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)

1-Oleoyl-2-acetylglycerol (OAG) stimulated IgG and IgM production in a dose-dependent manner in human peripheral blood mononuclear cells (PBM) but not PBM proliferation. 12-O-Tetradecanoyl phorbol-13-acetate (TPA) did not stimulate Ig production. OAG did not stimulate an increase in IL-2 generation or IL-2 receptor expression. H-7, a protein kinase C blocker completely inhibited OAG-stimulated Ig production. The results suggest that OAG stimulation of Ig production is independent of cell proliferation; a generalized increase in T-cell activation does not appear to be necessary in the OAG stimulation of Ig production. Finally, PBMs respond differently to OAG and TPA although both are protein kinase C activators.
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PMID:1-Oleoyl-2-acetylglycerol promotes immunoglobulin production independent of cell proliferation in human peripheral blood mononuclear cells. 278 53

An early consequence of stimulation of T cells via their Ag receptor is the activation of protein kinase C (PKC). It has recently been shown that PKC activity resides in a family of homologous proteins. Inasmuch as T cells are phenotypically and functionally heterogeneous, we examined the possibility that this heterogeneity may be reflected in differential expression of message for PKC isoenzyme genes. RNA from six leukemic T cell lines was probed for PKC-alpha, -beta, and -gamma message before and after activation. These studies revealed significant differences among these lines. None expressed mRNA for PKC-gamma. Whereas all cells possessed message for PKC-alpha, there was consistent variability in the level expressed. The greatest heterogeneity was seen with PKC-beta. Two cell lines, HUT 78 and HPB-ALL, did not hybridize with the beta probe under any conditions tested. We subsequently used these PKC-beta negative cells to study the role of this isoenzyme in mediating some of the effects seen with phorbol esters that directly bind to and activate PKC. Our results indicate that PKC-beta, which is expressed in some T cells, is not necessary for PMA-induced CD3 or CD4 internalization, IL-2 production, or acquisition of the p55 chain of the IL-2 receptor.
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PMID:Heterogeneity of protein kinase C isoenzyme gene expression in human T cell lines. Protein kinase C-beta is not required for several T cell functions. 278 92

Many cytokines have been documented to have a multiplicity of biological effects by acting on a variety of cells. In order to determine whether human BCGF-II acts on any cells in addition to normal B cells, the effect of human BCGF-II on murine thymocytes, human peripheral blood T cells, a human natural killer-like cell line, YT, and Epstein-Barr virus (EBV)-transformed B-cell lines was further examined. BCGF-II augmented incorporation of [3H]thymidine by murine thymocytes in combination with suboptimal doses (0.5 microgram/ml) of concanavalin A (Con A) but not at lower doses (0.1 microgram/ml) of Con A, a concentration usually used for interleukin 1 (IL-1) assays. BCGF-II could not induce proliferation or Tac antigen (Ag) expression on normal peripheral blood T cells stimulated with OKT3 antibody. Both proliferation and Tac Ag expression on YT cells were also augmented by BCGF-II. BCGF-II induced both high- and low-affinity IL-2 receptor (IL-2R) on YT cells as determined by 125I-IL-2-binding assay. Two of seven EBV-transformed B-cell lines tested (ORSON and AUM cells) in response to BCGF-II exhibited augmentation of proliferation and cell surface Tac Ag expression. BCGF-II in the presence of low doses (0.1 microgram/ml) of phorbol myristate acetate (PMA) also induced Tac Ag mRNA (3.5 and 1.5 kb) in these B-cell lines. The IL-2R induced on these B-cell lines, however, consisted mostly of low-affinity receptors. Both Tac Ag and its mRNA in these B-cell lines were not induced by Forskolin but by PMA, suggesting that this induction may involve protein kinase C. The present study shows that human BCGF-II can stimulate YT cells, murine thymocytes, and some EBV-transformed B-cell lines but not peripheral blood T cells. Consequently, BCGF-II can induce the growth and differentiation of a number of cell types in addition to normal B cells.
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PMID:A major 50-kDa human B-cell growth factor-II induces both Tac antigen expression and proliferation by several types of lymphocytes. 282 95

Toxic shock syndrome toxin-1 (TSST-1) is a 22-kDa exotoxin produced by most Staphylococcus aureus strains responsible for toxic shock syndrome. TSST-1 is a mitogen for human T cells. The mechanism of T cell activation by TSST-1 was investigated. TSST-1 induced IL-2R expression, IL-2 synthesis, and proliferation in T cells in a monocyte-dependent fashion. Neither IL-1 nor IL-2, alone or in combination, substituted for monocytes in supporting TSST-1-induced mitogenesis. We investigated the mechanism by which TSST-1 induces initogenesis. TSST-1 failed to induce ADP-ribosylation of T cell membrane proteins. However, the toxin induced transient translocation of protein kinase C from cytosol to plasma membranes and also induced the mobilization of cellular Ca2+ stores in both PBMC and the Jurkat human tumor T cell line, suggesting that TSST-1 triggered inositol phospholipid turnover. This was directly demonstrated to be the case in both cellular preparations studied. TSST-1 induced the increased synthesis of the inositol phospholipid phosphatidyl inositol, phosphatidyl inositol-4 phosphate, and phosphoinositol inositol-4,5-bisphosphate, and induced the breakdown of inositol phospholipid as evidence by the accumulation of phosphatidic acid and inositol phosphates. We conclude that the action of TSST-1 involves the induction of inositol phospholipid turnover, protein kinase C activation, and mobilization of cellular Ca2+ stores. This effect is similar to that of mitogenic lectins and of anti-CD3 antibodies.
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PMID:Toxic shock syndrome toxin-1 induces inositol phospholipid turnover, protein kinase C translocation, and calcium mobilization in human T cells. 283 Mar 36

The proliferative responses of natural killer (NK) cells to 12-O-tetradecanoylphorbol-13-acetate (TPA), which directly activates protein kinase c(PKC), and to the Ca2+ ionophores A23817 and ionomycin, known to enhance the intracellular calcium, have been investigated. Highly purified large granular lymphocytes (LGL) were cultured for 12-30 hr in the presence of TPA, ionomycin, or A23817. TPA alone (1-20 ng/ml) triggered rapid LGL proliferation, whereas the calcium ionophores were ineffective. The addition of either calcium ionophore to suboptimal doses or TPA (0.1-0.5 ng/ml) resulted in a synergistic effect on LGL proliferation. Under these conditions high levels of IL-2 activity were released by the LGL. Phenotypic analysis revealed the rapid loss of the Fc gamma receptors (CD16) on LGL and the induction of the expression of IL-2 (CD25) and transferrin receptors and of HLA-DR, but not of CD3. Removal of extracellular Ca2+ by addition of EGTA at the beginning of the culture greatly depressed LGL proliferation and IL-2 production, and blocked phenotypic changes, such as the expression of Tac antigen. Finally, progression to the proliferative phase of LGL, activated by TPA alone or with ionomycin, was completely abrogated by a hyperimmune anti-IL-2 antiserum.
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PMID:Proliferative effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and calcium ionophores on human large granular lymphocytes (LGL). 283 70

Conjugation between human NK cells and susceptible target cells (K562 and Jurkat) leads to breakdown of inositol lipids in the effector cells but not when conjugated with resistant target cells. Extracellular Ca2+ is required for this activation. Sphingosine inhibits NK killing in both normal and IL-2-activated NK cells. Phorbol esters, TPA, and PDBU enhanced NK killing at low concentrations, where 4-alpha-PDIDE did not. The diacylglycerol derivative OAG increased NK cell killing and activated PKC from human lymphocytes. These results strongly suggest that phosphoinositide breakdown and activation of PKC is involved in NK killing.
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PMID:Phosphoinositide breakdown and evidence for protein kinase C involvement during human NK killing. 283 72

The regulation of the activation of T lymphocyte proliferation is not well understood. It is known that the tumor promoter, PMA, which activates protein kinase C (PKC), can induce the proliferation of several murine CTL clones; in combination with calcium ionophores, which raise the level of intracellular Ca2+, PMA can also stimulate the proliferation of several HTL clones. Activation of the TCR is believed to result in the liberation of diacylglycerol, which is an activator of PKC, and inositol 1,4,5-trisphosphate, which stimulates an increase in intracellular levels of calcium. We now report that pretreatment with cholera toxin (CT) inhibits the proliferation of murine T cell clones stimulated through the TCR/CD3 complex. In addition, CT-pretreatment blocks the proliferation of CTL clones activated with PMA or of HTL clones activated with PMA + calcium ionophore. In contrast, CT-pre-treatment inhibits much less effectively (100- to 1000-fold) the proliferation of these T cell clones stimulated with IL-2. Furthermore, activators of PKC, but not IL-2, potentiate the CT-induced cAMP elevation in T cell clones. The ability of CT to inhibit much more effectively the proliferation triggered by putative activators of PKC than that induced by IL-2 may be mediated by cAMP-dependent mechanisms.
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PMID:Cholera toxin discriminates between murine T lymphocyte proliferation stimulated by activators of protein kinase C and proliferation stimulated by IL-2. Possible role for intracellular cAMP. 284 87

Mice infected with the protozoan parasite Trypanosoma cruzi, the causative agent of human Chagas' disease, are profoundly immunodepressed in their response to various Ag and mitogens. A key factor in this immunosuppression is the essential inability to produce the T cell growth factor IL-2. In this study we demonstrate that this failure to produce IL-2 in response to mitogen stimulation is not the result of the absence of production of soluble or membrane-bound IL-1 by macrophages. Limiting dilution analysis of the precursor frequency of IL-2 producers suggests that an adequate number of precursors for IL-2 production are present in the spleens of infected mice, but that their activity may be regulated by suppressor cells. The presence of precursor cells for IL-2 production is supported by experiments showing that the combination of calcium ionophores and PMA elicits IL-2 production by spleen cells from both normal and T. cruzi-infected mice. Although Con A can provide either of the signals necessary for IL-2 production, calcium flux or protein kinase C activation, to T cells from normal mice, Con A in combination with either calcium ionophore or phorbol ester failed to activate T cells from infected mice to produce IL-2. Preculture of spleen cells from infected mice for 48 to 72 h before addition of Con A results in near normal production of IL-2. This recovery of the capacity to produce IL-2 does not occur if parasite Ag is present during the preculture period. These results suggest that the inability of T cells from T. cruzi-infected mice to produce IL-2 in vitro in response to Con A is not due to the lack of IL-2-producing cells, but may be the result of the maturational state of the T cells or to the presence of a suppressor population.
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PMID:Trypanosoma cruzi-induced suppression of IL-2 production. I. Evidence for the presence of IL-2-producing cells. 296 29

The murine T-lymphoma cell line LBRM-33 is known to require synergistic signals delivered through the antigen receptor (Ti-CD3) complex, together with interleukin 1 (IL-1), for activation of IL-2 gene expression and IL-2 production. Although 12-O-tetradecanoylphorbol-13-acetate (TPA) was capable of replacing IL-1 as an activating stimulus under certain conditions, biologic studies indicated that TPA failed to synergize with Ti-CD3-dependent stimuli under conditions in which IL-1 was clearly active. Acute exposure to TPA and other active phorbol esters resulted in a concentration-dependent inhibition of the increases in phosphoinositide hydrolysis and intracellular free Ca2+ concentration stimulated by phytohemagglutinin or anti-Ti antibodies. TPA treatment induced no direct alteration of phospholipase C enzymatic activities in LBRM-33 cells. In contrast, both Ti-CD3 cross-linkage and TPA rapidly stimulated the phosphorylation of identical CD3 complex polypeptides, presumably via activation of protein kinase C. Exposure of LBRM-33 cells to TPA resulted in a time-dependent, partial down-regulation of surface Ti-CD3 expression. Thus, TPA treatment inhibited the responsiveness of LBRM-33 cells to Ti-CD3-dependent stimuli by inducing an early desensitization of Ti-CD3 receptors, followed by a decrease in membrane receptor expression. These studies indicate that phorbol esters deliver bidirectional signals that both inhibit Ti-CD3-dependent phosphoinositide hydrolysis and augment IL-2 production in LBRM-33 cells.
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PMID:Inhibition of T-cell antigen receptor-mediated transmembrane signaling by protein kinase C activation. 297 23

The polypeptide hormones that govern the proliferation and differentiation of the mature immune system and hematopoiesis are collectively referred to as lymphokines. We have examined a number of biochemical and molecular events stimulated by several unique lymphokines that exhibit proliferative activity on lymphoid and myeloid cell lines. IL-2 and several members of the colony-stimulating factors (multi-CSF, G-CSF, and GM-CSF) stimulate a similar pattern of cellular phosphorylation, including the prominent phosphorylation of a 68-kD substrate present in numerous distinct lineage cell lines. The 68-kD substrate is phosphorylated by protein kinase C on threonine residues and is primarily cytosolic. Another kinase system activated by either physiological ligand or synthetic diacylglycerol phosphorylated the 40S ribosomal S6 protein in a dose-dependent manner. The increased phosphorylation of S6 protein was associated with enhanced chain elongation in vitro. The kinase responsible for the in situ phosphorylation, however, was not protein kinase C but another physicochemically distinct Mg++-dependent enzyme (termed S6 kinase). These studies suggested that although protein kinase C was activated by diacylglycerol, another kinase, S6 kinase, was the effector enzyme involved in the phosphorylation of the 40S protein. IL-2 and all other lymphokines tested stimulated the transcription of the nuclear protooncogenes c-fos, c-myc, and c-myb, as well as a member of the heat shock family of proteins, HSP 70. Phorbol esters also stimulated similar gene expression; however, cAMP analogue inhibited phorbol ester- or ligand-induced c-myc expression. cAMP agonists are antiproliferative to all the growth factors tested.
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PMID:Biochemical and molecular events controlled by lymphokine growth factors. 307 55


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