Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcription factor NF-kappa B has been implicated in the mitogen-induced expression of several genes that are critical for the immunologic function of T cells such as those encoding IL-2 and the IL-2R alpha chain (IL-2R alpha). We show here that NF-kappa B is induced in T cells activated by Ag, anti-CD3 antibody, or allogeneic stimulation. The induction of NF-kappa B via the TCR was dependent on protein kinase C. IL-2, which also activates IL-2R alpha expression and proliferation in T cells, was not able to induce NF-kappa B. TCR-mediated induction of NF-kappa B suggests a central role for this factor in activated T cells and also provides a mechanism for activation of latent HIV provirus during the normal immune response.
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PMID:Physiologic activation of T cells via the T cell receptor induces NF-kappa B. 183 61

Th cell development inside the thymus can be defined on the basis of qualitative and quantitative CD4 and CD8 marker expression and follows the pathway of CD4-8- cells----CD4+8+ cells----CD4+8low cells----CD4+8- cells, which presumably emigrate to seed the periphery and serve as functionally mature Th cells. The various cell subpopulations at defined developmental stages were isolated by electronic cell sorting and examined for mitogen induced IL-2 production and cell proliferation responses. For TCR-alpha beta-bearing CD4+8+ and CD4+8low thymocytes that are actively engaged in positive and negative selection processes, negligible to low levels of IL-2 production and cell proliferation were observed in response to TCR:CD3 triggering or to the combined activation of protein kinase C and calcium mobilization mediated by PMA and ionomycin, respectively. For CD4-8- TCR-alpha beta early thymocytes that have not yet entered the selection process, PMA + ionomycin induced significant cell proliferation but little IL-2 production, in the absence of added IL-1. However, addition of IL-1 caused a powerful induction of IL-2 production that was accompanied by increased cell proliferation. Triggering of the TCR:CD3 complex had no effect on CD4-8-TCR(-)-alpha beta thymocytes as they do not express detectable levels of TCR-alpha beta. For thymus CD4+8- Th cells, the first cells that have completed TCR repertoire selection, vigorous proliferation was observed in response to TCR:CD3 triggering in the presence of added IL-2. However, the development of IL-2 responsiveness was not accompanied by high level IL-2 inducibility as TCR:CD3 triggering caused only marginal IL-2 production. In contrast, spleen CD4+8- T cells, the most "mature" representatives of Th cells, expressed high levels of IL-2 production as well as IL-2 responsiveness in response to TCR:CD3-mediated stimulation. The lack of anti-TCR-induced IL-2 production by thymus CD4+8- T cells was not due to an intrinsic defect as high levels of IL-2 production was induced by PMA + ionomycin. Possible reasons for the temporal acquisition and differential control of IL-2 inducibility and IL-2 responsiveness are discussed in the context of established Th cell development pathway.
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PMID:Mitogen-induced IL-2 production and proliferation at defined stages of T helper cell development. 183 Jun 1

The effect of cyclosporin A on the initial phase of activation of human peripheral blood lymphocytes (PBL) by anti-CD3 was studied in a two-step incubation process. Cyclosporin A treatment in the initial phase of activation blocked the second phase activation of a cell population by anti-CD3, IL-2, or concanavalin A (ConA). In contrast, similar treatment with the calcium ionophore, ionomycin, enhanced the activation of anti-CD3. Only a marginal synergistic increase of intracellular [Ca2+] was elicited by cyclosporin A during anti-CD3 stimulation and this drug prevented activation-induced depolarization of lymphocytes by its ability to hyperpolarize cells. The hyperpolarization effect of cyclosporin A is related to the K+ flux but not the Na+ or Ca2+ flux and is unlikely to be mediated through calmodulin and protein kinase C. We postulate that the K+ flux-modulating ability of cyclosporin A renders T cells non-responsive in the initial phase of activation.
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PMID:Cyclosporin elicits a non-responsive state and a shift in K+ fluxes in the early phase of activation of human lymphocytes with anti-CD3. 183 31

In this study, genistein, a selective protein tyrosine kinase (PTK) inhibitor, inhibited peripheral blood mononuclear cell (PBMC) proliferation and interleukin-2 production from cultures that were stimulated with phytohemagglutinin (PHA), phorbol 12-myristate 13-acetate (PMA) plus A23187, or PHA plus PMA, and genistein effectively blocked the PHA plus IL-2-induced PBMC proliferation. Further, we also found that genistein inhibited LTB4 production from A23187-stimulated cultures whereas H-7, a PKC inhibitor, had no effect on LTB4 production. Our results suggest that PTK may be necessary for the synthesis of LTB4.
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PMID:Genistein, a selective protein tyrosine kinase inhibitor, inhibits interleukin-2 and leukotriene B4 production from human mononuclear cells. 185 73

DNA synthesis in response to mitogens has been studied in T cells from nine patients with common variable immunodeficiency (CVI) and seven normal individuals. Five out of the nine patients had cells with subnormal responses to the mitogen phytohaemagglutinin (PHA). As PHA-induced responses are largely mediated through activation of Ca(2+)-dependent protein kinase C, we studied whether the defective response was still present on direct activation of protein kinase C. This was done using combinations of concentrations of phorbol 12,13,-dibutyrate and the calcium ionophore ionomycin which induced proliferation in normal T cells. We found that in CVI patients with T cells which had normal responses to PHA, responses to phorbol ester and ionomycin were at the same level as in normal T cells. However, with this treatment, in which the linkage between the membrane receptor and protein kinase C is bypassed, the level of DNA synthesis was still depressed in the patient group whose T cells had subnormal responses to PHA. IL-2 failed to restore the DNA synthesis to normal levels when added with the phorbol ester and ionomycin to T cells from one patient in this group. These data suggest that in a group of CVI patients there are defects in T cell activation pathways at or down-stream of protein kinase C.
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PMID:Defects in proliferative responses of T cells from patients with common variable immunodeficiency on direct activation of protein kinase C. 186 99

We have studied an 8-yr-old male patient with adenosine deaminase-positive severe combined immunodeficiency disease with a normal number of peripheral CD3+, T cell receptor-alpha beta+ T cells. The majority of these T cells expressed the CD8 molecule and were oligoclonal in nature as proven by Southern blot analysis of the T cell receptor genes. T cells failed to proliferate in vitro either upon stimulation with T cell mitogens or when stimulated with a combination of the phorbol ester phorbol myristate acetate and the Ca-ionophore ionomycin. High doses of recombinant IL-2, when added to in vitro cultures, were able to restore proliferation induced by phorbol myristate acetate and ionomycin but the response to concanavalin A remained severely defective. However, activation of the patient's T cells with phytohemagglutinin or concanavalin A induced an increase of free cytoplasmic Ca++, which was 2- to 5-fold higher than in normal CD8+ T cells. Furthermore, phorbol myristate acetate or phytohemagglutinin induced the translocation of protein kinase C from cytosol to plasma membrane. Analysis of membrane phospholipid composition of the patient's T cells disclosed that the ratio of phosphatidylcholine to phosphatidylserine was 5-fold higher than in normal T cells. The abnormal Ca++ response after activation with T cell mitogens as well as the high phosphatidylcholine/phosphatidylserine ratio may be causally linked to the defective in vitro T cell proliferation. Because the capacity of T lymphocytes to produce or respond to IL-2 may vary, the oligoclonality of the T cells of the patient should be considered as well in the explanation of defective cell proliferation.
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PMID:Abnormal signal transduction in a patient with severe combined immunodeficiency disease. 190 23

Recent evidence from our laboratory has demonstrated that NK/LAK cell activation of human lymphocytes is protein kinase C (PKC)-dependent. Here, we have investigated the translocation of PKC in human NK cells exposed to sensitive targets or to PMA, a phorbol ester. In NK cells exposed to K562 for 6 hr, we observed a weak translocation of PKC whereas in NK cells exposed to PMA more than 90% of cytosolic PKC was translocated to the membrane in less than 5 min. Stimulation of NK cells with an NK-resistant target, however, did not translocate PKC even after 6 hr. Translocation of PKC to the membrane was followed by the appearance of PKM, the cytosolic calcium/phospholipid (Ca2+/PL)-independent form of PKC. The conversion of PKC to PKM was mediated by calpain, an intracellular calcium-dependent thiol proteinase. When we used two inhibitors of calpain, calpain inhibitor I (CI-I) and calpain inhibitor II (CI-II), both caused a dose-related enhancement of NK-CMC when the inhibitors were present throughout the 3-hr chromium release assay. This enhancement could be circumvented by PMA or by the PKC inhibitor H-7. CI-I and CI-II added together caused a greater increase in NK-CMC than when each was added alone. CI-I and CI-II also enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), substantiating further our previous contention that the activation of both NK-CMC and ADCC may involve a common lytic pathway. Activation of NK cells with IL-2 for 18 hr at 37 degrees C was inhibited in the presence of CI-I. To investigate a possible feedback inhibition mechanism due to the buildup of PKC, we examined phosphatidylinositol (PI) metabolism in NK cells activated by IL-2 in either the presence or the absence of CI-I. We observed a significant decrease in PI turnover when NK cells, activated in the presence of IL-2 and CI-I, were stimulated with K562 as compared to NK cells activated by IL-2 alone, then stimulated with K562.
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PMID:Inhibition of the calpain-mediated proteolysis of protein kinase C enhances lytic activity in human NK cells. 191 39

The c-fos protooncogene is suspected to play a major role during the activation of cells from different lineages. In particular, c-fos transcription is induced upon entry into a proliferation cycle in a wide variety of cell types. In this study, we have transfected an IL-2-dependent murine T cell line with chloramphenicol acetyl transferase (CAT) reporter constructs, harboring various regions of the human c-fos promoter. We show that IL-2 induces activation of fos CAT reporter constructs in these cells. Furthermore, the induction by IL-2 is mediated through a dyad symmetry element, the serum response element, which is also responsible for fos CAT reporter constructs activation by PMA, a pharmacologic activator of the protein kinase C (PKC). To assess any involvement of PKC in signal transduction for fos CAT reporter activation by IL-2, CTL-L2 cells were PKC-depleted by treatment with high doses of PMA. Such a treatment abolished the transcriptional response of fos CAT reporter constructs to PMA. In contrast, IL-2 was still able to activate fos CAT transcription, albeit with a lower efficiency. These results suggest that PMA-sensitive PKC might be part of intracellular transduction pathways leading to c-fos transcriptional activation by IL-2, and that at least one alternate pathway participates in the complete response. However, these distinct signal transduction pathways have the same DNA target on c-fos promoter, the serum response element.
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PMID:c-fos transcriptional activation by IL-2 in mouse CTL-L2 cells is mediated through two distinct signal transduction pathways converging on the same enhancer element. 191 70

Resting T lymphocytes proliferate in response to a combination of a calcium ionophore and a phorbol ester. This observation suggests that an increase in intracellular calcium free ion concentration [Ca2+]i and activation of protein kinase C (PKC) are sufficient signaling events for the initiation of T cell proliferation. In contrast, an accessory cell-generated costimulatory signal, acting independently of the rise in [Ca2+]i and PKC activation, is required for Ag-induced proliferation of type I T cell clones. We now report that this costimulatory signal is unexpectedly also being delivered via a cell-cell interaction during the response to ionomycin and phorbol ester. In the absence of this signal (at limiting cell numbers), T cells fail to divide. We also demonstrate that proliferation in response to immobilized anti-CD3 mAb requires the cell-cell interaction. These results suggest a model of T cell stimulation in which activation of a costimulatory signaling pathway is important in the regulation of the IL-2 gene, and only in the presence of this (third) signal can an increase in [Ca2+]i and PKC activity induce T cell proliferation. Such a model predicts that IL-2-dependent expansion of T cell clones in vivo in response to Ag receptor occupancy requires the delivery of an independent accessory cell-derived co-stimulatory signal.
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PMID:An intracellular calcium increase and protein kinase C activation fail to initiate T cell proliferation in the absence of a costimulatory signal. 197 May 90

Transmembrane signaling of normal human T cells was explored with mAbs directed at TCR, CD2, CD4, CD5, or CD8 antigens and highly purified CD4+ T cells and CD8+ T cells. Our experiments explicitly show that: (a) crosslinkage of TCR with the CD2 antigen, and not independent crosslinking of TCR and of CD2 antigen or crosslinking of either protein with the CD4 or CD8 antigen induces significant proliferation independent of co-stimulatory signals (e.g., accessory cells, recombinant lymphokines, or tumor promoter), (b) F(ab')2 fragments of mAb directed at the TCR and F(ab')2 anti-CD2, crosslinked with F(ab')2 fragments of rabbit anti-mouse IgG, promote the proliferation of highly purified T cells, (c) a prompt and sustained increase in intracellular free Ca2+ concentration results from crosslinkage of TCR with the CD2 antigen, (d) T cell proliferation induced by this novel approach is curtailed by EGTA and by direct or competitive inhibitors of PKC, (e) crosslinkage of TCR with the CD2 antigen results in the transcriptional activation and translation of the gene for IL-2 and in the expression of IL-2 receptor alpha (CD25), (f) anti-CD25 mAbs inhibit T cell proliferation initiated by crosslinkage of TCR with the CD2 antigen, and recombinant IL-2 restores the proliferative response. Our first demonstration that crosslinkage of TCR with the CD2 antigen induces proliferation of normal human CD4+ T cells and CD8+ T cells, in addition to revealing a novel activation mechanism utilizable by the two major subsets of T cells, suggest that the CD2 antigen might be targeted for the regulation of antigen-specific T cell immunity (e.g., organ transplantation).
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PMID:A novel model for antigen-dependent activation of normal human T cells. Transmembrane signaling by crosslinkage of the CD3/T cell receptor-alpha/beta complex with the cluster determinant 2 antigen. 197 76


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