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At least 667 records · Page 37Linked to original sources
PubMed1975

Cell-mediated immunity to Moloney sarcoma virus in mice. II. Analysis of antigenic specificities involved in T lymphocyte-mediated in vivo rejection of murine sarcoma virus-induced tumors.

Sublethally irradiated BALB/c mice innoculated with Moloney sarcoma virus (MSVm) develop progressively growing tumors and die within 30 days of virus innoculation. These animals can be protected from tumor progression (and death) by innoculation of small numbers of MSV-immune T lymphocytes from MSV-M innoculated (but unirradiated) animals. T lymphocytes in these donor animals have been shown to express immunity to a variety of viral and virally-induced antigens. We have investigated whether immunity to any one of these antigens was critically important in leading to protection of the irradiated animals by sensitizing normal T lymphocytes in vitro to different viral antigens and examining the ability of these sensitized cells to protect the irradiated recipients. Data is presented to show that cells sensitized in vitro to MSV-transformed fibroblasts, and to purified antigens with group specificity, but not to viral envelope antigens, or whole virus, are capable of protecting the irradiated MS innoculated animals.

Animals↗
PubMed1992

Interleukin-4 differentially regulates interleukin-2-mediated and CD2-mediated induction of human lymphokine-activated killer effectors.

Natural killer (NK) cells can be differentiated into lymphokine-activated killer (LAK) effectors following stimulation with interleukin (IL)-2. This induction can be negatively regulated by IL-4. In this study, we demonstrate that the stimulation of NK cells through the CD2 pathway with (9-1 + 9.6) monoclonal antibodies can also induce these cells to secrete tumor necrosis factor-alpha (TNF-alpha) and to differentiate into LAK effectors. More importantly, our data indicate that, in contrast to the IL-2-induced LAK generation, the anti-CD2-triggered LAK activity was not regulated by IL-4. IL-4 was found to enhance the LAK activity as well as NK cell proliferation following activation with anti-CD2 by a mechanism involving, at least in part, an increased TNF-alpha production. Using immobilized monoclonal antibodies against the Fc receptor (Fc gamma RIII or CD16) for NK stimulation, we also observed that the anti-CD16-induced LAK activity was not inhibited by IL-4. These data further point to a pivotal role of TNF-alpha as a regulatory cytokine in anti-CD2-induced LAK generation, and suggest that IL-4 could serve as a discriminatory factor between two distinct pathways involved in the activation of non-MHC-restricted cytotoxicity.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2003

T-cell cytotoxicity of human Schwann cells: TNFalpha promotes fasL-mediated apoptosis and IFN gamma perforin-mediated lysis.

The ability of resident cells to induce apoptosis of invading immune cells is a major regulatory factor operating in immune-privileged tissues, including the nervous system. We investigated the cellular and molecular factors participating in modulation of immune response in peripheral nerves, focusing on two cytotoxic pathways: fas ligand (fasL) and perforin. fasL and perforin expression was found by immunochemistry on Schwann cells (Sc) in nerve biopsies from patients with chronic inflammatory demyelinating polyneuritis and on human Sc cultures. Treatment of Sc with tumor necrosis factor (TNF) alpha and interferon (IFN) gamma upregulated the expression of both molecules. In a coculture model, Sc exposed to TNFalpha or IFN gamma were able to induce both apoptotic and lytic injury of T-lymphocytes. Inactivation of fasL with the neutralizing antibody NOK-2 abolished T-cell apoptosis induced by Sc treated with TNFalpha, but not by Sc treated with IFN gamma. Conversely, T-cell lysis was significantly decreased when IFN gamma-activated Sc were treated with concanamycin A, which inhibited perforin release. At variance with T-lymphocytes, B-cells were less sensitive to cytokine-treated Sc toxicity. Thus, Sc exposed to inflammatory cytokines have the capacity of inducing selective damage of T-lymphocytes and have the potential of regulating the immune response in the peripheral nervous system.

Apoptosis↗
PubMed1980

Non-T-cell-mediated cytotoxicity in MSV tumor-bearing mice. III. Macrophage-mediated cytotoxicity against autochthonous MSV tumor-isolated target cells.

Cytotoxic macrophages have been isolated from Moloney sarcoma virus (MSV) tumors induced in uncompromised, immunosuppressed and athymic nude mice. Macrophages from compromised mice were at least as active as those from uncompromised mice when tested against the autochthonous MSV target cells. Although both cytolytic and cytostatic activity could be demonstrated with all tumor-derived macrophages, cytostatic and cytolytic effects could be distinguished from each other only at high effector target-cell ratios. A variety of target cells were compared for sensitivity to the various tumor-associated macrophages. The autochthonous virus-infected MSV-target cells appeared to be more sensitive to the macrophage effects than fastgrowing, established cell lines. Normal embryo fibroblasts were only slightly affected. Peritoneal exudate cells from tumor-bearers were much less active than either the tumor-isolated macrophages or bone-marrow culture-derived macrophages. Both were more active than control peritoneal cells. Although no quantitative or qualitative differences in macrophage activity could be detected in mice with regressing lesions and immuno-compromised mice with progressing lesions, the ratio of macrophages to "sarcoma" cells was three to five times higher in regressing tumors.

Animals↗
PubMed2005

Inhibition of extracellular signal regulated kinase (ERK) leads to apoptosis inducing factor (AIF) mediated apoptosis in epithelial breast cancer cells: the lack of effect of ERK in p53 mediated copper induced apoptosis.

Recent studies have shown that MEK/ERK-mediated signals play a major role in regulation of activity of p53 tumor suppressor protein. In this study, we investigated whether or not there is functional interaction between p53 and MEK/ERK pathways in epithelial breast cancer cells exposed to copper or zinc. We demonstrated that expression of wild-type p53 induced by copper or zinc significantly reduced phosphorylation of extracellular signal regulated kinase (ERK) in epithelial breast cancer MCF7 cells. Mutation or suppression of p53 in MDA-MB231 and MCF7-E6 cells, respectively, resulted in a strong ERK phosphorylation in the presence of metals. Weak ERK phosphorylation in MCF7 cells induced by copper or zinc was linked to mitochondrial disruption and apoptosis. Furthermore, inhibition of ERK through addition of PD98059 stimulated p53 activation in MCF7 cells and also led to upregulation of p53 downstream targets, p21 and Bax, which is a proapototic member of Bcl-2 family triggering mitochondrial pore opening. Moreover, blockage of the MEK/ERK pathway caused a breakdown of the mitochondrial membrane potential accompanied by an elevation in the ROS production. Disruption of p53 expression attenuated the depolarization of the mitochondrial membrane and ROS generation. Furthermore, PD98059 initiated apoptosis inducing factor (AIF) translocation from mitochondria to the nucleus in MCF7 cells; which are depleted in caspase 3. Interestingly, repression of MEK/ERK pathway did not intensify the cell stress caused by metal toxicity. Therefore, these findings demonstrate that MEK/ERK pathway plays an important role in downregulation of p53 and cell survival. Inhibition of ERK can lead to apoptosis via nuclear relocation of AIF. However, metal-induced activation of p53 and mitochondrial depolarization appears to be independent of ERK. Our data suggest that copper induces apoptosis through depolarization of mitochondrial membrane with release of AIF, and this process is MEK/ERK independent.

Apoptosis↗
PubMed2006

1Alpha,25-dihydroxyvitamin D3-mediated stimulation of steroid sulphatase activity in myeloid leukaemic cell lines requires VDRnuc-mediated activation of the RAS/RAF/ERK-MAP kinase signalling pathway.

1Alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) stimulates the activity of steroid sulphatase (STS) in myeloid cells [Hughes et al., 2001, 2005]. This was attenuated by inhibitors of phospholipase D (PLD) (n-butanol, 2,3-diphosphoglyceric acid, C(2)-ceramide) and phosphatidate phosphohydrolase (PAP) (propranolol and chlorpromazine), but was unaffected by inhibitors of phospholipase C. The 1alpha,25(OH)(2)D(3)-induced STS activity was also attenuated by inhibitors of protein kinase Calpha and protein kinase Cdelta (Go 6976, HBDDE and rottlerin), but not by an inhibitor of protein kinase Cbeta (LY379196). Additionally, 1alpha,25(OH)(2)D(3)-induced STS activity was attenuated by inhibitors of RAS (manumycin A), RAF (GW5074), MEK (PD098059 and U1026) and JNK (SP600125), but not p38 (PD169316). 1alpha,25(OH)(2)D(3) produced a rapid and long lasting stimulation of the ERK-MAP kinase signalling cascade in HL60 myeloid leukaemic cells. This 'non-genomic' effect of 1alpha,25(OH)(2)D(3) blocked by pharmacological antagonists of nuclear vitamin D receptors (VDR(nuc)) and does not appear to require hetero-dimerisation with the retinoid-X receptor (RXR). Inhibitors of the Src tyrosine kinase (PP1), RAS (manumycin A), RAS-RAF interactions (sulindac sulphide and RAS inhibitory peptide), RAF (GW5074 or chloroquine), and protein kinase Calpha (HBDDE) abrogated the 1alpha,25(OH)(2)D(3)-stimulated increase in ERK-MAP kinase activity. Taken together, these results show that 1alpha,25(OH)(2)D(3)/VDR(nuc) activation of the RAS/RAF/ERK-MAP kinase signalling pathway plays an important role in augmenting STS activity in human myeloid leukaemic cell lines.

Calcium Signaling↗
PubMed1976

Excitation-mediating and inhibition-mediating dopamine-receptors: a new concept towards a better understanding of electrophysiological, biochemical, pharmacological, functional and clinical data.

A great number of earlier reported experimental data dealing with the role of dopamine in dopamine-loaded structures within the mammalian brain have raised questions concerning the concept of dopamine as an inhibitory agent acting on one type of receptor. A critical review of the anatomical, histochemical, electrophysiological, pharmacological and functional studies reveals that the dopamine-loaded structures are marked by an internal differentiation at various levels. It is attempted to demonstrate that this is due to a heterogeneous distribution of two distinct types of dopamine-receptors, each characterized by their own properties: DAe and DAi-receptors. Furthermore, the experimental and clinical implications are discussed in view of the hypothesis that balance between both types of receptors is essential for normal psychomotor functioning.

Amphetamines↗
PubMed1984

Adriamycin inhibits PTH-mediated but not PGE2-mediated stimulation of cyclic AMP formation in isolated bone cells.

We have examined the effect of adriamycin, an anthracycline antibiotic which modifies plasma membrane functions, on the cyclic AMP response to PTH and PGE2 in isolated osteoblastlike cells. Adriamycin blunted the increment in bone cell cyclic AMP caused by exposure to PTH. This effect appeared rapidly (within 3 min after bone cells were exposed to adriamycin) and disappeared soon after exposure of adriamycin-treated cells to adriamycin-free incubation medium. Inhibition was evident over the entire time course of PTH action, at low as well as high PTH concentrations, and was one-half maximal at 31 microM adriamycin. It could not be attributed to alterations in cyclic AMP exodus, degradation or interference with the cyclic AMP assay, nor to impaired cell viability. Adriamycin also reduced the stimulatory effect of PTH on adenylate cyclase activity in a crude plasma membrane preparation. By contrast, adriamycin failed to modify the effects of PGE2 on cyclic AMP generation in intact bone cells, and on adenylate cyclase activity in broken cells. Moreover, concentrations of adriamycin that blunted the effect of PTH on adenylate cyclase activity did not inhibit the stimulatory effects of sodium fluoride or of GppNHp. These results suggest that adriamycin selectively alters the interaction between PTH and its receptor or impairs the transmission of information from hormone-receptor complex to adenylate cyclase (or both), perhaps by binding to specific lipid domains in the plasma membrane. Structural analogues of adriamycin, which vary in their lipophilic properties, also varied in their capacity to perturb the cyclic AMP response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed2003

Insulin-mediated capillary recruitment in skeletal muscle: is this a mediator of insulin action on glucose metabolism?

The possibility that insulin stimulates microvascular access for itself and glucose in muscle in vivo is discussed. The application of new techniques suggests that capillary recruitment is a normal part of insulin's action and that this process becomes impaired in insulin resistance. Exercise, which also leads to capillary recruitment, may involve a different mechanism than that used by insulin.

Animals↗
PubMed1985

Differential effects of tumor promoters on cAMP production: inhibition of receptor-mediated and potentiation of cholera toxin-mediated stimulation.

Tetradecanoylphorbol-acetate and other tumor promoters inhibit prostaglandin E2 and isoproterenol-induced cAMP accumulation in mouse thymocytes but markedly potentiate cAMP production induced by cholera toxin. Cholera toxin is known to stimulate cAMP production by inducing ADP-ribosylation of the alpha-subunit of a guanine nucleotide-binding regulatory (G) protein, resulting in activation of the catalytic unit of adenylate cyclase. G proteins have been implicated as plasma membrane transducers for a variety of additional signals. It is possible that the growth promoting and co-mitogenic properties of tumor promoters are related to their effects on G proteins.

Animals↗