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

We have investigated the mitogenic action of the phorbol ester 12-O-tetrade-canoylphorbol-13-acetate (TPA) and the calcium ionophore A23187 on peripheral blood mononuclear leucocytes (PBML) from human neonates (cord), their mothers and other unrelated adults. TPA induced similar proliferation among maternal and unrelated adult PBML. In contrast, cord PBML regularly gave lower responses, on average 40-45% at optimal TPA concentration, than either maternal or other adult cells. A23187 had only a weak mitogenic effect on cord and maternal/adult cells. However, A23187 added together with TPA induced a strong proliferative response at low, non-mitogenic concentrations of either agent. Furthermore, TPA and the mitogenic OKT3 antibody showed a marked synergism (5- to 6-fold, on average) among cord PBML, whereas this effect was weaker (up to 2-fold) among maternal/adult cells. Prostaglandin E2 (PGE2), at 1.4 x 10(-6) M, inhibited cord and maternal/adult PBML proliferation induced by A23187 (an average 50% inhibition at optimal ionophore concentration). In contrast, PBML cultures stimulated by TPA or by TPA combined with A23187, OKT3 or PHA were virtually insensitive to PGE2-mediated suppression. Our results suggest that PGE2 can down-regulate ionophore-induced, receptor-mediated lymphocyte responses, whereas post-protein kinase C activation events (induced by TPA) are insensitive to PG-mediated inhibition.
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PMID:Mitogenic action of phorbol ester TPA and calcium ionophore A23187 on human cord and maternal/adult peripheral lymphocytes: regulation by prostaglandin E2. 312 Dec 21

The present study was performed in an attempt to understand the mechanism involved in the inhibition of interleukin 2 (IL-2) synthesis by lipoxygenase (LO) pathway inhibitors. Using the two IL-2-producing lymphoid cell lines, (Jurkat and EL4 cells), we showed first that the inhibitory effect of the phenolic compounds tested (NDGA, BHA and caffeic acid) acted on lymphoid cells themselves and not on eventual monocytic or granulocytic contaminant cells. Secondly, these inhibitors were demonstrated as exerting their effect on two levels: they affected the events controlled by both second messengers implicated in T cell activation, namely rise of intracellular free calcium concentration [( Ca++]i) and protein kinase C (PKC) activation. For this purpose, LO inhibitor effects have been compared: (a) on IL-2 production by the two different lines: Jurkat cells, which need both signals, and EL4 cells, which require only PKC activation for the induction of this production; and (b) on the events induced by the different ways of Jurkat cell activation: PHA (or anti-CD3 monoclonal antibody) versus calcium ionophore. These results are discussed with respect to an eventual involvement of arachidonic acid [AA] derivatives in IL-2 synthesis.
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PMID:Lipoxygenase inhibitors suppress IL-2 synthesis: relationship with rise of [Ca++]i and the events dependent on protein kinase C activation. 312 78

Patterns of the cell cycle distribution in human peripheral blood lymphocytes, stimulated by PHA alone and PHA plus 12-o-tetradecanoylphorbol-13-acetate (TPA), were studied using DNA cytometry in different times after PHA stimulation. In the first period (nearly 3 days after PHA stimulation) TPA induces no significant differences in the characters under consideration, but in the later period, when the proliferation of the cultures stimulated by PHA alone is reducing, in other cultures stimulated by PHA plus TPA the percentage of cells in S-phase does not reduce, whereas the percentage of cells in G2-phase is rising, which may suggest that this phase is blocked. Concurrently the tetraploid cells are appearing. Accumulation of cells in G2-phase can be overcome by the application of chlorpromazine, which is known to inhibit the membrane-associated protein kinase C.
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PMID:[Effect of the tumor promoter TPA on the distribution of PHA-stimulated human lymphocytes by cell cycle phases]. 320 45

Human T and B cells produce leukocyte migration inhibitory factor (T-LIF and B-LIF, resp.). Some properties of T-LIF and B-LIF were compared in this study. T cells were activated by PHA or by a synthetic peptide, representing the Epstein-Barr virus (EBV) nuclear antigen, EBNA1, B cells were exposed to polyclonal activators, anti-IgM or EBV. The kinetic profile of T-LIF and B-LIF released into the culture supernatants from 6 hrs until 24 hrs after activation was identical and termed "peak 2". B cells, in addition, released LIF activity after 30-60 min ("peak 1"). Molecular weight determinations by HPLC gel filtration showed that both peaks contained activity in fractions around 70 Kd. B-LIF also showed a lower molecular weight activity peak. T-LIF and B-LIF activity was equally abrogated with a rabbit anti- human LIF serum. Polymixin-B, a protein kinase C inhibitor and verapamil, a calcium channel-blocking drug, inhibited antigen-induced T-LIF and B-LIF present in "peak 2", whereas the lysosomotropic chloroquine abrogated "peak 1" early activity. We conclude that T-LIF and B-LIF are identical or very similar molecules. B cells might store presynthetized LIF in lysosomic granulae which will be degranulated very early after activation. The second peak represents de novo LIF synthesis, that requires external calcium and intact protein kinase C activity.
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PMID:Studies on leukocyte migration inhibitory factor (LIF) produced by activated T and B cells. 328 66

Mo3e is a protease-sensitive membrane antigen (p75,50) selectively expressed by human monocytic cells (monocytes and U-937 cells) stimulated in vitro by exposure to a variety of activating factors, including phorbol diester compounds, bacterial lipopolysaccharide (LPS), and muramyl dipeptide (MDP)(R.F. Todd et al., J. Immunol. 135, 3869, 1985). Here we report that primary and multiply-passaged cultures of HUVEC also express the Mo3e determinant after stimulation by phorbol myristate acetate (PMA) and related inducers of protein kinase C. As measured in a radioimmunoassay of anti-Mo3e antibody binding to monolayer cultures of HUVEC, unstimulated cells bore little if any Mo3e. After culture for 4-120 hr in medium containing PMA, 4 beta-phorbol dibutyrate, 4 beta-phorbol didecanoate, or mezerein (each at a concentration of 81 nM), or 1-oleoyl-2-acetoyl-sn-3-glycerol (1 mM), HUVEC were found to selectively express the Mo3e determinant. The magnitude of expression was dependent upon the concentration of the stimulus, maximal by 24 hr, and inhibited by cycloheximide. The combination of PMA and the calcium ionophore, ionomycin, had an additive or synergistic effect on HUVEC Mo3e expression. The biologically inactive phorbol compounds 4 beta-phorbol and 4 alpha-phorbol didecanoate failed to stimulate Mo3e expression. Also inactive as inducers of HUVEC Mo3e expression were crude lymphokine and monokine supernatants, recombinant human lymphokines (interferon-gamma and interleukin-2), recombinant human monokines (interleukin-1 and tumor necrosis factor), bacterial cell wall products including LPS and MDP, pharmacologic agents that increase intracellular cyclic adenosine monophosphate (prostaglandin E2, cholera toxin, theophylline, isoproterenol and isobutylmethylxanthine), lectins (Con A and PHA), and heparin. These results indicate that Mo3e is an inducible plasma membrane antigen of not only mononuclear phagocytes but also cultured HUVEC.
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PMID:Expression of Mo3e antigen by cultured human umbilical vein endothelial cells (HUVEC) stimulated by phorbol myristate acetate (PMA) and related pharmacological inducers of protein kinase C. 334 69

Phytohemagglutinin and its isolectins PHA-E4 an PHA-L4 act antiproliferatively on an actively dividing leukemia T-cell line. Both PHA and the isolectins caused an increase in soluble protein kinase C (PK-C) activity without a corresponding decrease in particulate activity. The increase was at a maximum after 10 min and the soluble kinase activity remained high for at least 3 h. There was no direct correlation between the observed antiproliferative potency of the 2 isolectins and their ability to initially affect the distribution of PK-C activity.
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PMID:Antiproliferative response of human leukemic cells. Modulation of cytosolic protein kinase C activity by phytohemagglutinin. 348 41

Stimulation of the T-cell line JURKAT with PHA or anti-T3 antibody leads to a rapid and sustained rise of cytosolic free Ca2+, as determined by quin2 fluorescence measurements. Pertussis toxin and N-ethylmaleimide, substances known to inactivate a regulatory N-protein, caused partial to complete inhibition of the cytosolic free Ca2+ response induced both by anti-T3 or PHA. The high cytosolic free Ca2+ level induced by anti-T3 or PHA declined more rapidly after addition of phorbol ester, phorbol myristate acetate (PMA). PMA did not affect cytosolic free Ca2+ changes induced by ionomycin indicating that the effect of PMA is due to a direct inhibitory effect on a transduction mechanism and not to activation of Ca2+ extrusion. Our data suggest that a regulatory N-protein is involved in the transduction of the PHA and anti-T3 response into a rapid and sustained elevation of cytosolic free Ca2+. Activation of protein kinase C by PMA modulates the calcium response in JURKAT cells, suggesting that protein kinase C may be involved in feedback regulation of the transduction mechanism.
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PMID:Characterization of PHA and anti-T3 induced transduction mechanisms in a human T-cell leukaemia line. 349 99

Anti-Tac monoclonal antibody identifies the receptor for interleukin 2 (IL 2, or T cell growth factor) present on activated human T lymphocytes. By using tritiated anti-Tac, we now report a sensitive and specific binding assay to evaluate cell surface IL 2 receptor expression. IL 2 receptors on human peripheral blood lymphocytes can be detected within 6 hr after PHA stimulation. PHA-induced receptor expression is inhibited by actinomycin D and cycloheximide, but not by mitomycin C, suggesting a requirement for de novo RNA and protein synthesis, but not DNA synthesis. Scatchard analysis of [3H]-anti-Tac binding to lymphocytes stimulated with PHA for 3 days revealed from 20,000 to 60,000 molecules of antibody bound per cell, and a Kd of 1 to 3 x 10(-10) mol/l. Sequential binding studies of activated human lymphocytes maintained in long-term culture with IL 2 demonstrated a progressive decline in receptor number correlating with diminished growth rate. Restimulation with lectin or antigen increased the number of IL 2 receptors, suggesting that IL 2 dependent immune responses may be regulated, at least in part, by IL 2 receptor expression. Receptor number was also increased by PMA. Moreover, similar effects were produced by incubation with phospholipase C but not interleukin 1. Because both PMA and phospholipase C result in activation of protein kinase C, these data suggest the possibility that activation of protein kinase C may induce IL 2 receptor expression.
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PMID:Regulation of interleukin 2 receptor expression: effects of phorbol diester, phospholipase C, and reexposure to lectin or antigen. 609 66

The HLA-B8, DR3 haplotype is overrepresented in several autoimmune diseases, implying that genes predisposing to these disorders are linked to this haplotype. In the patients affected by these diseases, as well as in healthy HLA-B8, DR3 individuals, various dysfunctions reflecting an impairment of T-cell activation have been found. To better characterize T-cell impairment of HLA-B8, DR3-positive healthy individuals, we analyzed the surface expression of early (CD69) and late (CD71) activation phenotypes. MNC cultures were stimulated with PHA and used for T-cell phenotyping by flow cytometry analysis. The results showed that the percentage of CD69+ T cells was significantly decreased in MNC from HLA-B8, DR3+ subjects. This defect was detected in cell cultures from all subjects studied, but it attained significance only in females in the early hours after stimulation. The difference in CD69 expression between HLA-B8, DR3-positive individuals and -negative ones was not due to differences in CD4 and CD8 ratios in the HLA-B8, DR3 cells that underwent activation, as following activation the pattern of CD4 and CD8 antigen expression was the same in both groups of subjects. Concerning the late antigen CD71, no significant difference in percentage was observed between T lymphocytes from HLA-B8, DR3+ and HLA-B8, DR3- subjects at all the times studied. The analysis of the requirements for CD69 expression has suggested that sustained PKC activation and an increase of intracellular CA2+ could be responsible for TCR/CD3-mediated CD69 induction. Thus, present data suggest a defect in the signal transduction pathway of the TCR/CD3 complex.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:T-cell activation in HLA-B8, DR3-positive individuals. Early antigen expression defect in vitro. 755 12

Beta-adrenergic receptor kinase (beta ARK) is a serine-threonine kinase involved in the process of homologous desensitization of G-coupled receptors. beta ARK is a member of a multigene family, consisting of six known subtypes, also named G protein-coupled receptor kinases (GRK 1-6). In this study we investigated the expression of GRKs during the process of T cell activation, which is of fundamental importance in regulating immune responses. T cell activation was induced by exposing mononuclear leukocytes (MNL) to PHA and confirmed by tritiated thymidine incorporation measurement. A substantial increase of GRK activity (as measured by in vitro phosphorylation of rhodopsin) was found after 48 h (331 +/- 80% of controls) and 72 h (347 +/- 86% of controls) of exposure to PHA. A threefold increase of beta ARK1 immunoreactivity was found in MNL exposed to PHA for 72 h. Persistent activation of protein kinase C (PKC) by 10 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) was able to increase beta ARK activity to the same extent as PHA, suggesting a PKC-mediated mechanism. The kinetic of beta-adrenergic-stimulated cAMP production was substantially modified in TPA and PHA-activated cells, indicating that the increased GRK activity resulted in an increased beta-adrenergic homologous desensitization. A three- to fourfold increase in GRK activity was also observed in a population of T cell blasts (> 97% CD3+) exposed to PHA for 48-72 h. A significant increase in beta ARK1 and beta ARK2 mRNA expression was observed 48 h after mitogen stimulation, while mRNA expression of GRK5 and GRK6 was not changed. In conclusion our data show that the expression of GRK subtypes is actively and selectively modulated according to the functional state of T lymphocytes.
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PMID:Regulation of G protein-coupled receptor kinase subtypes in activated T lymphocytes. Selective increase of beta-adrenergic receptor kinase 1 and 2. 781 17


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