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At least 577 records · Page 32Linked to original sources
PubMed1994

The mucin epiglycanin on TA3/Ha carcinoma cells prevents alpha 6 beta 4-mediated adhesion to laminin and kalinin and E-cadherin-mediated cell-cell interaction.

TA3/Ha murine mammary carcinoma cells grow in suspension, do not adhere to extracellular matrix molecules, but do adhere to hepatocytes and form liver metastases upon intraportal injection. Recently we showed that the integrin alpha 6 beta 4 on the TA3/Ha cells is involved in adhesion to hepatocytes. However, despite high cell surface levels of alpha 6 beta 4, TA3/Ha cells do not adhere to the alpha 6 beta 4 ligands laminin and kalinin. Here we show that this is due to the mucin epiglycanin that is highly expressed on TA3/Ha cells. Some monoclonal antibodies generated against epiglycanin induced capping of most of the epiglycanin molecules. TA3/Ha cells treated with these mAb did adhere to laminin and kalinin, and an epithelial monolayer was formed on kalinin, with alpha 6 beta 4 localized in HD1-containing hemidesmosome-like structures and E-cadherin at the cell-cell contact sites. Similar results were obtained after treatment of TA3/Ha cells with O-sialoglycoprotein endopeptidase which removes all epiglycanin. In addition, the enzyme induced E-cadherin-mediated cell-cell aggregation. Both treatments also enhanced the adhesion to hepatocytes, but given the potent antiadhesive effect of epiglycanin it is remarkable that nontreated TA3/Ha cells adhere to hepatocytes at all. We found that during this interaction, epiglycanin was redistributed. We conclude that epiglycanin can completely prevent both intercellular and matrix adhesion, but that this effect can be overcome in certain intercellular interactions because of the induced redistribution of the mucin.

Animals↗
PubMed1974

Regulation of cell-mediated cytotoxicity. I. Augmentation of cell-mediated cytotoxicity induced by radiation.

Mice were treated with sublethal and midlethal doses of irradiation (500-700 rads) and injected intravenously with allogeneic or semiallogeneic F(1) hybrid spleen cells. The cytotoxicity developed by their spleen cells was measured with the lysis of (51)Cr-labeled target cells and was found to be stronger (although delayed in time) than the cytotoxic activity of spleen cells from nonirradiated mice. The injection of syngeneic thymus or spleen cells in the irradiated mice after their treatment with allogeneic spleen cells exerted a suppressor activity, i.e., reduced the level of cell-mediated cytotoxicity (CMC). The majority of effector cells involved in the modified CMC response of irradiated mice was shown to be of host origin and lysed specifically target cells of the same genotype as the donor. A small percentage of the cells obtained from the spleens of irradiated recipients of allogeneic spleen cells was composed of donor cells which lysed specifically target cells of the same genotype as the host. These results demonstrate that the precursors of the cytotoxic cells responsible for target cell lysis are relatively radioresistant and suggest that their response is regulated by radiosensitive thymus-dependent cells.

Animals↗
PubMed1975

Cell-mediated immunity: differential maturation of mixed leukocyte reaction and cell-mediated lympholysis.

While spleen cells from neonatal B10 (H-2b) are reactive (proliferate) in one-way mixed leukocyte culture, cell-mediated lympholysis reactivity does not arise until 7 days of age. When B10 cells are sensitized to B10.D2 (H-2d), cross-killing of third-party B10.BR (H-2k) target is always lower than the specific killing of B10.D2 targets and is not demonstrable until 27 days after birth.

Aging↗
PubMed1982

Anaphylatoxin-mediated regulation of the immune response. I. C3a-mediated suppression of human and murine humoral immune responses.

The C3a fragment of the third component of complement was found to have immunosuppressive properties. C3a is capable of suppressing both specific and polyclonal antibody responses. In contrast, C3a had no effect on antigen- or mitogen-induced B or T cell proliferative responses. The carboxy-terminal arginine is essential for C3a to exhibit its immunosuppressive properties. The serum carboxypeptidase inhibitor 2-mercaptomethyl-5-guanodinopentanoic acid, which prevents cleavage of the terminal arginine that would produce C3ades Arg-77, allowed us to assay the effects of C3a on in vitro immune response systems where serum is required. When the terminal arginine is removed from C3a, the resulting C3ades Arg-77 molecule is nonsuppressive. Helper T lymphocytes are the target of C3a-mediated suppression of the immune response. Substitution of T cells by soluble T cell factors was found to abrogate the C3a suppressive activity.

Anaphylatoxins↗
PubMed2000

Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal inflammation in crescentic glomerulonephritis.

Protease-activated receptor (PAR)-1 is a cellular receptor for thrombin that is activated after proteolytic cleavage. The contribution of PAR-1 to inflammatory cell-mediated renal injury was assessed in murine crescentic glomerulonephritis (GN). A pivotal role for thrombin in this model was demonstrated by the capacity of hirudin, a selective thrombin antagonist, to attenuate renal injury. Compared with control treatment, hirudin significantly reduced glomerular crescent formation, T cell and macrophage infiltration, fibrin deposition, and elevated serum creatinine, which are prominent features of GN. PAR-1-deficient (PAR-1(-/-)) mice, which have normal coagulation, also showed significant protection from crescentic GN compared with wild-type mice. The reductions in crescent formation, inflammatory cell infiltration, and serum creatinine were similar in PAR-1(-/-) and hirudin-treated mice, but hirudin afforded significantly greater protection from fibrin deposition. Treatment of wild-type mice with a selective PAR-1-activating peptide (TRAP) augmented histological and functional indices of GN, but TRAP treatment did not alter the severity of GN in PAR(-/-) mice. These results indicate that activation of PAR-1 by thrombin or TRAP amplifies crescentic GN. Thus, in addition to its procoagulant role, thrombin has proinflammatory, PAR-1-dependent effects that augment inflammatory renal injury.

Animals↗
PubMed2001

Caspase-11 mediates oligodendrocyte cell death and pathogenesis of autoimmune-mediated demyelination.

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. The mechanisms underlying oligodendrocyte (OLG) injury in MS and EAE remain unknown. Here we show that caspase-11 plays crucial roles in OLG death and pathogenesis in EAE. Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions. OLGs from caspase-11-deficient mice were highly resistant to the cell death induced by cytotoxic cytokines. EAE susceptibility and cytokine concentrations in the CNS were significantly reduced in caspase-11-deficient mice. Our findings suggest that OLG death is mediated by a pathway that involves caspases-11 and -3 and leads to the demyelination observed in EAE.

Animals↗
PubMed2000

Inhibition of the CD8+ T cell-mediated cytotoxicity reaction by hypericin: potential for treatment of T cell-mediated diseases.

The cytotoxicity reaction of murine CD8 T lymphocytes has been found to be strongly inhibited by nanomolar concentrations of hypericin, a lipophilic dianthraquinone with photodynamic properties. Cytotoxic T lymphocyte (CTL)-induced target cell apoptosis, as well as exocytosis of cytolytic granules from these cells, were ablated by hypericin, administered at the onset of the reaction, without affecting CTL viability. The inhibition of cytolysis occurred without the light irradiation which is essential for photosensitization. The findings suggest that the action of hypericin targets the effector CTL; however, apoptosis induced in murine L-cells with recombinant tumor necrosis factor (TNF)-alpha was also prevented by hypericin. Since hypericin is a known inhibitor of protein kinase C, MAP kinase and at least one other tyrosine kinase, this inhibitory activity could play a role in the down-modulation of CTL-induced cytotoxicity. Furthermore, our studies show that the action of hypericin induces rapid dephosphorylation of phospholipids associated with low-density membranes in CTL, but not with membranes of the cytotoxic granules. The ability of hypericin to interfere with cytotoxicity may render it useful in the treatment of T cell-mediated diseases.

Animals↗
PubMed1998

Computer model of antiepileptic effects mediated by alterations in GABA(A)-mediated inhibition.

Results from a computer model of a thalamic network predict that agents augmenting GABA(A)-mediated inhibition in the reticular thalamic (RE) nucleus will be antiepileptic or desynchronizing. This provides support for the hypothesis that antiepileptics like benzodiazepines may exert their effects through an isolated increase of inhibition in the RE nucleus. When desynchronized, the model thalamocortical neurons showed a decreased probability of firing a low threshold spike, a decreased secondary inhibitory postsynaptic potential and a higher frequency of oscillations. The transition to desynchrony was also accompanied by an increased frequency in the firing of the model RE neurons.

Anticonvulsants↗
PubMed1991

A naturally occurring 6-9-kilodalton interleukin-1 (IL-1) inhibitor prevents IL-1-mediated islet cytotoxicity but not IL-1-mediated suppression of insulin secretion.

Earlier studies have shown direct effects of interleukin-1 (IL-1) on isolated pancreatic islets. Coculture of isolated rat pancreatic islets with human rIL-1 beta for 6 days resulted in dose-dependent cytotoxicity (up to 100%) and suppression of insulin secretion (up to 88.5%). The cytotoxic effects of rIL-1 beta beta were blocked by the simultaneous presence of a naturally occurring 6-9-kilodalton (kDa) inhibitor of IL-1-induced T-cell proliferation. However, the ability of rIL-1 beta to suppress insulin secretion was not blocked by the 6-9-kDa inhibitor of IL-1 activity. This IL-1 inhibitor is produced by mononuclear cells and is resistant to pH 2, sensitive to heating at 56 degrees C for 30 min, has a pI of 4.5-5.6, and appears to be different from other recognized IL-1 inhibitors in both composition and mechanism of action. Unlike this IL-1 inhibitor, a monoclonal antibody specific for rIL-1 beta was able to neutralize both the islet cytotoxic and insulin modulatory effects of rIL-1 beta. These results demonstrate the use of an IL-1 inhibitor to prevent at least one mechanism of islet destruction, and suggest separate pathways for IL-1 mediated islet cytotoxicity and suppression of insulin secretion.

Animals↗
PubMed1976

Studies on the induction and expression of T cell-mediated immunity. V. Lectin-induced nonspecific cell-mediated cytotoxicity by alloimmune lymphocytes.

Murine lymphoid cells sensitized against allografts express two types of cytotoxicity measured in vitro in short-term assays of 2 to 3 hr by 51Cr release. One type of cytotoxicity is specific against target cells carrying the sensitizing alloantigens, and the other type is nonspecific against both syngeneic and unrelated target cells and requires the presence of phytohemagglutinin (PHA) or concanavalin A (ConA). Several lines of evidence are presented which demonstrate that both cytotoxic systems are mediated by the same clone of alloimmune effector T lymphocytes and that the lectin-induced cytotoxicity is not attributable to mitogenic polyclonal activation of effector cells. Studies with ConA inhibitor alpha-methyl-D-mannoside suggest a mechanism of interaction that requires the lectin to be present during the reaction. Experiments with other reagents, however, that bring about physical contact of the cells but not lysis, indicate that cytolysis can occur only through specific lectin receptors on the cells. The significance of this lectin-induced cytotoxicity is discussed.

Animals↗
PubMed1995

Fas-mediated cytotoxicity. An immunoeffector or immunoregulatory pathway in T cell-mediated immune responses?

Fas/Fas ligand interactions serve as a signaling pathway for apoptosis (1-3), an important regulatory mechanism in the development and function of the immune system (4-9). Recent evidence that Fas-dependent apoptosis is also an important mode of T cell cytotoxicity (10-13) suggested that Fas might play a critical role in the effector phase of T-dependent immune responses, such as allograft rejection. We observed that Fas transcripts are constitutively expressed in syngeneic and allogeneic murine cardiac transplants, while Fas ligand (FasL) is up-regulated only in rejecting allografts. Surprisingly, the absence of an intact Fas/FasL pathway did not alter the tempo of allograft rejection, even CD4-dependent rejection. These results indicate that Fas/FasL interactions are not essential mediators of T cell-induced allograft damage. Rather, as suggested in other studies, the Fas pathway may be principally involved in the regulation of clonal expansion and subsequent contraction of T cell populations during immune responses.

Animals↗
PubMed2003

Adenovirus-mediated expression of human CD55 or CD59 protects adult porcine islets from complement-mediated cell lysis by human serum.

BACKGROUND: Protection against complement activation may reduce acute islet damage in pig-to-human islet xenotransplantation. Expression of the human complement regulatory proteins decay-accelerating factor (DAF, CD55) or CD59 was induced on intact adult porcine islets (APIs) by adenoviral transduction. The functional capacity of the transgenes was examined in vitro after exposure to fresh human serum. METHODS: Intact APIs were transduced with adenoviral vectors Ad.hDAF or Ad.hCD59 or a control vector. After 3 days, the islets were trypsin dissociated to a single-cell suspension. A cytotoxicity assay was performed in which the islet cells were incubated with human complement active AB serum. Flow cytometry and immunohistochemistry were used to evaluate transgene expression. RESULTS: APIs could be transduced to express hDAF or hCD59. Flow cytometry analysis of islet single cells revealed that only a fraction of the cells expressed the transgene; immunohistochemical staining of transduced islets demonstrated that mainly cells located in the periphery of the islets were expressing the protein. Cells from nontransduced islets or islets expressing the control protein were sensitive to lysis in human sera (66+/-4.0% and 73+/-3.7% cytotoxicity, respectively). Single cells from islets transduced with hDAF and hCD59 were partially protected from lysis. Islet cells expressing hCD59 were slightly less sensitive to lysis (33+/-3.3%) than cells expressing hDAF (45+/-3.5%). CONCLUSIONS: These data show that intact pig islets can be transduced to express human regulators of complement activation on the surface and that pig islet cells expressing hDAF or hCD59 are less sensitive to complement-mediated lysis.

Adenoviridae↗
PubMed2000

GcvA binding site 1 in the gcvTHP promoter of Escherichia coli is required for GcvA-mediated repression but not for GcvA-mediated activation.

GcvA binds to three sites in the gcvTHP control region, from base -34 to -69 (site 1), from base -214 to -241 (site 2) and from base -242 to -271 (site 3). Previous results suggested that sites 3 and 2 are required for both GcvA-dependent activation and repression of a gcvT::lacZ fusion. However, the results were less clear as to the role of site 1. To determine the role of site 1 in regulation, single and multiple base changes were made in site 1 and tested for their ability to alter GcvA-mediated activation and GcvA/GcvR-mediated repression. Several of the mutants were also tested for effects on GcvA binding to site 1 and the ability of GcvA to bend DNA at site 1. The results are consistent with site 1 playing primarily a role in negative regulation of the gcvTHP operon.

Bacterial Proteins↗
PubMed2004

The WRKY70 transcription factor: a node of convergence for jasmonate-mediated and salicylate-mediated signals in plant defense.

Cross talk between salicylic acid (SA)- and jasmonic acid (JA)-dependent defense signaling has been well documented in plants, but how this cross talk is executed and the components involved remain to be elucidated. We demonstrate that the plant-specific transcription factor WRKY70 is a common component in SA- and JA-mediated signal pathways. Expression of WRKY70 is activated by SA and repressed by JA. The early induction of WRKY70 by SA is NPR1-independent, but functional NPR1 is required for full-scale induction. Epistasis analysis suggested that WRKY70 is downstream of NPR1 in an SA-dependent signal pathway. Modulation of WRKY70 transcript levels by constitutive overexpression increases resistance to virulent pathogens and results in constitutive expression of SA-induced pathogenesis-related genes. Conversely, antisense suppression of WRKY70 activates JA-responsive/COI1-dependent genes. The effect of WRKY70 is not caused by subsequent changes in SA or JA levels. We suggest that WRKY70 acts as an activator of SA-induced genes and a repressor of JA-responsive genes, integrating signals from these mutually antagonistic pathways.

Arabidopsis↗
PubMed1980

Cell-mediated immunity to mouse adenovirus infection. Blocking of macrophage migration inhibition and T cell-mediated cytolysis of infected cells by anti-S antigen or anti-alloantigen serum.

Migration of peritoneal exudate cells (PEC), which were prepared from mice immunized against mouse adenovirus (M-Ad), was inhibited upon exposure to the antigenic extract of M-Ad-infected cells. This inhibition was shown to be blocked when infected cells or their extracts were pretreated with antiserum against M-Ad-induced cell surface (S) antigen(s) or with antisera against alloantigens of infected cells. Immune spleen cell-mediated cytolysis of M-Ad-infected cells was also blocked in the presence of anti-S, anti-alloantigen or anti-beta 2m serum. Immunofluorescent antibody staining of S antigen(s) was blocked when infected cells were pretreated with anti-alloantigen or anti-beta 2m serum, whereas it was not blocked when they were pretreated with anti-mouse immunoglobulin or anti-Thy-1.2 serum. Conversely, immunofluorescent antibody staining of alloantigens was blocked when infected cells were pretreated with anti-S serum. These findings indicate that S and alloantigens are associated with each other or at least located very close to each other.

Adenoviridae↗
PubMed1990

A cell-to-cell mediated interaction involving monocytes and non-T/CD16+ natural killer (NK) cells is required for histamine H2-receptor-mediated NK-cell activation.

Histamine (10(-4) to 10(-7) M) augmented natural killer cell cytotoxicity (NKCC) of human CD16+, non-T lymphocytes in vitro against the NK-sensitive target cells K562 erythroleukaemic, Molt-4 lymphoma, Chang liver cells and against Epstein-Barr virus (EBV)-transformed, NK-insensitive Daudi B-lymphoblastoid target cells by a mechanism of action involving a prostaglandin- and interleukin 1 (IL-1)-independent accessory function of monocytes. No evidence for the production of intermediary, NK-enhancing cytokines by histamine was obtained, indicating a cell-to-cell mediated interaction between monocytes and NK cells as a plausible mechanism of action for the NK-augmenting effect. Monocytes recovered by countercurrent centrifugal elutriation (CCE), but not monocytes recovered by adherence, reconstituted the effect of histamine when added to non-adherent NK cells. The development of NKCC in response to histamine was time-dependent with (i) an induction phase, dependent on the presence of accessory monocytes and ongoing histamine H2-receptor activation (half-maximal response required approximately 30 min treatment of large granular lymphocyte (LGL)-enriched lymphocytes and monocytes with histamine), and (ii) an effector phase, independent of the presence of monocytes or histamine receptor activation. Histamine-activated mononuclear cells (MNC) continued to exert augmented cytotoxicity for at least 8 h after removal of histamine and monocytes. In several experiments, histamine-activated NK-effector cells killed greater than 90% of the target cells at low baseline NKCC. We suggest that histamine may have a role in non-specific tumour defence by regulating an earlier unrecognized interplay between monocytes and NK cells.

Antigens, Differentiation↗
PubMed1996

Dopamine D1 receptor-mediated facilitation of GABAergic neurotransmission in the rat strioentopenduncular pathway and its modulation by adenosine A1 receptor-mediated mechanisms.

By using in vivo microdialysis it was found that one of the main functions of striatal dopamine D1 receptors is to selectively facilitate GABAergic neurotransmission in the 'direct' strioentopeduncular pathway. D1 receptors localized in the entopeduncular nucleus were also found to facilitate GABA release. However, results obtained from in vivo microdialysis, in vivo electrochemistry, immunohistochemistry and confocal laser microscopy suggested that entopeduncular D1 receptors could only be activated under pharmacological conditions. Adenosine A1 receptors were found to antagonistically modulate the D1-mediated regulation of the strioentopeduncular pathway. Furthermore, using in situ hybridization D1 and A1 receptors were shown to be colocalized in medium-sized striatal neurons. These results show that the strioentopeduncular neuron is a main locus for adenosine-dopamine interactions in the brain.

Animals↗
PubMed2006

Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR-induced release of Ca++ from intracellular stores and is prevented by estradiol.

Hypoxic/ischemic (HI) brain injury in newborn full-term and premature infants is a common and pervasive source of life time disabilities in cognitive and locomotor function. In the adult, HI induces glutamate release and excitotoxic cell death dependent on NMDA receptor activation. In animal models of the premature human infant, glutamate is also released following HI, but neurons are largely insensitive to NMDA or AMPA/kainic acid (KA) receptor-mediated damage. Using primary cultured hippocampal neurons we have determined that glutamate increases intracellular calcium much more than kainic acid. Moreover, glutamate induces cell death by activating Type I metabotropic glutamate receptors (mGluRs). Pretreatment of neurons with the gonadal steroid estradiol reduces the level of the Type I metabotropic glutamate receptors and completely prevents cell death, suggesting a novel therapeutic approach to excitotoxic brain damage in the neonate.

Animals↗