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)

A23187 in combination with phorbol myristate acetate (PMA) strongly induces production of interferon-gamma (IFN-gamma) by human peripheral blood mononuclear cells (PBMC) and even by murine PBMC, which respond poorly to A23187 alone. Macrophage depletion of PBMC strongly reduces IFN-gamma production induced by several mitogens, but does not affect IFN-gamma production induced by A23187 and PMA. In addition the same stimuli are able in combination to induce strong amounts of IFN-gamma, even in the Jurkat T cell line. The protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7) and the calmodulin antagonist N-(6-aminoehexyl)-5-chloro-1-naphthalenesulfonamide (W-7) were examined for their ability to inhibit IFN-gamma production induced by PMA and A23187. At concentrations near the Ki for protein kinase C, H-7 failed to inhibit PMA- and A23187-induced IFN-gamma production. In contrast, W-7 at low concentrations inhibited IFN-gamma production induced by the same stimuli. In addition OAG, which is known to directly activate protein kinase C, failed to act synergistically with A23187 in the induction of IFN-gamma. On the basis of these results we propose that A23187 and PMA may mimic the early steps of lymphocyte activation, without the requirement of macrophage, bypassing antigen-, or lectin-induced signal. Our results suggest that Ca2+-calmodulin-dependent reactions other than protein kinase C activation may be essential for IFN-gamma production, at least at level of the producing cells.
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PMID:Early steps in interferon-gamma production: possible involvement of Ca2+-calmodulin-dependent enzymes. 313 11

We have previously shown that recombinant murine interferon-gamma, rIFN-gamma, and recombinant human interleukin-1 alpha, rIL-1 alpha, induce differentiation of murine pre-B-like cell line 70Z/3, a finding associated with stimulation of Na+/H+ exchange across the plasma membrane. The present study was designed to test whether the enhanced Na+/H+ exchange is mediated by Ca2+/phospholipid-dependent protein kinase C. The results show that two structurally different peptides, rIFN-gamma and rIL-1 alpha, induce identical patterns of transient translocation of protein kinase C from the cytosol to the membranes. The increase in membrane-associated protein kinase C activity was first detected 20 min after exposure to the lymphokines. This activity peaked at 30 min and was back to baseline by 2 h. At each time point, the increase in membrane-associated protein kinase C activity corresponded to a decrease in the activity of protein kinase C in the cytoplasmic fraction. The total cellular activity (cytosol + membrane) remained the same. Two series of experiments were carried out to test the role of protein kinase C in mediating the lymphokine-stimulated Na+/H+ exchange. In the first, the effects of rIFN-gamma and rIL-1 alpha on cytoplasmic pH were measured in the presence of a protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, H-7. In the second, rIFN-gamma- and rIL-1 alpha-induced cytoplasmic alkalinization was determined in cells containing decreased protein kinase C activity. Under both experimental conditions, lymphokine-induced cytoplasmic alkalinization was not attenuated. These results indicate that, although both rIFN-gamma and rIL-1 alpha cause association of protein kinase C with membranes, activation of protein kinase C is not required for rIFN-gamma or rIL-1 alpha to stimulate Na+/H+ exchange across the plasma membrane.
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PMID:Interferon-gamma and interleukin-1 alpha induce transient translocation of protein kinase C activity to membranes in a B lymphoid cell line. Evidence for a protein kinase C-independent pathway in lymphokine-induced cytoplasmic alkalinization. 313 39

The content of Ca2+-, phospholipid-dependent protein kinase activity (protein kinase C) in murine peritoneal macrophages treated with recombinant interferon-gamma (IFN-gamma) has been investigated. Protein kinase C activity was solubilized by nonionic detergent extraction of sonicated cells and separated by high performance liquid chromatography on a TSK 4000 SW gel filtration column. The enzyme eluted from the column in a molecular weight range of 60-80 X 10(3) and was identified by virtue of Ca2+ and phospholipid requirements. Macrophages treated with recombinant IFN-gamma exhibited a substantial increase in total protein kinase activity which could be accounted for entirely by increased protein kinase C activity. This activity was enhanced as much as 5-fold over that seen in untreated macrophages and was specific for IFN-gamma in that other agents known to signal changes in macrophage function had no effect. The time required for the elevation of kinase activity was identical to that required for induction of other functions by IFN-gamma in macrophages. These observations suggest that protein kinase C may be a focus of regulatory action in IFN-gamma-mediated macrophage activation.
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PMID:Interferon-gamma modulates protein kinase C activity in murine peritoneal macrophages. 315 35

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

Fas antigen is a cell membrane protein that has been suggested to mediate apoptosis. Using SV40-transformed human keratinocytes, we investigated the Fas-antigen-dependent apoptotic process. The expression of Fas antigen mRNA was markedly induced by interferon-gamma (IFN-gamma) treatment (500 U/ml). After IFN-gamma treatment in the presence of anti-Fas monoclonal antibody, apoptosis was induced, as detected by the formation of nucleosome-sized fragments of DNA and morphologically by apoptotic cells with round homogeneous nuclear beads detected by acridine orange staining. The apoptotic SV40-transformed keratinocytes were analyzed quantitatively by enzyme-linked immunosorbent assay using antihistone and peroxidase-conjugated anti-DNA antibodies to detect cell death. The IFN-gamma- and anti-Fas antibody-dependent apoptotis was observed by 3 h, and the maximal response was observed by 12 h. The induction of apoptosis was significantly augmented by treatment with 10 ng/ml 12-o-tetradecanoyl-phorbol-13-acetate (TPA). TPA alone had no effect on either Fas antigen expression or on the apoptotic process. Other protein kinase C activators (1-oleoyl-2-acetylglycerol and mezerein) also stimulated IFN-gamma-dependent apoptosis, whereas 4-o-methyl phorbol myristate acetate, a very weak protein kinase C activator, had only a slight effect. The TPA-induced augmentation of apoptosis was inhibited by the protein kinase C inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine dihydrochloride (H-7). However, H-7 inhibited only the TPA-induced augmentation of apoptosis; the basal IFN-gamma- and anti-Fas-dependent apoptosis remained in the presence of H-7. Northern blot analysis revealed that c-jun mRNA was induced by IFN-gamma plus anti-Fas antibody treatment as well as by TPA treatment; the addition of IFN-gamma alone to the incubation medium had no effect on the expression of c-jun mRNA. These results indicate that IFN-gamma induces a Fas-antigen-dependent apoptotic process in SV40-transformed keratinocytes and that TPA augments the process through the activation of protein kinase C.
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PMID:Interferon-gamma-dependent stimulation of Fas antigen in SV40-transformed human keratinocytes: modulation of the apoptotic process by protein kinase C. 749 Apr 76

Murine macrophages express high levels of nitric oxide synthase and produce large amounts of nitric oxide (NO) when stimulated with certain cytokines in the presence of a trace amount of lipopolysaccharide (LPS). The stimulatory cytokines include interleukin-1 (IL-1), interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and migration inhibitory factor. Activated macrophages are highly effective killers of intra- and extra-cellular pathogens. However, as excessive NO can lead to immunopathology (diabetes, graft-v.-host disease, EAE, liver cirrhosis, rheumatoid arthritis), NO production is necessarily under tight regulation. A number of cytokines, including IL-4, IL-10 and transforming growth factor-beta, can down regulate the induction of NO synthase in macrophages. In addition, macrophages exposed to LPS alone and then stimulated with a mix of IFN-gamma and LPS express significantly lower levels of NO synthase than cells stimulated without pre-exposure to LPS. Furthermore, NO can reduce the activity of NO synthase by feedback inhibition, and also inhibit the production of IFN-gamma by Th1 cells (thus turning off its own synthesis from upstream). The regulatory pathways involve tyrosine kinase and protein kinase C.
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PMID:The role of nitric oxide in parasitic diseases. 751 Jan

The murine macrophage cell line, J774, when activated with interferon-gamma (IFN-gamma), expressed high level of inducible nitric oxide synthase (iNOS) and bound significantly more [3H]-phorbol-dibutyrate (PBu2) compared to non-activated cells. The increased PBu2 binding to the particulate fraction of the cells is a measure of activation and translocation of protein kinase C (PKC). Both the expression of iNOS and the enhanced. PBU2 binding in the activated J774 cells were significantly inhibited by the pretreatment of the cells with murine recombinant interleukin-4 (IL-4). Stimulation of J774 cells by IFN-gamma and lipopolysaccharide results in the translocation predominantly of the epsilon isoform of PKC (PKC-epsilon), and this is inhibited by IL-4. The inhibition of PKC activation was also evident by measuring the PKC activity in the cytosolic-fraction of the IL-4-treated cells. Activated J774 cells pretreated with IL-4 or a PKC-specific inhibitor (RO31-8220) failed to express mRNA of iNOS analyzed by PCR. These results, therefore, suggest that the inhibition of nitric oxide synthesis in activated murine macrophages by IL-4 is at the transcriptional level and may involve the inhibition of the activation of PKC-epsilon.
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PMID:Inhibition of nitric oxide synthesis by interleukin-4 may involve inhibiting the activation of protein kinase C epsilon. 752 36

Increased blood flow and vascular permeability of early diabetes have been associated with increased nitric oxide formation in diabetic rats, but the specific nitric oxide synthase responsible is unknown. We examined the modulation of the induction and activity of the inducible NOS isoform by high glucose concentration in a murine macrophage cell line, RAW 264.7, and murine glomerular mesangial cells. Culturing both cell types in high glucose concentration led to significant increases in nitrite production and the mRNA encoding iNOS upon stimulation with LPS plus interferon-gamma, as compared with normal glucose concentration. High glucose also modestly enhanced LPS/IFN-gamma-induced stimulation of the iNOS promoter in transient transfection experiments in mesangial cells. Protein kinase C activation led to enhanced mRNA expression of iNOS, and inhibitors of protein kinase C blocked nitrite accumulation in mesangial cells. These findings suggest that high glucose in combination with stimulation by LPS plus IFN-gamma enhances iNOS expression, and protein kinase C activation may be playing a role in this enhancement.
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PMID:Enhanced expression of inducible nitric oxide synthase in murine macrophages and glomerular mesangial cells by elevated glucose levels: possible mediation via protein kinase C. 753 75

The in vitro effect of K+ channel blockers quinidine and verapamil, anion channel blocker SITS and K+ channel openers diazoxide, pinacidil, and BRL 38227 on interferon-gamma (IFN-gamma) induced MHC class I and II expression of Lewis rat peritoneal macrophages was investigated by cell ELISA assay. MHC class I expression was significantly enhanced by diazoxide at concentrations of 10(-5)M to 10(-6)M and by pinacidil and BRL 38227 at the concentration of 10(-6)M. MHC class II expression was enhanced by pinacidil and BRL 38227 at concentrations of 10(-5)M to 10(-6)M. The enhancing effect of pinacidil could be blocked by inhibitors of the protein kinases PKA and PKC suggesting that activation of both is required for optimum induction of MHC molecule expression. K+ and anion channel blockers were less active in modulation of MHC molecule expression. Verapamil had no influence, quinidine suppressed MHC class I expression at concentrations of 10(-4)M to 10(-5)M, and SITS suppressed MHC class I expression at the concentration of 10(-3)M. Since MHC class II expression is essential for efficient antigen presentation to T helper cells and MHC class I expression is required for target cell lysis by cytotoxic T cells, ion channel modulating drugs may be potential candidates for immunopharmacological intervention in inflammatory diseases.
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PMID:Influence of ion channel modulation on in vitro interferon-gamma induced MHC class I and II expression on macrophages. 753 17

To study the potential interaction between cytokine and serotonin (5-HT) signal transduction, we evaluated the effect of interleukin-1 beta (IL-1 beta) on the 5-HT2 receptor-mediated mobilization of intracellular Ca2+ in cultured rat C6BU-1 glioma cells. Pretreatment of cells with IL-1 beta significantly inhibited the 5-HT-induced mobilization of Ca2+ in a dose (30-1000 U/ml)- and time (12-24 h)-dependent manner. Inhibition was observed when cells were stimulated with concentrations of 5-HT of > or = 1 microM, which induced the maximal 5-HT response. Lipopolysaccharide (1 microgram/ml) also inhibited 5-HT-induced Ca2+ mobilization, but heat-inactivated IL-1 beta as well as interferon-alpha (1000 U/ml), interferon-gamma (1000 U/ml), and tumor necrosis factor-alpha (2000 U/ml) did not. The inhibitory effects of IL-1 beta and LPS were significantly prevented by genistein, a selective tyrosine kinase antagonist, and by H7, a potent inhibitor of protein kinase C. These results indicate that IL-1 beta and LPS inhibit 5-HT2 receptor-mediated Ca2+ mobilization via pathways that include the activation of a tyrosine kinase and protein kinase C. The interaction between cytokines (IL-1 beta) and monoamines (5-HT) may serve to modulate signal transduction in the central nervous system.
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PMID:Inhibition of serotonin-induced Ca2+ mobilization by interleukin-1 beta in rat C6BU-1 glioma cells. 755 6


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