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Selective, α2β1 integrin-dependent secretion of il-6 by connective tissue mast cells.
McCall-Culbreath KD, Li Z, Zhang Z, Lu LX, Orear L, Zutter MM
(2011) J Innate Immun 3: 459-70
MeSH Terms: Animals, Antigens, Bacterial, Calcium Signaling, Cell Degranulation, Cells, Cultured, Connective Tissue, Humans, Immunity, Innate, Immunoglobulin E, Integrin alpha2beta1, Interleukin-6, Listeria monocytogenes, Mast Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor Aggregation
Show Abstract · Added February 16, 2014
Mast cells, critical mediators of inflammation and anaphylaxis, are poised as one of the first lines of defense against external assault. Mast cells release several classes of preformed and de novo synthesized mediators. Cross-linking of the high-affinity FcεRI results in degranulation and the release of preformed, proinflammatory mediators including histamine and serotonin. We previously demonstrated that mast cell activation by Listeria monocytogenes requires the α2β1 integrin for rapid IL-6 secretion both in vivo and in vitro. However, the mechanism of IL-6 release is unknown. Here, we demonstrate the Listeria- and α2β1 integrin-mediated mast cell release of preformed IL-6 without the concomitant release of histamine or β-hexosaminidase. α2β1 integrin-dependent mast cell activation and IL-6 release is calcium independent. In contrast, IgE cross-linking-mediated degranulation is calcium dependent and does not result in IL-6 release, demonstrating that distinct stimuli result in the release of specific mediator pools. These studies demonstrate that IL-6 is presynthesized and stored in connective tissue mast cells and can be released from mast cells in response to distinct, α2β1 integrin-dependent stimulation, providing the host with a specific innate immune response without stimulating an allergic reaction.
Copyright © 2011 S. Karger AG, Basel.
1 Communities
1 Members
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17 MeSH Terms
Tirofiban blocks platelet adhesion to fibrin with minimal perturbation of GpIIb/IIIa structure.
Hantgan RR, Stahle MC, Jerome WG, Nagaswami C, Weisel JW
(2002) Thromb Haemost 87: 910-7
MeSH Terms: Adult, Circular Dichroism, Dose-Response Relationship, Drug, Fibrin, Humans, Microscopy, Electron, Nephelometry and Turbidimetry, Platelet Adhesiveness, Platelet Aggregation Inhibitors, Platelet Glycoprotein GPIIb-IIIa Complex, Protein Conformation, Protein Interaction Mapping, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Subunits, Receptor Aggregation, Tirofiban, Tyrosine
Show Abstract · Added December 10, 2013
A biophysical approach tested the hypothesis that tirofiban, like eptifibatide, perturbs GpIIb/IIIa structure. Tirofiban bound tightly to platelet GpIIb/IIIa (EC50 approximately 24 nmol/L) and effectively inhibited platelet aggregation (IC50 approximately 37 nmol/L) but blocked platelet adhesion to clotted fibrin only at much higher doses (IC50 approximately 580 nmol/L). Electrophoretic analyses demonstrated that tirofiban protected GpIIb/IIIa from SDS-induced subunit dissociation. However, saturating tirofiban concentrations had little or no effect on GpIIb/IIIa secondary or tertiary structure, as determined by circular dichroic spectroscopy, dynamic light scattering, and sedimentation velocity measurements performed with purified receptors in octyl glucoside. Moderate dose-dependent effects on GpIIb/IIIa quaternary structure were detected by sedimentation equilibrium. Transmission electron microscopy showed minimal tirofiban-induced receptor activation or oligomerization. Thus, even at the increased concentrations needed to block platelet:fibrin adhesive interactions, tirofiban exhibited only limited effects on GpIIb/IIIa conformation and clustering. Our results provide new insights into the mechanisms and potential prothrombotic complications of integrin antagonists.
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18 MeSH Terms
PSD-95 involvement in maturation of excitatory synapses.
El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS
(2000) Science 290: 1364-8
MeSH Terms: Animals, Cells, Cultured, Dendrites, Disks Large Homolog 4 Protein, Excitatory Postsynaptic Potentials, Hippocampus, Interneurons, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Nerve Tissue Proteins, Patch-Clamp Techniques, Presynaptic Terminals, Protein Structure, Tertiary, Pyramidal Cells, Rats, Receptor Aggregation, Receptors, AMPA, Receptors, Glutamate, Receptors, N-Methyl-D-Aspartate, SAP90-PSD95 Associated Proteins, Synapses, Synaptic Transmission, Synaptic Vesicles, Transfection
Show Abstract · Added April 2, 2019
PSD-95 is a neuronal PDZ protein that associates with receptors and cytoskeletal elements at synapses, but whose function is uncertain. We found that overexpression of PSD-95 in hippocampal neurons can drive maturation of glutamatergic synapses. PSD-95 expression enhanced postsynaptic clustering and activity of glutamate receptors. Postsynaptic expression of PSD-95 also enhanced maturation of the presynaptic terminal. These effects required synaptic clustering of PSD-95 but did not rely on its guanylate kinase domain. PSD-95 expression also increased the number and size of dendritic spines. These results demonstrate that PSD-95 can orchestrate synaptic development and are suggestive of roles for PSD-95 in synapse stabilization and plasticity.
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MeSH Terms
Costimulation reverses the defect in IL-2 but not effector cytokine production by T cells with impaired IkappaBalpha degradation.
Aune TM, Mora AL, Kim S, Boothby M, Lichtman AH
(1999) J Immunol 162: 5805-12
MeSH Terms: Animals, CD28 Antigens, CD4-Positive T-Lymphocytes, Cytokines, DNA-Binding Proteins, I-kappa B Proteins, Interferon-gamma, Interleukin-2, Interleukin-4, Mice, Mice, Mutant Strains, Mice, Transgenic, Mutation, NF-KappaB Inhibitor alpha, NF-kappa B, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-rel, Receptor Aggregation, Receptors, Antigen, T-Cell, Response Elements, Signal Transduction
Show Abstract · Added December 10, 2013
Although the transcriptional basis for states of unresponsiveness in primary T cells is unclear, tolerant B lymphocytes exhibit inhibition of both c-Jun N-terminal kinase induction and IkappaBalpha (inhibitor of NF-kappaBalpha) degradation, leading to lower levels of both nuclear AP-1 and NF-kappaB. Expression of an IkappaBalpha mutant resistant to signal-induced degradation in transgenic T cells caused markedly deficient effector cytokine (IL-4, IFN-gamma) production after primary TCR stimulation despite a detectable level of nuclear NF-kappaB. A TCR response element from the IFN-gamma promoter, despite lacking detectable NF-kappaB/Rel sites, was also unresponsive to TCR ligation. Nuclear induction of AP-1 proteins in response to T cell activation was diminished in transgenic T cells. Costimulation induced by anti-CD28 mAb increased IL-2 production, but failed to reverse the defects in effector cytokine production. Taken together, these data indicate that impaired NF-kappaB/Rel signaling in T cells interferes with the signal transduction pathways required for efficient induction of effector cytokine production.
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21 MeSH Terms
Cooperative binding of androgen receptors to two DNA sequences is required for androgen induction of the probasin gene.
Kasper S, Rennie PS, Bruchovsky N, Sheppard PC, Cheng H, Lin L, Shiu RP, Snoek R, Matusik RJ
(1994) J Biol Chem 269: 31763-9
MeSH Terms: Androgen-Binding Protein, Androgens, Base Sequence, Binding Sites, DNA-Binding Proteins, Gene Expression Regulation, Humans, In Vitro Techniques, Macromolecular Substances, Molecular Sequence Data, Oligodeoxyribonucleotides, RNA, Messenger, Receptor Aggregation, Receptors, Androgen, Regulatory Sequences, Nucleic Acid, Tumor Cells, Cultured
Show Abstract · Added June 11, 2010
The functional and structural interactions of two androgen receptor-binding sites in the 5'-flanking DNA of the rat probasin gene were determined. Deletion mapping and DNase I footprinting analysis had previously identified two androgen receptor-binding sites (ARBS) necessary for androgen induction of the probasin gene: ARBS-1, which resembled a glucocorticoid-responsive element, and ARBS-2, which had a unique sequence. In this study, maximal androgen induction in transient transfection studies only occurred when both sites were present. Neither binding site functioned independently, and deletion of the DNA sequence between the sites resulted in a 60% loss of androgen inducibility. Moreover, point mutations in either ARBS-1 or ARBS-2 led to > 90% loss in activity. Scatchard analysis indicated that ARBS-1 and ARBS-2 bound a synthetic androgen receptor, AR2, with Kd values of 20.0 and 6.7 nM, respectively. Consistent with the higher affinity, ARBS-2 bound AR2 at half the threshold concentration (200 ng) of that required in reciprocal DNase I footprinting experiments with ARBS-1. By comparison, protection occurred at a much lower threshold concentration of AR2 (60 ng) and to the same extent over each site when both sites were present, suggesting a cooperative interaction between the two sites. The cooperative effect was further substantiated when a point mutation in ARBS-1 blocked AR2 binding not only to ARBS-1, but also to ARBS-2. Similarly, a point mutation in ARBS-2 also prevented receptor binding to both sites. Androgen-specific regulation of probasin gene transcription therefore required an androgen-responsive region (positions -286 and +28) containing two androgen receptor-binding sites, where the binding of the androgen receptor to both sites occurred in a cooperative, mutually dependent manner.
1 Communities
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16 MeSH Terms
Tyrosine kinase activation provides an early and requisite signal for Fas-induced apoptosis.
Eischen CM, Dick CJ, Leibson PJ
(1994) J Immunol 153: 1947-54
MeSH Terms: Antigens, Surface, Apoptosis, Cell Line, Enzyme Activation, Humans, In Vitro Techniques, Phosphoproteins, Phosphotyrosine, Protein-Tyrosine Kinases, Receptor Aggregation, Receptors, Cell Surface, Signal Transduction, Tyrosine, fas Receptor
Show Abstract · Added March 5, 2014
Selective cell death plays a critical role in the development of the immune repertoire and in the elimination of target cells expressing foreign Ags. The apoptosis induced by ligation of the Fas Ag, a member of the TNFR/nerve growth factor receptor superfamily, contributes to both of these modes of cell loss. However, in spite of the molecular cloning of the Fas Ag and the identification of a specific cytoplasmic domain required for its function, it remains unclear as to which Fas-induced second messengers mediate the development of programmed cell death. We, therefore, evaluated Fas-initiated signal transduction in susceptible cell types. We determined that Fas ligation induces the rapid tyrosine phosphorylation of multiple cellular proteins. These phosphorylation events occur within 1 min and decline toward baseline by 30 min. In addition, Fas ligation increases the in vitro protein kinase activity of the tyrosine phosphorylated proteins. Pharmacologic inhibitors of protein tyrosine kinases block, in a concentration-dependent manner, Fas-induced DNA fragmentation and prolong cell survival. These results suggest that protein tyrosine kinase activation is an early and obligatory signal in Fas-induced apoptosis.
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14 MeSH Terms