Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interactions of membrane proteins are important in various aspects of cell function. However, weak membrane protein-protein interactions are difficult to study using techniques such as co-immunoprecipitations. CD4 is a cell surface protein involved in T cell activation and the binding of the human immunodeficiency virus to HIV target cells. Here we report the use of cross-linking followed by affinity purification of CD4 in combination with mass spectrometry for identification of proteins that are in the proximity of CD4. Besides the components of the CD4 receptor complex, CD4 and lck, we have identified by tandem mass spectrometry 17 tryptic peptides from transferrin receptor CD71, three peptides from protein phosphatase CD45, and one peptide from 4F2 lymphocyte activation antigen CD98. The efficiency of the cross-linking did not correlate with the level of cell surface expression of the detected molecules, excluding a possible bias of the cross-linking toward the most abundant cell surface molecules. Whereas the association of CD4 with CD45 has been reported, the associations with CD71 and CD98 have not been previously described. We used small-scale immunoprecipitation after cross-linking in combination with fluorescence resonance energy transfer (FRET) measurements to investigate the association between CD4 and CD71. Our data show that CD71 self-associates on the cell surface, that a small fraction of CD4 can be detected by copurifying it with CD71 after cross-linking, and that the level of association between CD4 and CD71 significantly increases after phorbol 12-myristate 13-acetate-induced endocytosis of CD4. This suggests that a small fraction of CD4 associates with clusters of CD71. As both molecules undergo endocytic recycling, the association and cross-linking result from their clustering in the same pit and/or vesicle. The CD4-CD98 association probably results from nonspecific cross-linking.
...
PMID:Lateral membrane protein associations of CD4 in lymphoid cells detected by cross-linking and mass spectrometry. 1470 53

T cell development is dependent on the integration of multiple signaling pathways, although few links between signaling cascades and downstream nuclear factors that play a role in thymocyte differentiation have been identified. We show here that expression of the HMG box protein TOX is sufficient to induce changes in coreceptor gene expression associated with beta-selection, including CD8 gene demethylation. TOX expression is also sufficient to initiate positive selection to the CD8 lineage in the absence of MHC-TCR interactions. TOX-mediated positive selection is associated with up-regulation of Runx3, implicating CD4 silencing in the process. Interestingly, a strong T cell receptor-mediated signal can modify this cell fate. We further demonstrate that up-regulation of TOX in double positive thymocytes is calcineurin dependent, linking this critical signaling pathway to nuclear changes during positive selection.
...
PMID:TOX provides a link between calcineurin activation and CD8 lineage commitment. 1507 95

Acquisition of the anergy phenotype in T cells is blocked by inhibitors of protein synthesis and calcineurin activity, suggesting that anergic T cells may have a unique genetic program. Retroviral transduction of hemopoietic stem cells from TCR transgenic mice and subsequent reconstitution of syngeneic mice to express the E3 ubiquitin ligase, gene related to anergy in lymphocytes (GRAIL), or an enzymatically inactive form, H2N2 GRAIL, allowed analysis of the role of GRAIL in T cell anergy in vivo. Constitutive expression of GRAIL was sufficient to render naive CD4 T cells anergic, however, when the enzymatically inactive form H2N2 GRAIL was expressed, it functioned as a dominant negative of endogenous GRAIL and blocked the development of anergy. These data provide direct evidence that a biochemical pathway composed of GRAIL and/or GRAIL-interacting proteins is important in the development of the CD4 T cell anergic phenotype in vivo.
...
PMID:The gene related to anergy in lymphocytes, an E3 ubiquitin ligase, is necessary for anergy induction in CD4 T cells. 1521 Jul 61

1. Liver transplantation for human immunodeficiency virus (HIV)-positive patients with end-stage liver disease in the era of highly active retroviral therapy has proven to be an effective treatment. The concerns of HIV progression have not been borne out by the growing worldwide experience. 2. CD4 counts are stable and HIV viral load is controllable with medication following liver transplantation. 3. Hepatitis C virus (HCV) coinfection in HIV-positive recipients is universal, but the severity of recurrence does not appear to be different from that in HIV-negative patients with HCV liver disease. 4. Complex pharmacokinetic interactions between the calcineurin inhibitors used for immunosuppression along with protease inhibitors are present, but management directed at recognizing the need for monitoring levels does not appear to increase the risk of toxicity. 5. The degree of immunosuppression from iatrogenic drug therapy and HIV does not lead to increased risk of infectious complications.
...
PMID:Liver transplantation in patients with HIV infection. 1538 19

The cause of common polygenic autoimmune diseases is not understood because of genetic and cellular complexity. Here, we pinpoint the action of a subset of autoimmune susceptibility loci in the NOD mouse strain linked to D1mit181, D2mit490, D7mit101, and D15mit229, which cause a generalized resistance to thymic deletion in vivo that applies equally to Aire-induced organ-specific gene products in the thymic medulla and to systemic antigens expressed at high levels throughout the thymus and affects CD4(+), CD4(+)8(+), and CD4(+)25(+) thymocytes. Resistance to thymic deletion does not reflect a general deficit in TCR signaling to calcineurin- or ERK-induced genes, imbalance in constitutive regulators of apoptosis, nor excessive signaling to prosurvival genes but is distinguished by failure to induce the proapoptotic gene and protein, Bim, during in vivo encounter with high-avidity autoantigen. These findings establish defects in thymic deletion and Bim induction as a key mechanism in the pathogenesis of autoimmunity.
...
PMID:Generalized resistance to thymic deletion in the NOD mouse; a polygenic trait characterized by defective induction of Bim. 1558 70

The transcription factor c-Maf plays a critical and selective role in IL-4 gene transcription. Little is known about the mechanism that guides c-Maf regulation during early T cell activation. We report that IL-6 but not IL-4 or other cytokines, rapidly up-regulates c-Maf transcription, as early as 3 h after TCR activation in naive CD4(+) T cells. c-Maf induction requires both IL-6- and TCR-initiated signals, and is independent of IL-4/Stat6 signals. Cyclosporin A and FK506, which target calcineurin and thereby inhibit TCR-mediated Ca(2+) signal pathways, block IL-6-mediated c-Maf expression. We show that Stat3 binds the c-maf promoter in CD4 T cells after IL-6 stimulation, and also transactivates the c-maf promoter in reporter gene assays. IL-6 induces similar c-Maf expression in protein kinase Ctheta-deficient CD4(+) T cells. Furthermore, IL-6 enhances IL-4 gene expression very early after TCR activation in both wild-type and Stat6-deficient CD4(+) T cells. Our findings suggest that IL-6 plays a unique role in initiating c-Maf expression after TCR engagement, and may subsequently regulate early IL-4 production and Th2 commitment.
...
PMID:IL-6 plays a unique role in initiating c-Maf expression during early stage of CD4 T cell activation. 1572 80

Prior DNA microarray studies suggested that IL-16 mRNA levels decrease following T cell activation, a property unique among cytokines. We examined pro-IL-16 mRNA and protein expression in resting and anti-CD3 mAb-activated primary murine CD4(+) T cells. Consistent with the microarray reports, pro-IL-16 mRNA levels fell within 4 h of activation, and this response is inhibited by cyclosporin A. Total cellular pro-IL-16 protein also fell, reaching a nadir at 48 h. Pro-IL-16 comprises a C-terminal cytokine domain and an N-terminal prodomain that are cleaved by caspase-3. Pro-IL-16 expressed in transfected tumor cells was previously shown to translocate to the nucleus and to promote G(0)/G(1) arrest by stabilizing the cyclin-dependent kinase inhibitor p27(Kip1). In the present study, we observed increased S-phase kinase-associated protein 2 mRNA expression in IL-16 null mice, but basal expression and activation-dependent regulation of p27(Kip1) were no different from wild-type mice. Stimulation with anti-CD3 mAb induced transiently greater thymidine incorporation in IL-16-deficient CD4(+) T cells than wild-type controls, but there was no difference in cell survival or in the CFSE dilution profiles. Analysis of CD4(+) T cell proliferation in vivo using BrdU labeling similarly failed to identify a hyperproliferative phenotype in T cells lacking IL-16. These data demonstrate that pro-IL-16 mRNA and protein expression are dynamically regulated during CD4(+) T cell activation by a calcineurin-dependent mechanism, and that pro-IL-16 might influence T cell cycle regulation, although not in a dominant manner.
...
PMID:Pro-IL-16 regulation in activated murine CD4+ lymphocytes. 1572 82

Cryptococcus neoformans is an opportunistic fungal pathogen that threatens individuals with impaired cell-mediated immunity (CMI). Presently, there are no standardized vaccines available to prevent cryptococcal infections and conventional anti-fungal drug therapy does not induce host immune reactivity and thus cannot efficiently resolve C. neoformans infections in immunocompromised individuals. The present study was designed to characterize pulmonary immune responses following infection with an avirulent temperature-sensitive (ts) mutant, calcineurin A1 (cna1) compared to the pathogenic C. neoformans strain H99 and its potential to induce protective anti-cryptococcal immunity. Host CMI responses in cna1-inoculated mice were observed to be dose-dependent, and comprise increases in pulmonary macrophages and CD4(+) T lymphocytes. However, cytokine analysis demonstrated a mixed pulmonary cytokine response (increases in IL-4, and MCP-1) with no induction of IFN-gamma. Also, pre-immunization with the ts cna1 mutant did not result in protection from a subsequent secondary pulmonary infection with the pathogenic C. neoformans strain H99. Taken together, these results suggest that host pulmonary CMI responses to the ts cna1 mutant that is eventually eliminated from the host without the induction of IFN-gamma appear to be dose-dependent, diverse, and require further stimulation to induce C. neoformans-specific Th1-type cytokine responses to resolve subsequent experimental pulmonary cryptococcal infections.
...
PMID:Evaluation of host immune responses to pulmonary cryptococcosis using a temperature-sensitive C. neoformans calcineurin A mutant strain. 1574 13

Reversible leukoencephalopathy syndrome (RLS) is a rare brain disorder, characterized by diffuse attenuation of cerebral white matter, which has been most commonly observed in transplant patients receiving calcineurin inhibitors or in patients with severe hypertension. We report an episode of RLS in a 22-year-old male patient on chronic hemodialysis with well-controlled moderate hypertension who presented with de novo headache and generalized seizures. Cranial magnetic resonance image (MRI) revealed multiple areas of increased signal intensity in the white matter on T2-weighed images which resolved spontaneously at subsequent MRIs. White blood cell count showed leucopenia with normal CD4 count at flow cytometry. A viral etiology could not be demonstrated. Reversible leukoencephaolopathy syndrome symptoms remitted within 72 h but leukopenia persisted over 10 months. The patient received a kidney transplant 15 months after RLS onset and has received cyclosporine since the second post-transplant day. No recurrence of RLS symptoms has been observed. The etiology of the MRI changes in the present case seemed not to be either vasogenic or cytotoxic.
...
PMID:Reversible leukoencephalopathy syndrome associated to leukopenia in a chronic hemodialysis patient. 1582 10

CD25 (IL-2 receptor alpha-chain) marks a population of CD4-positive T cells with a suppressor phenotype. These CD4+CD25+ regulatory T cells can suppress both effector T cells and antigen-presenting cells and have been identified as a principle regulator of tolerance in experimental transplantation models. In the setting of human liver transplantation, however, little is known about the dynamics of these cells in relation to rejection, tolerance, and immunosuppression. In the current study we determined CD4+CD25+ T cell in blood of liver transplant recipients using flow cytometry and investigated a possible link with immunosuppressive therapies. Peripheral blood mononuclear cells (PBMC) of 27 liver transplant patients (pretransplantation and 12 months posttransplantation) and 16 healthy controls were included. We found that the percentages of CD25+ cells within the CD4 T-cell population was significantly reduced in more than two-thirds of patients 1 year after transplantation. Also the total percentage of CD4-positive T cells declined significantly within this period, making the absolute reduction of regulatory T cells after transplantation even more profound. Comparing PBMC samples of patients and healthy controls revealed an increased percentage of CD4+ T cells in the patients before transplantation, probably related to the chronic liver illness. The reduction in CD4+CD25+ T cells after transplantation was similar for different immunosuppression regiments. All patients, however, received calcineurin inhibitors, suggesting a possible suppressive effect of this therapy on regulatory T-cell levels in peripheral blood. Currently, assays for regulatory T-cell activity are used to further support this hypothesis.
...
PMID:Decrease of CD4+CD25+ T cells in peripheral blood after liver transplantation: association with immunosuppression. 1584 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---