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)

Human polymorphonuclear neutrophil granulocytes (PMN) were incubated with recombinant interferons (IFNs) and tested for O2 consumption, hydrogen peroxide formation, and chemiluminescence. N-formyl-methionyl-leucyl-phenylalanine (f-MLP, a bacterial peptide analogue) and phorbol myristate acetate (PMA, a protein kinase C activator) were used as PMN stimuli. An increase in O2 consumption after f-MLP-stimulation was seen when PMN had been incubated 2-4 h with either 1000 IU/ml IFN-alpha or 100 IU/ml IFN-gamma, but this increase in O2 consumption was not observed with 1000 IU/ml IFN-beta. Likewise, 100 U/ml IFN-gamma enhanced f-MLP stimulated chemiluminescence, whereas IFN-alpha or IFN-beta (1000 U/ml) had no detectable effects. None of the interferons affected baseline or PMA-stimulated O2 consumption and chemiluminescence, nor did they influence the H2O2-dependent oxidation of intracellular dichlorofluorescein (DCFH) (baseline, f-MLP-stimulated or PMA-stimulated). Our data indicate that some--but not all--aspects of oxygen metabolism in PMN can be affected by IFN, and that there are differences between various subtypes of IFNs regarding their neutrophil priming potential.
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PMID:Interferons affect oxygen metabolism in human neutrophil granulocytes. 246 14

Freshly harvested murine peritoneal macrophages and a line of transformed murine macrophages (RAW) were used in experiments designed to investigate the effect of different interferons (IFN) and interleukin-1 (IL-1) on tumor necrosis factor (TNF) receptors. Low concentrations of IFN-gamma or somewhat higher concentrations of IFN-alpha drastically downregulated the TNF receptors of RAW cells. A similar, but less pronounced, downregulation of TNF receptors was observed in peritoneal macrophages treated with these IFNs. This downregulation could not be accounted for by an induction of TNF secretion. Furthermore, IFN-alpha and gamma interacted synergistically in downregulating TNF receptors of RAW cells. IL-1 also downregulated TNF receptors. When RAW cells were treated with inhibitors of protein kinase C, the downregulation of TNF receptors by IFNs or IL-1 was reversed, and TNF binding increased up to 2-fold over that of untreated cells. Such increase was also observed in RAW cells treated only with the inhibitor of protein kinase C, staurosporine. However, TNF receptors decreased in peritoneal macrophages treated with staurosporine. This finding was explained by activation of macrophages by staurosporine, which induced secretion of TNF. These findings indicate that protein kinase C activity regulates TNF receptors in macrophages.
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PMID:Downregulation of tumor necrosis factor receptors of macrophages by interferons and interleukin-1. Role of protein kinase C activation. 247 93

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

Bacterial lipopolysaccharide (LPS) induces interferon (IFN) secretion and an antiviral state in murine peritoneal macrophages (PM). These cells secrete predominantly IFN-beta, as shown by neutralization assays with monoclonal antibodies. Secretion of IFN-beta is also induced in PM by IFN-gamma. LPS and IFN-gamma synergistically stimulated PM to produce IFN in amounts almost comparable to those induced by infection with Newcastle disease virus. Low levels of IFN-beta mRNA can be detected in freshly harvested PM by hybridization assays. The accumulation of this mRNA is markedly increased in PM treated with LPS or IFN-gamma, and it is further enhanced in the presence of the inhibitor of protein synthesis, cycloheximide. Similar studies were carried out on the RAW 264.7 line of transformed macrophages. These cells are induced to secrete IFN-beta by LPS but not by IFN-gamma, suggesting that this cytokine may elicit such specific response only in PM. IFN-beta mRNA is undetectable in untreated RAW 264.7 cells, and accumulation of this mRNA is induced by LPS but not by IFN-gamma. The secretion of IFN induced by these agents in PM and by LPS in RAW 264.7 cells and the corresponding accumulation of IFN-beta mRNA are blocked by an inhibitor of protein kinase C, staurosporine. The activity of this kinase is apparently necessary to stimulate accumulation of IFN-beta mRNA. The induction of IFN-beta by IFN-gamma appears to be a characteristic response of PM and may be at least in part responsible for the resistance of these cells to viral infections.
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PMID:Bacterial lipopolysaccharide and gamma interferon induce transcription of beta interferon mRNA and interferon secretion in murine macrophages. 249 30

The CD69 (Leu-23) activation Ag is a phosphorylated 28 to 32-kDa disulfide-linked homodimer that is rapidly induced after lymphocyte activation. CD69 is not present on the surface of peripheral blood resting T cells, but is constitutively expressed by CD3bright thymocytes. Activation of protein kinase C (PKC) by stimulation of the TCR/CD3 or by phorbol esters directly induces CD69 expression on T cells. In the attempt to elucidate the function of CD69 we investigated the ability of the CD69 glycoprotein to transmit an activation signal. Cross-linking of CD69 by mAb induced a prolonged elevation of intracellular [Ca2+], mostly due to an influx of extracellular Ca2+. This signal alone was unable to effectively activate PKC. When PKC was simultaneously activated by PMA, stimulation of CD69 induced IL-2 and IFN-gamma gene expression, enhancement of CD25 expression, and ultimately IL-2-dependent T cell proliferation. Both CD4+ and CD8+ peripheral T cells responded to CD69-mediated activation. Stimulation of CD69 induced proliferation of thymocytes as well as peripheral T cells, but both required independent PKC activation by PMA. Cyclosporin A, which does not prevent PKC-induced CD69 expression, completely suppressed CD69-induced IL-2 and IFN-gamma gene expression. Although the signal delivered by the CD69 initiates T cell proliferation, it is unable to trigger cytotoxicity programs in CD69+-activated T cells or T cell clones.
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PMID:T cell activation via Leu-23 (CD69). 250 89

Multinucleated giant cells (MGC) of mononuclear phagocyte origin occur in different tissues in various inflammatory states and pathological conditions. Although MGC are believed to be derived from monocyte-derived macrophages by fusion, their mechanism of formation is not known. In this study, we investigated the role of PMA, a protein kinase C activator, in the induction and formation of MGC from blood monocyte-derived macrophages in in vitro culture. The addition of PMA (1 x 10(-9) to 8 x 10(-8) M) to 3-wk-old cultures of blood-derived monocytes induces cell fusion with a 30% to 80% fusion rate. Moreover, IFN-gamma-treated blood-derived monocyte cultures showed an additional enhancement of fusion rate with the addition of PMA. 1(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride, a protein kinase inhibitor, inhibited the formation of macrophage-derived giant cells when added before phorbol ester and IFN-gamma. These findings suggest that protein kinase C may play an important role in the formation of macrophage-derived MGC.
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PMID:Induction of multinucleated giant cell formation from human blood-derived monocytes by phorbol myristate acetate in in vitro culture. 250 79

The biochemical mechanisms involved in the activation and killing of tumor targets by large granular lymphocytes (LGL) have not yet been clearly defined. This laboratory has investigated these processes by analyzing the effects of protein kinase C (PKC) inhibitors (1-(5-isoquinolinesulfonyl)2-methyl-piperazine-dihydrochloride and retinol) on LGL cytotoxicity and IFN-gamma production. We now report that PKC inhibitors block the LGL functions of 1) NK activity, 2) IFN-gamma production, and 3) LAK activity induced by IL-2. Complete inhibition of cytotoxic activity occurs rapidly because only 2.5 h treatment of the LGL with the inhibitors was required. However, the inhibition of NK activity by the PKC inhibitors could be reversed by IL-2 or the synthetic diacylglycerol, L-gamma-1-oleyl-2-acetol-sn-3-glycerol (OAG), but not by IFN-alpha. The reversal of inhibition observed with OAG indicates that, in these studies, (1-(5-isoquinolinesulfonyl)2-methyl-piperazine-dihydrochloride is inhibiting PKC activity and not the activity of other cellular kinases. Furthermore, inhibition of LGL functional activity with PGE2 could not be reversed with OAG, supporting the contention that PG inhibition of NK activity is mediated by a pathway that does not directly involve PKC. These results indicate, in addition to IL-2-mediated events, that basal NK activity is under PKC regulatory control.
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PMID:Modulation of CD3- large granular lymphocyte functions by agonist and antagonists of protein kinase C: effects on NK and lymphokine-activated killer activity and production of IFN-gamma. 254 2

We have demonstrated that IFN-gamma, a potent peptide mediator in inflammatory responses, operates via the protein kinase C dependent transduction pathway in the induction of class II MHC antigens on rat microvascular endothelial cells. Stimulators of protein kinase C, like PMA, replaced IFN-gamma in the induction of MHC class II on endothelial cells in a dose-dependent manner. Selective enzyme inhibitors of protein kinase C, H-7 as well as sphingosine down-regulated the IFN-gamma induced class II expression in a dose-dependent manner. Addition of cAMP or cGMP in the culture, had no effect on the class II expression on the endothelial cells. Transient rise of cytosolic Ca2+ by calcium ionophore A23187, or a calmodulin antagonist W-7, had no effect on the IFN-gamma induced class II expression.
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PMID:Protein kinase C is crucial in signal transduction during IFN-gamma induction in endothelial cells. 254 4

Indoleamine 2,3-dioxygenase (IDO) is a flavin-dependent enzyme which uses superoxide anion as a cosubstrate to catalyze the decyclization of the pyrrole ring of L-tryptophan to form formylkynurenine. This enzyme is induced in some tumor cells after treatment with IFN-gamma. The mechanism of induction of IDO in tumor cells by IFN-gamma was studied in THP-1 human monocytic leukemia cells. Before the addition of IFN-gamma, no IDO could be detected in these cells. Treatment of THP-1 cells with IFN-gamma produced an induction of IDO, with peak activity occurring 72 to 96 h after addition of IFN-gamma. Because phorbol esters are known to induce many enzymes in cells, most likely through the activation of protein kinase C, the effects of PMA on the induction of IDO were determined. PMA potentiated the IFN-gamma-induced elevation of IDO, but by itself, was unable to induce enzyme activity. Maximum induction of IDO in the presence of PMA and IFN-gamma was obtained by preexposure of the cells to PMA for 48 h before the addition of IFN-gamma. Maximum induction of IDO after the addition of IFN-gamma occurred 24 to 48 h after addition of the cytokine to the culture medium. However, the induction of IDO does not appear to be potentiated through the activation of protein kinase C, because the addition of the protein kinase C inhibitor H-7 had no effect on the induction of IDO when the cells were exposed to PMA and IFN-gamma. Moreover, diacylglycerol was unable to replace PMA in these studies. Studies with cAMP and cGMP analogs suggest a role for these compounds in the regulation of IDO expression.
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PMID:Synergistic effects of phorbol ester and INF-gamma on the induction of indoleamine 2,3-dioxygenase in THP-1 monocytic leukemia cells. 255 14

Interferons (IFNs) play a key role in the defense against virus infection and the regulation of cell growth and differentiation, in part through changes in specific gene transcription in target cells. We describe several differences between the signal transduction events that result in transcriptional activation of the human gene coding for a guanylate-binding protein (GBP) by alpha interferon (IFN-alpha) and gamma interferon (IFN-gamma). Activation by IFN-alpha was rapid, transient, and cycloheximide resistant. Activation by IFN-gamma was slower, sustained, and delayed by cycloheximide. IFN-gamma led to the formation of a stable intracellular signal which led to continued GBP transcription even if the ligand was withdrawn, whereas IFN-alpha-induced GBP transcription decayed rapidly if IFN-alpha was withdrawn. Perturbations of signaling pathways involving classical second messengers (cyclic AMP, Ca2+, protein kinase C) did not induce GBP transcription. However, various kinase inhibitors blocked the transcriptional response to IFN-gamma but not IFN-alpha, suggesting that a specific and possibly novel kinase is involved in gene activation by IFN-gamma.
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PMID:Alpha interferon and gamma interferon stimulate transcription of a single gene through different signal transduction pathways. 255 98


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