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)

Selective inhibition by pertussis toxin (PT) of mitogenic activation of mouse B lymphocytes by bacterial mitogens (peptidoglycan and lipopolysaccharide) and muramyl dipeptide (a synthetic analog of peptidoglycan fragment) was demonstrated. Mitogenic activation of B cells by protein kinase C activators and ionomycin was insensitive to PT. Also PT did not inhibit peptidoglycan- and lipopolysaccharide-induced differentiation of B cells into Ig-secreting cells, when it was added to the cultures after the proliferative stage of the response. B lymphocyte membranes contained two major PT substrates (40 and 41 kDa). The extent of PT-mediated ADP ribosylation of these substrates correlated with the degree of PT-mediated inhibition of mitogenic stimulation of B cells. B cell stimulation by all mitogens tested was not inhibited by cholera toxin at nontoxic concentrations that are known to cause maximal increase in cAMP in B cells. Since the only known substrates for PT-mediated ADP ribosylation in mammalian cells are the alpha subunits of some G proteins, our data suggest that G proteins are present in B cell membranes and that they are involved in B cell activation induced by bacterial mitogens.
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PMID:Correlation between ribosylation of pertussis toxin substrates and inhibition of peptidoglycan-, muramyl dipeptide- and lipopolysaccharide-induced mitogenic stimulation in B lymphocytes. 253 32

Murine bone marrow-derived macrophages (BMM) undergo DNA synthesis in response to growth factors such as colony stimulating factor-1 (CSF-1) and granulocyte-macrophage CSF (GM-CSF). These macrophages can also be "activated," but without subsequent DNA synthesis, by a number of other agents, including lipopolysaccharide (LPS), concanavalin A, zymosan, formyl-methionyl-leucyl-phenylalanine (FMLP), and the Ca2+ ionophore, A23187. When BMM are treated with a range of stimuli, there is some, although not perfect, correlation between transient elevations in both c-myc mRNA and c-fos mRNA levels and increases in DNA synthesis. However, enhanced DNA synthesis and oncogene expression are readily dissociated from rises in inositol phosphates and, by implication, phospholipase C-mediated hydrolysis of phosphatidyl inositol 4,5-bisphosphate. Superoxide formation in BMM can also be dissociated from the other responses and does not necessarily depend on protein kinase C activation.
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PMID:Activation and proliferation signals in murine macrophages: relationships among c-fos and c-myc expression, phosphoinositide hydrolysis, superoxide formation, and DNA synthesis. 255 11

The effect of phorbol esters and mezerein pretreatment on macrophage (M phi) activation for tumor cytolysis, tumor necrosis factor (TNF) secretion, and TNF-alpha mRNA expression was investigated. Following pretreatment with various concentrations (0.01 to 10 micrograms/ml) of phorbol 12-myristate 13-acetate (PMA), phorbol-12,13-dibutyrate (PDBu), or mezerein for 16 h, murine peritoneal M phi were activated with M phi-activating factor (MAF) or calcium ionophore A23187 and tested for cytotoxicity in a 24-h cytolysis assay against 125-I-UdR-labeled P815 mastocytoma and NS-1 myeloma target cells. It was found that pretreatment with all three protein kinase C (PKc) activators inhibited M phi activation for cytotoxicity against P815 cells in a dose-dependent manner. Fifty percent inhibition was achieved at concentrations less than 0.1 micrograms/ml. The inhibition was partially reversible. In contrast, the pretreatment did not at all inhibit but significantly enhanced M phi activation for cytolysis against NS-1 cells. Furthermore, exposure to PMA augmented M phi activation by MAF and A23187 for TNF secretion upon stimulation with trace amounts of lipopolysaccharide (LPS). Although the pretreatment neither enhanced nor significantly reduced the synergistic effect of MAF and A23187 on TNF-alpha mRNA expression, it did increase the expression stimulated by LPS alone. Finally, the PKc activity in M phi treated with PMA, PDBu, and mezerein was down-regulated to about 10% of control. Taken together, our results suggest that: 1) PKc plays an important role in the transduction of activating signals for M phi activation by MAF and A23187 to mediate cytotoxicity against some (P815) but not other (NS-1) tumor cells, 2) the induction of TNF-alpha mRNA expression and TNF secretion may be achieved via a PKc-independent pathway, and 3) M phi are equipped with more than one signal transduction pathways for affecting distinct functional activities.
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PMID:Effects of pretreatment with protein kinase C activators on macrophage activation for tumor cytotoxicity, secretion of tumor necrosis factor, and its mRNA expression. 261 73

Phorbol esters are known to alter microfilaments but it is not clear if the changes correspond to modulation of the phosphoinositide turnover/protein kinase C system. The novel technique of laser scanning confocal epifluorescence was used to study fiber orientation in phorbol ester treated cells. We treated endothelial cells with control agents and agents known to stimulate protein kinase C: 4 alpha-phorbol, phorbol 12-myristate 13-acetate (PMA), phorbol dibutyrate (PDB), or lipopolysaccharide. After incubation with the test agents, the endothelial cell microfilaments were stained with rhodamine pholloidin and viewed by conventional epifluorescence and by laser scanning confocal epifluorescence microscopy. The images obtained by the confocal microscopy corresponded to a thin optical section through the cells, 300 nm or more in thickness. The microfilaments extended predominantly in the plane of focus. After exposure of the cells to phorbol esters, the stress fibers became more nearly parallel in arrangement or were shortened, but remained in the plane of focus. The modification of microfilaments in response to phorbol esters was quantitated by a single blind analysis. In order to compare the morphological changes with a biochemical action of the phorbol esters, we measured phosphoinositide turnover. The dose-dependence of morphological changes was compared and contrasted to the dose-dependent effect of phorbol esters on bradykinin-stimulated phosphoinositide turnover. PMA had about the same EC50 (1-5 nM) for both biochemical and morphological processes. PDB was less potent in inducing the disruption of microfilament structure than in inhibiting phosphoinositide turnover. Lipopolysaccharide was ineffective in inducing a morphological change under these conditions. A simple activation of protein kinase C is insufficient to explain the dose-dependent effects of phorbol esters. Thus a morphometric analysis can help distinguish the potency of cytoskeleton modulators.
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PMID:Effects of phorbol esters on endothelial cell microfilaments: laser scanning confocal microscopy and quantitative morphometry of dose dependent changes. 262 64

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

Human endothelial cells exposed to lipopolysaccharide (LPS), tumor necrosis factor (TNF), or interleukin-1 (IL-1) in vitro acquire a cell surface property that promotes the adherence of neutrophils (PMNs). The common mechanism by which endothelial cells are activated by these agents is unknown. We examined adherence of PMNs to cultured human umbilical vein endothelium (HUVE) pretreated with LPS (100 ng/ml), TNF (100 U/ml), and IL-1 (1 U/ml) in medium alone or medium containing protein kinase inhibitors H-7 or HA-1004. Both compounds inhibit a similar spectrum of protein kinases, but H-7 is an effective inhibitor of protein kinase C, whereas HA-1004 is not. We found that H-7 (25 mumol/L) reduced the adherence of PMNs to LPS-, TNF-, and IL-1-stimulated HUVE monolayers to 16.7% +/- 3.0%, 12.1% +/- 2.5%, and 18.3% +/- 2.9% of control, respectively (mean plus or minus standard error of three experiments); HA-1004 (25 mumol/L) did not inhibit endothelial adhesiveness. Cytotoxicity of H-7 was less than 10% in LPS-, TNF-, and IL-1-treated HUVE. Protein synthesis, as measured by the incorporation of tritiated amino acids, was not significantly impaired in LPS-treated HUVE concurrently exposed to H-7. We conclude that protein kinase C appears to be a necessary common mediator of endothelial cell activation by LPS, TNF, and IL-1.
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PMID:Protein kinase C: a potential pathway of endothelial cell activation by endotoxin, tumor necrosis factor, and interleukin-1. 266 97

Bacterial lipopolysaccharide (LPS) potentiates protein kinase C (PKC)-dependent responses such as the activation of arachidonic acid metabolism in macrophages (Aderem, A. A., Cohen, D. S., Wright, S. D., and Cohn, Z. A. (1986) J. Exp. Med. 164, 165-179). Concomitantly, LPS promotes the myristoylation of a 68K PKC substrate, shown to be equivalent to the 80/87K PKC substrate found in brain and fibroblasts (Aderem, A. A., Albert, K. A., Keum, M. M., Wang, J. K., Greengard, P., and Cohn, Z. A. (1988) Nature 332, 362-364). We have now examined the effect of LPS on the phosphorylation of this 68K PKC substrate. We report here that LPS modifies the kinetics and extent of phosphorylation of the 68K protein. While treatment with LPS alone induces low level phosphorylation of the 68K protein, it markedly increases the rate of subsequent phorbol 12-myristate 13-acetate (PMA)-dependent phosphorylation of this protein. Phosphorylation in LPS-treated macrophages was maximal 1-2 min after administration of PMA, while maximal phosphorylation in macrophages not exposed to LPS was only achieved 6 min after addition of PMA. In addition to increasing the rate of PMA-dependent phosphorylation of the 68K protein in macrophages, LPS also promoted the phosphorylation of a novel peptide on the 68K protein. Thus while PMA stimulated the phosphorylation of two thermolytic phosphopeptides (phosphopeptides 1 and 2), the low level of phosphorylation observed with LPS alone was found to occur on phosphopeptides 1 and 2 as well as on a novel phosphopeptide (phosphopeptide 3). Furthermore, LPS treatment of macrophages potentiated phosphorylation of all three phosphopeptides when the cells were subsequently stimulated with PMA. While phosphorylation stimulated by LPS and PMA was slightly more than additive for phosphopeptides 1 and 2, it was markedly synergistic (increased 14.5-fold) for phosphopeptide 3. Phosphorylation of all three phosphopeptides occurred exclusively on serine. It is possible that LPS-induced myristoylation of the 68K protein directs it to the membrane where its phosphorylation is enhanced by its close association with PKC.
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PMID:Bacterial lipopolysaccharide regulates the phosphorylation of the 68K protein kinase C substrate in macrophages. 272 20

Proteoglycan biosynthesis was studied in human monocytes and monocyte-derived macrophages (MDM) after exposure to typical activators of the monocyte/macrophage system: interferon-gamma (IFN-gamma), lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate (PMA). By morphological examination, both monocytes and MDM were stimulated by these activators. Treatment with IFN-gamma resulted in a slight decrease in the expression of [35S]chondroitin sulfate proteoglycan (CSPG) in both monocytes and MDM, whereas LPS treatment increased the [35S]CSPG expression 1.8 and 2.2 times, respectively. PMA, in contrast, decreased the CSPG expression 0.4 times in monocytes, whereas MDM were stimulated to increase the biosynthesis 1.9 times. An increase in the sulfate density of the chondroitin sulfate chains was evident following differentiation of monocytes into MDM due to the expression of disulfated disaccharide units of the chondroitin sulfate E type (CS-E). However, monocytes exposed to PMA did also express disaccharides of the chondroitin sulfate E type. Furthermore, the expression of CS-E in MDM was increased 2 times following PMA treatment. An inactive phorbol ester, phorbol 12,13-diacetate, did not affect the expression of CS-E in either monocytes or MDM when compared with control cultures, suggesting that protein kinase C-dependent signal pathways may be involved in the regulation of sulfation of CSPG. Exposure to LPS or IFN-gamma did not lead to any changes in the sulfation of the chondroitin sulfate chains.
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PMID:Modulation of the expression of chondroitin sulfate proteoglycan in stimulated human monocytes. 276 47

Human adherent monocytes stimulated with 1 microgram/ml pertussis toxin (PT) produced interleukin-1 (IL-1), as measured by thymocyte co-stimulation assay and enzyme-linked immunosorbent assay (ELISA), specific for IL-1 alpha and IL-1 beta. To clarify the role of protein kinase C (PKC) and calmodulin in IL-1 production, we investigated the effects of a PKC inhibitor, H-7, and a calmodulin antagonist, W-7 on PT- and lipopolysaccharide (LPS)-induced IL-1 production by monocytes. Addition of 10 microM and 20 microM H-7 to the culture medium markedly suppressed both PT- and LPS-induced IL-1 production. PT-induced IL-1 production was significantly suppressed by 5 microM and 10 microM W-7. However, LPS-induced IL-1 production was not suppressed by W-7 at the concentrations tested. When monocytes were labelled with Quin 2/AM, IL-1 production by monocytes stimulated with PT and LPS was markedly suppressed. These results indicate that different pathways are involved in the IL-1 production by PT and LPS; both calmodulin- and PKC-dependent processes are necessary for the IL-1 production induced by PT, whereas LPS-induced IL-1 production is dependent on the PKC. Inhibition of IL-1 production by interfering with intracellular Ca2+ trafficking in Quin 2/AM-loaded monocytes may be associated with the inhibition of PKC and calmodulin activity.
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PMID:Effect of protein kinase C inhibitor (H-7) and calmodulin antagonist (W-7) on pertussis toxin-induced IL-1 production by human adherent monocytes. Comparison with lipopolysaccharide as a stimulator of IL-1 production. 278 78

Lipopolysaccharide treatment of platelets in basal conditions does not produce any effect on serotonin secretion or on phosphatidic acid synthesis or arachidonic acid release. However, a brief exposure of platelets to endotoxin enhances the thrombin-stimulated activation of these parameters, whereas a more prolonged treatment with lipopolysaccharide impairs thrombin action. The results presented here also suggest that very short-term treatment of platelets with lipopolysaccharide activates the inositol 1,4,5-trisphosphate 3-kinase. The long-term effects of endotoxin could be mediated by protein kinase C activation.
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PMID:Effects of Escherichia coli lipopolysaccharide on the phosphoinositide metabolism and serotonin secretion in thrombin-activated platelets. 282 90


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