, 42 +/- 22% of control (P = 0.006). Using immunofluorescence microscopy, we observed Cx43 localization at specific sites of contact (plaques) between adjacent cells. In cells grown in high-glucose medium, we observed reduced plaque counts (63 +/- 6% of control; P = 0.009) and decreased intensity of Cx43 immunofluorescence compared with cells grown in normal medium. Furthermore, using scrape load dye transfer (SLDT) technique, we found that these cells exhibited reduced GJIC activity (60% of control; P = 0.01, n = 5). The reduction in GJIC activity correlated with the decreased Cx43 protein levels (r = 0.9). These results indicate that high glucose concentrations inhibited GJIC activity by reducing Cx43 synthesis in RME cells. Impaired intercellular communication may contribute to breakdown of homeostatic balance in diabetic microangiopathy.

Adipose Tissue↗
PubMed2002

Alterations in gap junction protein expression in human benign prostatic hyperplasia and prostate cancer.

PURPOSE: Gap junctions composed of connexin proteins have an essential role in intercellular communication and differentiation. Dysregulation of connexin expression is believed to have a role in carcinogenesis. The human prostate has been reported to express connexin 32 and 43. However, the expression pattern in prostate cancer is controversial, while to our knowledge connexin expression has not been reported in benign prostatic hyperplasia (BPH). To understand the potential involvement in prostate disease connexin 32 and 43 expression was evaluated in a series of normal prostate, BPH and prostate cancer specimens that were surgically removed due to bladder outlet obstruction. MATERIALS AND METHODS: Frozen sections of 23 normal, 43 BPH and 40 cancer involved prostates were evaluated for the presence, staining intensity and pattern of connexin 32 and 43 by immunocytochemical testing. RESULTS: In all specimens examined connexin 43 stain was punctate along the borders of the basal epithelial cells, whereas connexin 32 immunolocalized to luminal epithelial cells. In normal prostate connexin 43 and 32 were present in 87% and 65% of specimens, respectively, at low to moderate stain intensity. Importantly none of the normal samples were negative foreach connexin. In BPH specimens there was a marked increase in the incidence and intensity of connexin 43 and 32 immunostaining within epithelial cells. In addition, 23% of BPH samples showed strong connexin 43 expression in stromal cells. In contrast, connexin was decreased in prostate cancer specimens, of which 65% and 38% were negative for connexin 43 and 32, respectively, and 28% were negative for each type. In poorly differentiated tumors connexin 43 and 32 were present in only 10% and 40% of tumors, respectively, at low immunostaining intensity. CONCLUSIONS: In normal human prostate basal cells communicate via connexin 43 gap junctions, whereas luminal cells communicate via connexin 32 gap junctions. In BPH gap junctional intercellular communication is increased in epithelial and stromal cells, which may have a role in BPH pathogenesis. In prostate cancer gap junctional intercellular communication is decreased, is as indicated by decreased expression of connexin 43 and 32 with severe loss in poorly differentiated prostate cancer. These alterations in connexin expression may have a role in dedifferentiation and tumor progression.

Adenocarcinoma↗
PubMed2001

Alterations in gap junction protein expression in human benign prostatic hyperplasia and prostate cancer.

PURPOSE: Gap junctions composed of connexin proteins have an essential role in intercellular communication and differentiation. Dysregulation of connexin expression is believed to have a role in carcinogenesis. The human prostate has been reported to express connexin 32 and 43. However, the expression pattern in prostate cancer is controversial, while to our knowledge connexin expression has not been reported in benign prostatic hyperplasia (BPH). To understand the potential involvement in prostate disease connexin 32 and 43 expression was evaluated in a series of normal prostate, BPH and prostate cancer specimens that were surgically removed due to bladder outlet obstruction. MATERIALS AND METHODS: Frozen sections of 23 normal, 43 BPH and 40 cancer involved prostates were evaluated for the presence, staining intensity and pattern of connexin 32 and 43 by immunocytochemical testing. RESULTS: In all specimens examined connexin 43 stain was punctate along the borders of the basal epithelial cells, whereas connexin 32 immunolocalized to luminal epithelial cells. In normal prostate connexin 43 and 32 were present in 87% and 65% of specimens, respectively, at low to moderate stain intensity. Importantly none of the normal samples were negative foreach connexin. In BPH specimens there was a marked increase in the incidence and intensity of connexin 43 and 32 immunostaining within epithelial cells. In addition, 23% of BPH samples showed strong connexin 43 expression in stromal cells. In contrast, connexin was decreased in prostate cancer specimens, of which 65% and 38% were negative for connexin 43 and 32, respectively, and 28% were negative for each type. In poorly differentiated tumors connexin 43 and 32 were present in only 10% and 40% of tumors, respectively, at low immunostaining intensity. CONCLUSIONS: In normal human prostate basal cells communicate via connexin 43 gap junctions, whereas luminal cells communicate via connexin 32 gap junctions. In BPH gap junctional intercellular communication is increased in epithelial and stromal cells, which may have a role in BPH pathogenesis. In prostate cancer gap junctional intercellular communication is decreased, is as indicated by decreased expression of connexin 43 and 32 with severe loss in poorly differentiated prostate cancer. These alterations in connexin expression may have a role in dedifferentiation and tumor progression.

Adenocarcinoma↗
PubMed2002

Gap junction synthesis and degradation as therapeutic targets.

The synthesis and the degradation of gap junctions involve multiple steps that may provide targets for the modulation of intercellular communication. Many studies using cultured cells have examined the effects of inhibitors of protein synthesis, trafficking, or degradation upon connexins. Similarly, activators or inhibitors of various protein kinases have been shown to affect connexin assembly or proteolysis. These studies have helped to elucidate the connexin life-cycle. But, because of their lack of specificity for gap junction proteins, these agents would be expected to have limited therapeutic utility and to produce several deleterious side effects. However, more selective agents are being developed based on specific features of the connexin sequences. Molecular genetic approaches have been used to introduce wild-type connexins to increase intercellular communication in otherwise poorly coupled cells. Decreased intercellular communication may be obtained by application of peptides that mimic the extracellular loops and may prevent docking of hemi-channels. Alternatively, introducing mutant connexins that interfere with the oligomerization/export of endogenous connexins or with channel function by formation of non-functional heteromeric hemi-channels can also reduce intercellular communication.

Animals↗
PubMed1998

Targeting and modification of prokaryotic cell-cell junctions by tobacco mosaic virus cell-to-cell movement protein.

The movement protein (MP) of tobacco mosaic virus (TMV) facilitates the cell-to-cell spread of infection by altering the structure and function of plasmodesmata, the intercellular communication channels in plants. Because the protein was shown to interfere with intercellular communication when expressed in the cyanobacterium Anabaena sp. strain PCC 7120, whether the ability of the protein to target and to modify intercellular communication channels in plants is conserved in this prokaryote was investigated. It was found that the MP localizes to the cell junctions and induces the formation of filamentous structures that traverse the septa. It is proposed that the protein interacts with host components that are similar between plants and Anabaena and that may be evolutionarily related. The observations in Anabaena suggest that the MP modifies plasmodesmata by forming a filamentous aggregate within the pore.

Cell Communication↗
PubMed2002

Dupuytren's disease: physiologic changes in nodule and cord fibroblasts through aging in vitro.

The pathogenesis of the fibrotic disease Dupuytren's contracture remains unclear. The disease process includes two structurally distinct fibrotic elements, the nodule and the cord. It has been proposed that as the disease progresses, nodules develop into cords. To corroborate that hypothesis, the authors took advantage of cultured fibroblast differences found between gap junction intercellular communication and fibroblast-populated collagen lattice contraction. Paired fibroblast cell lines of nodules and cords derived from four patients with Dupuytren's disease were maintained in culture for at least eight passages. The presence of gap junction intercellular communication in nodule- and cord-derived fibroblasts was documented and reported as a coupling index. The contraction of free-floating nodule- or cord-derived collagen lattices was also documented and reported. Early passage (passage 4) cord-derived fibroblasts showed a significant increase in coupling index compared with passage 4 nodule-derived fibroblasts (4.0 +/- 0.4 versus 2.5 +/- 0.3, respectively), where p < or = 0.01. However, late passage (passage 8) nodule- and cord-derived fibroblasts were equivalent in their coupling index (4.1 +/- 0.4 versus 4.4 +/- 0.4, respectively). Early passage nodule-derived fibroblast-populated collagen lattices contracted by 64 percent, whereas late passage nodule-derived lattices showed less contraction, at only 40 percent. Early and late passage cord-derived lattices contracted 46 and 37 percent, respectively. All nodule- and cord-derived cell lines were statistically equivalent at lattice contraction by passage 8. These in vitro studies support the hypothesis that fibroblasts derived from Dupuytren's contracture nodules change their phenotype after undergoing repeated cell passage, acquiring a cord-like fibroblast phenotype. Dupuytren's nodules represent the early, active form of fibrosis in which cells are more proliferative, better at fibroblast-populated collagen lattice contraction, and display less gap junction intercellular communication. The speculation is that alterations in gap junction intercellular communication may be involved in the progression of Dupuytren's nodules to cords as the disease progresses.

Cell Communication↗
PubMed1999

Peroxynitrite diminishes gap junctional communication: protection by selenite supplementation.

Loss of intercellular communication via gap junctions has been correlated with progression of cells to a malignant phenotype. Here, we show that peroxynitrite, a mediator of toxicity in inflammatory processes, diminishes gap junctional intercellular communication (GJIC) in WB-F344 rat liver epithelial cells, assayed by the scrapeloading dye-transfer technique as well as by microinjection of a fluorescent dye into single cells. Exposure of cultured cells to a steady-state concentration of peroxynitrite of 1.6 microM for 4 min or to 3-morpholinosydnonimine (SIN-1) at 0.5 mM strongly diminished GJIC. These concentrations of peroxynitrite or SIN-1 were not cytotoxic. When cells were grown in a medium supplemented with sodium selenite (0.1-1 microM) for 72 h, substantial protection was afforded against the decrease in GJIC by peroxynitrite. Thus, peroxynitrite can disrupt GJIC, and selenium-containing proteins protect.

Animals↗
PubMed1987

Characterization of a rat liver epithelial cell line to detect inhibitors of metabolic cooperation.

A normal rat liver epithelial cell line, with phenotype characteristics of "oval" cells (WB-F344), was examined for its ability to perform gap-junctional intercellular communication as measured by metabolic cooperation. To test for gap-junctional intercellular communication, 6-thioguanine-sensitive cells were cocultivated with 6-thioguanine-resistant cells. It was found that the recovery of 6-thioguanine-resistant cells depended on the densities of the 6-thioguanine-sensitive cells. Higher densities of 6-thioguanine-sensitive cells reduced the recovery of 6-thioguanine-resistant cells. These observations demonstrate that rat liver epithelial cells could metabolically cooperate, implying they could perform gap-junctional intercellular communication. Two tumor-promoting organochlorine pesticides, aldrin and dieldrin, were potent inhibitors of metabolic cooperation for these cells, but 12-0-tetradecanoyl-phorbol-13-acetate and teleocidin, known mouse skin tumor promoters, were not significantly effective in inhibiting metabolic cooperation. The results suggest that these cells might provide the basis for an in vitro assay specifically to study liver tumor promoters.

Animals↗
PubMed1998

Sequence-specific antibodies to connexins block intercellular calcium signaling through gap junctions.

Mechanical stimulation of a single cell in primary airway epithelial cell cultures induces an intercellular Ca2+ wave that has been proposed to be mediated via gap junctions. To investigate directly the role of gap junctions in this multicellular response, the effects of intracellularly-loaded sequence-specific connexin (gap junction) antibodies on the propagation of intercellular Ca2+ waves were evaluated. Electroporation of antibodies to the cytosolic loop (Des 1, generated to amino acids 102-112 + 116-124; and Des 5, amino acids 108-119), or to the carboxyl tail (Gap 9, amino acids 264-283) of connexin 32 inhibited the propagation of intercellular Ca2+ waves. The inhibitory effect of Des 1 antibody was competitively reversed by the co-loading of a peptide derived from a similar cytosolic loop sequence (Des 5 peptide). Conversely, the inhibitory effects on intercellular Ca2+ wave propagation of Gap 9 antibody was not altered by co-loading with the Des 5 peptide. Antibodies raised to peptide sequences within the extracellular loop (Gap 11, amino acids 151-187), or the cytoplasmically located amino terminus (Gap 10, amino acids 1-21) of connexin 32 did not inhibit mechanically-induced intercellular communication. Also ineffective in perturbing intercellular communication were antibodies raised to peptide sequences of the cytosolic loops of connexin 43 (Gap 15, amino acids 131-142) or connexin 26 (Des 3, amino acids 106-119). These data suggest that mechanically-induced Ca2+ waves in airway cell cultures are propagated through gap junctions made up of connexin 32 proteins.

Amino Acid Sequence↗
PubMed1985

Potential role of the src gene product in inhibition of gap-junctional communication in NIH/3T3 cells.

The effects of the src gene on the activity of protein kinase C and intercellular communication have been studied in transformed NIH/3T3 clones isolated from soft agar following transfection with the plasmid carrying the v-src gene (psrc-11). Six transformed clones that were studied contained newly incorporated v-src genes in the genome, had an increased amount of pp60src, and showed enhanced activities of protein kinase C. Intercellular communication, studied by observing with autoradiography the transfer of [3H]uridine nucleotide from prelabeled donor cells to recipient cells in contact, was found to be reduced in transformed clones as compared to parental NIH/3T3 cells. Treatment with phorbol 12-myristate 13-acetate was also found to increase protein kinase C activity and to reduce intercellular communication in normal NIH/3T3 cells. These results suggest that the v-src gene product, in a manner similar to some of the powerful tumor promoters, may directly or indirectly affect cell-cell communication.

Animals↗