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

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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)

The activation of protein kinase C involves its translocation from a cytosol fraction to a membrane fraction. Effects of interferon-gamma (IFN-gamma) on the epidermal protein kinase C were investigated. The treatment of recombinant human IFN-gamma on intact human epidermis resulted in the translocation of protein kinase C from a cytosol to a membrane fraction. The human IFN-gamma had no translocation effect on pig epidermal protein kinase C. Tumor promoter, 12-o-tetradecanoylphorbol-13-acetate (TPA), and a membrane-permeable diacylglycerol analogue, 1-oleoyl-2-acetylglycerol (OAG), both of which are well-known activators of protein kinase C, translocated the epidermal protein kinase C. The IFN-gamma had no direct effect on the epidermal protein kinase C; the addition of the IFN-gamma to partially-purified pig epidermal protein kinase C had no effect on its activity. The effect of the IFN-gamma on human epidermal protein kinase C appears to be through the species specific IFN-gamma receptors. It has been reported that the epidermal beta-adrenergic adenylate cyclase response is decreased following the TPA- (and OAG-) induced activation of protein kinase C. Human recombinant IFN-gamma, however, had no effect on the beta-adrenergic response of the human epidermis. Our results indicate that IFN-gamma affects intact keratinocytes in vitro, resulting in the activation of protein kinase C, which might be related to the physiological effect of IFN-gamma on keratinocyte.
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PMID:Translocation of protein kinase C from cytosol to membrane fractions in human epidermal keratinocytes by recombinant human interferon-gamma. 215 6

The roles of intracellular second messengers in interferon-gamma (IFN-gamma)-induced Ia antigen (Ag) expression by astroglia and microglia were examined. Ia Ag on both glia types was induced by IFN-gamma. Reagents known to increase intracellular cAMP or activate intracellular protein kinase C (PKC) reduced IFN-gamma-induced Ia Ag expression by astroglia. In contrast, increasing intracellular cAMP had no suppressive effect on Ia Ag expression by microglia. These results indicate (1) cAMP and PKC negatively regulate IFN-gamma-induced Ia expression on astroglia, and (2) Ia expression is regulated differentially in astroglia vs. microglia. These findings may explain the frequent observation of Ia+ microglia (or macrophages) but not astroglia in various neurodegenerative diseases.
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PMID:Differential suppression of interferon-gamma-induced Ia antigen expression on cultured rat astroglia and microglia by second messengers. 217 Apr 39

A human T-leukaemic cell line, HSB.2-C5B2, which produces high levels of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) when stimulated with phytohaemagglutinin (PHA) plus IL-1, was recloned to obtain spontaneous variants in IL-2 production in response to the stimuli. In these subclones, the ability of one clone to produce IL-2 correlated well with that to produce IFN-gamma. Three C5B2 subclones: clone no. 28, a high IL-2 producer, clone no. 61, an intermediate IL-2 producer, and clone no. 40, a non-producer, were selected and examined for differences in signal transduction mechanisms. Since the three subclones were shown to express about the same number of IL-1 binding sites with similar affinities, the loss of ability to produce IL-2 was not due to decreased cell-surface receptor or changes in receptor property. In support of this, IL-1 induced expression of the IL-2 receptor (Tac/p55 antigen) to the same extent on the three subclones. The levels of conventional intracellular second messengers were compared and it was revealed that loss of responsiveness was closely related to the subclones' degree of (poly)phosphoinositide (PI) turnover, protein kinase C (PKC) activation and cyclic AMP formation in response to PHA. Moreover, resting intracellular cyclic AMP concentrations were found to be increased in subclones with attenuated IL-2 production. These results indicate that the variation of IL-1-induced production of IL-2 and IFN-gamma in this T-cell line is attributed to the difference in the PHA-mediated signal transduction pathway and, presumably, to the different regulation of intracellular cyclic AMP.
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PMID:IL-1-induced production of IL-2 and IFN-gamma in subclones of human T-cell derived leukaemia HSB.2 cells: regulation by phytohaemagglutinin-mediated (poly)phosphoinositide breakdown and cyclic AMP. 217 58

Murine macrophages from sites of inflammation develop toward tumoricidal competence by exposure to a macrophage-activating factor such as interferon-gamma (IFN-gamma). To explore the biochemical transductional events initiated by IFN-gamma, peritoneal macrophages from C57BL/6J mice elicited by various sterile irritants were treated in vitro with two pharmacologic agents that mimic the action of certain second messengers. Phorbol myristate acetate (PMA) and the ionophore A23187 cooperatively reproduced the ability of IFN-gamma to prime macrophages for tumoricidal function. Neither agent alone was able to prime macrophages. The two agents acted on the macrophages, and target susceptibility to kill was not altered by PMA and A23187. Only active phorbol esters, which are known to bind and stimulate protein kinase C, were able to cooperate with A23187 to induce priming. A cell-permeable synthetic diacylglycerol (sn-1,2-dioctanoyl glycerol) could also prime for cytolysis. In the presence of PMA, A23187, and EGTA, addition of Ca++ was sufficient for priming, whereas the addition of Mg++ was much less efficient. Priming by IFN-gamma, however, was not blocked by EGTA. Efflux of 45Ca++ from preloaded cells was significantly increased by A23187 and by IFN-gamma. Quin-2/AM, an intracellular chelator of Ca++, blocked priming by IFN-gamma. In summary, the data suggest that priming of macrophages for tumoricidal function by IFN-gamma involves, at least in part, alterations in protein kinase C and in levels of intracellular Ca++.
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PMID:Phorbol esters and calcium ionophore can prime murine peritoneal macrophages for tumor cell destruction. 242 76

At least two biologically significant responses are triggered by the crosslinking of the T-cell receptor (TcR) on the surface of cloned cytotoxic T lymphocytes (CTL): synthesis and secretion of macrophage-activating factor(s) (MAF) that can be attributed to interferon-gamma (IFN) and release of preformed cytolytic granules. We directly compared the molecular requirements for synthesis and secretion of IFN and secretion of granule enzymes triggered in the same cell by the same activating ligand (antigen or monoclonal antibody (mAb) to TcR). An increase in the surface density of activating ligand (immobilized anti-TcR mAb) enhanced both secretion of IFN and secretion of granules. Secretion of IFN occurred immediately after synthesis: only low (but detectable) levels of IFN were detected in cell cytosolic or particulate fractions isolated from Percoll gradients of lysed CTL, while very high levels of IFN were found in the stimulated CTL culture fluids. Inhibitors of RNA synthesis and protein synthesis blocked secretion of IFN, but did not inhibit release of preformed cytolytic granules. The requirement for TcR crosslinking in triggering both secretion of granules and secretion of IFN from CTL was pharmacologically reproduced by the synergistic action of PMA, a protein kinase C activator, and the Ca2+ ionophore A23187. Both secretion of IFN and secretion of granules were absolutely dependent upon extracellular Ca2+: EGTA completely blocked both TcR- and PMA/A23187-induced secretion of IFN and exocytosis of granules. These studies suggest that similar molecular mechanisms are involved in secretion of newly synthesized IFN and secretion of preformed cytolytic granules. One notable difference between the molecular requirements for the two secretory events was a much lower concentration requirement for PMA for IFN synthesis and secretion than for granule secretion in the synergistic interactions with A23187. Implications of these studies for the exocytosis model of cell-mediated cytotoxicity are discussed.
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PMID:Similar molecular requirements for antigen receptor-triggered secretion of interferon and granule enzymes by cytolytic T lymphocytes. 247 2

Among the cytokines tested here (IL-2, IL-3, IL-4, IL-5, IL-6, granulocyte colony stimulating factor (G-CSF), granulocyte/macrophage colony stimulating factor (GM-CSF), interferon-alpha (IFN-alpha), interferon-beta (IFN-beta) and interferon-gamma (IFN-gamma] only interleukin 1(IL-1) augmented HIV-long terminal repeat(LTR) directed chloramphenicol acetyl transferase(CAT) activity in protein kinase C(PKC)-independent manner. However, a stimulation by IL-1 was not as efficient as that due to tumor necrosis factor and the HIV production was not significant. IL-1 was not cytotoxic to MOLT-4/HIV cells.
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PMID:Effect of interleukin-1 on the augmentation of human immunodeficiency virus gene expression. 248 Jul 82

We have previously shown that interleukin-1 alpha (IL-1 alpha) and interferon-gamma (IFN-gamma) induce surface IgM expression, stimulate Na+/H+ exchange, and activate protein kinase C in the murine pre-B lymphocyte cell line, 70Z/3. Because the two structurally different lymphokines induce similar effects, in this study we set out to compare the properties of the IL-1 and IFN-gamma surface receptors. In contrast to their similar cellular effects, we found that IL-1 alpha and IFN-gamma receptors have different properties. 70Z/3 have high (100 sites/cell) and low (900 sites/cell) affinity IL-1 receptors with dissociation constants (KD) 6 x 10(-11) and 10(-9) M, respectively. In contrast, IFN-gamma receptors are of one class with a KD of 3 x 10(-10) M and are at a higher number, 8000 sites/cell. After binding to their receptors both IL-1 alpha and IFN-gamma are internalized and intracellularly degraded, but the rate of internalization of IFN-gamma is greater than IL-1 alpha. The effective median concentrations (EC50) of IL-1 alpha- or IFN-gamma-induced surface IgM expression are similar (4-5 x 10(-12) M). However, at this concentration 10-fold more of IFN-gamma than IL-1 alpha molecules are bound per cell. Our studies indicate that structurally different lymphokines can induce similar biological events even though their signaling is mediated by surface receptors whose properties are different.
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PMID:Properties of interleukin-1 and interferon-gamma receptors in B lymphoid cell line. 252 27

Human eosinophilic cell line EoL-1 was studied using luminol-dependent chemiluminescence (CL) for the ability to produce a respiratory burst upon stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). TPA, a potent activator of protein kinase C, induced a biphasic CL response in EoL-1. Treatment of EoL-1 with interferon-gamma (IFN-gamma) for 5 days dramatically enhanced TPA-inducible CL, and IFN-alpha A had a similar effect. Neither IFN-gamma nor IFN-alpha A strongly inhibited EoL-1 cell growth. Tumor necrosis factor (TNF) also enhanced TPA-inducible CL response of EoL-1 and, furthermore, was quite inhibitory to EoL-1 cell growth. The effects of IFN-gamma and TNF were synergistic, whereas those of IFN-alpha A and TNF were additive. Superoxide dismutase completely abrogated TPA-induced CL, but sodium azide suppressed only the late phase of CL. EoL-1 pretreated with IFN-gamma, IFN-alpha A, or TNF also became capable of producing CL response to a chemotactic peptide (fMLP). The effects of IFN-gamma and TNF were again synergistic. EoL-1 cells treated with IFN-gamma, IFN-alpha A, or TNF had abundant cytoplasm, but only TNF increased cells having distinct eosinophilic granules. IFN-gamma but not IFN-alpha A enhanced the cytological effect of TNF. It was further demonstrated that treatment of EoL-1 with IFN-gamma and TNF strongly increased the binding sites for phorbol diesters and also dramatically induced the surface expression of fMLP receptors. IFN-gamma had, however, little effect on the number or the ligand-binding affinity of TNF receptors on EoL-1. Thus, EoL-1 may provide a useful experimental model for the study of differentiation and regulation of human eosinophils.
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PMID:Membrane oxidative metabolism of human eosinophilic cell line EoL-1 in response to phorbol diester and formyl peptide: synergistic augmentation by interferon-gamma and tumor necrosis factor. 253 64

This study was designed to determine the effect of the phenothiazine chlorpromazine (CPZ) on the activation of human thymocytes. We provide evidence that CPZ inhibits the accumulation of mRNA specific for the lymphokines, interleukin 2, interferon-gamma, tumor necrosis factor alpha and the proto-oncogene c-myc; by contrast, the accumulation of mRNA specific for the alpha chain of the interleukin 2 receptor and the subsequent early expression of Tac antigen on the cell surface is not inhibited by CPZ. The inhibition of the expression of lymphokine-specific mRNA results in a decrease in interferon-gamma synthesis and in inhibition of thymocyte proliferation as determined by the incorporation of [3H]thymidine. In addition, we show that activation of protein kinase C (PKC) in human thymocytes by 12-O-tetradecanoyl phorbol 13-acetate (TPA) causes the phosphorylation of a protein of a molecular mass of approximately 75 kDa. The function of this protein is as yet not defined, but it is possible that it plays a role in the transduction of the signals to the nucleus which in turn elicit the expression of the genes coding for c-myc and for the lymphokines required for thymocyte activation. We also demonstrate that CPZ, like the immunosuppressant drug cyclosporin A does not inhibit the phosphorylation of the 75-kDa protein which is induced by the activation of PKC by TPA and does not affect phosphoinositide breakdown, indicating that it exerts its effect at a site distal to the activation of PKC. These observations demonstrate that CPZ has an immunoregulatory function in addition to its psychotropic activity.
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PMID:Inhibition by chlorpromazine of lymphokine-specific mRNA expression in human thymocytes. 255 Feb 48

Recent studies have identified some of the early molecular transductional events, which occur during the activation of murine macrophages. Our current evidence indicate a central role for protein kinase C for the priming effect of interferon-gamma (IFN gamma). IFN gamma also initiates Na+/H+ exchange and 45Ca efflux from murine macrophages (cascade I). Our data further indicate the involvement of multiple transductional pathways in the actions of bacterial lipopolysaccharide (LPS). Specifically, molecular events involved in the action of LPS include production of inositol phosphates and calcium mobilization as well as IFN gamma-regulated alterations in intracellular pH (cascade II). Our data further indicate that additional transductional events (e.g., synthesis of early or competence proteins) in response to LPS (cascade III) are also necessary for macrophage activation. Finally, regulation of important surface (e.g., Ia) and secreted molecules (TNF or IL-1) is exerted at the levels of both transcription and stabilization of specific mRNA in response to transductional cascades I, II and III. Taken together, the data indicate macrophage activation is complexly regulated at multiple levels.
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PMID:Molecular events in the activation of murine macrophages. 265 10


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