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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF) is able to induce a great diversity of cellular responses via modulating the expression of a number of different genes. The multitude of TNF activities may be explained by both structural and functional heterogeneity in TNF receptors as well as by a diversification of postreceptor signal transduction pathways. Purification of TNF receptors has revealed two major, distinct binding proteins (TR60 and TR80). TR60 seems to be an essential component for TNF signaling; the functional role of TR80 remains to be elucidated. The pathway of postreceptor signal transduction involves phospholipase A2, a phosphatidylcholine-specific phospholipase C, protein kinase C, and other serine/threonine and tyrosine-specific protein kinases with as yet unknown function. At the receiving end of TNF signaling, induction of gene expression is mediated through activation of nuclear transcription factors, such as NFkB, AP-1, IRF-1, and NF-GMa.
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PMID:Mechanisms of tumor necrosis factor action. 131 93

Tumor necrosis factor (TNF) is a proinflammatory polypeptide that is able to induce a great diversity of cellular responses via modulating the expression of a number of different genes. One major pathway by which TNF receptors communicate signals from the membrane to the cell nucleus involves protein kinase C (PKC). In the present study, we have addressed the molecular mechanism of TNF-induced PKC activation. To this, membrane lipids of the human histiocytic cell line U937 were labeled by incubation with various radioactive precursors, and TNF-induced changes in phospholipid, neutral lipid, and water-soluble metabolites were analyzed by thin layer chromatography. TNF treatment of U937 cells resulted in a rapid and transient increase of 1'2'diacylglycerol (DAG), a well-known activator of PKC. The increase in DAG was detectable as early as 15 s after TNF treatment and peaked at 60 s. DAG increments were most pronounced (approximately 360% of basal levels) when cells were preincubated with [14C]lysophosphatidylcholine, which was predominantly incorporated into the phosphatidylcholine (PC) pool of the plasma-membranes. Further extensive examination of changes in metabolically labeled phospholipids indicated that TNF-stimulated hydrolysis of PC is accompanied by the generation of phosphorylcholine and DAG. These results suggest the operation of a PC-specific phospholipase C. Since no changes in phosphatidic acid (PA) and choline were observed and the production of DAG by TNF could not be blocked by either propranolol or ethanol, a combined activation of phospholipase D and PA-phosphohydrolase in DAG production appears unlikely. TNF-stimulated DAG production as well as PKC activation could be blocked by the phospholipase inhibitor p-bromophenacylbromide (BPB). Since BPB did not inactivate PKC directly, these findings underscore that TNF activates PKC via formation of DAG. TNF stimulation of DAG production could be inhibited by preincubation of cells with a monoclonal anti-TNF receptor (p55-60) antibody, indicating that activation of a PC-specific phospholipase C is a TNF receptor-mediated event.
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PMID:Tumor necrosis factor induces rapid production of 1'2'diacylglycerol by a phosphatidylcholine-specific phospholipase C. 165 88

The effects of (human recombinant) tumor necrosis factor-alpha on phosphatidylinositol breakdown, release of 1,2-diacylglycerols, mobilization of arachidonate from diacylglycerol and prostaglandin synthesis were examined in a model osteoblast cell line (MC3T3-E1). Tumor necrosis factor-alpha (10 nM) caused a specific (30%) decrease in the mass of phosphatidylinositol (and no other phospholipids) within 30 min of exposure. Tumor necrosis factor-alpha doubled the rate of incorporation of [32P]orthophosphoric acid into phosphatidylinositol, indicating that the turnover of inositol phosphate was enhanced, and increased the content of diacylglycerol in parallel with phosphatidylinositol breakdown. The cytokine (10-50 nM; 4 h) also promoted a specific release of 24-34% of the [3H]arachidonate from prelabeled phosphatidylinositol, a release of 80% of the 3H-fatty acid from the diacylglycerol pool, and a 30-fold increase in the synthesis of prostaglandin E2. The tumor necrosis factor-alpha induced liberation of [3H]arachidonate from diacylglycerol, cellular arachidonate release and the synthesis of prostaglandin E2 were each blocked by an inhibitor of diacylglycerol lipase, the compound RHC 80267 (30 microM). Therefore, we conclude that, in the MC3T3-E1 cell line, tumor necrosis factor-alpha activates a phosphatidylinositol-specific phospholipase C (phosphatidylinositol inositolphosphohydrolase; EC 3.1.4.3) to release diacylglycerol, and increases the metabolism of diacylglycerol to liberate arachidonate for prostaglandin synthesis.
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PMID:Tumor necrosis factor-alpha stimulates phosphatidylinositol breakdown by phospholipase C to coordinately increase the levels of diacylglycerol, free arachidonic acid and prostaglandins in an osteoblast (MC3T3-E1) cell line. 200 18

Tumor necrosis factor (TNF) acts via a cell surface receptor to induce a variety of cellular events including cytolysis, differentiation, and mitogenesis. The mechanisms underlying the cell specific actions of TNF are not known. In the present study, postreceptor events associated with the autoinduction of TNF expression were examined in HL-60 cells. There was no detectable alteration in phospholipase C activity as measured by inositol phosphate generation or release of choline metabolites following TNF stimulation. However, TNF increased the release of arachidonic acid metabolites from HL-60 cells. This increase in arachidonic acid metabolism was associated with a 40% increase in phospholipase A2 activity. Furthermore, the release of arachidonic acid metabolites was blocked by inhibitors of phospholipase A2. Taken together, these findings indicated that TNF stimulates phospholipase A2 and arachidonic acid metabolism in HL-60 cells. The results also demonstrate that TNF expression is induced 15-30 min after stimulation with TNF and that this effect is associated with an increase in the rate of TNF transcription. This autoinduction of TNF mRNA was blocked by inhibitors of phospholipase A2. While the cyclooxygenase inhibitor indomethacin had no detectable effect, ketoconazole and nordihydroguaiaretic acid, inhibitors of lipoxygenase, also blocked the induction of TNF expression by TNF. These findings suggest that phospholipase A2 and lipoxygenase activity are required for the transcriptional activation of TNF gene expression associated with TNF stimulation of HL-60 cells.
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PMID:Phospholipase A2 activation and autoinduction of tumor necrosis factor gene expression by tumor necrosis factor. 212 30

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are cytokines with pleiotropic biological activities, exerting a broad range of overlapping biological functions. The redundancy of TNF and IL-1 activities may be based on the utilization of shared key components of intracellular signaling pathways. Two lipid second messengers have been found to transmit TNF and IL-1 intracellular signals: 1,2-diacylglycerol (DAG), generated by a phosphatidylcholine-specific phospholipase C, and ceramide, generated by sphingomyelinase (SMase). DAG is a well established activator of the important signaling system protein kinase C (PKC), which appears to mediate various cellular responses to TNF or IL-1. In addition, it is obvious that DAG also activates other enzyme systems like acidic sphingomyelinase. SMases have been implicated in a number of TNF responses, including stimulation of cell growth and differentiation, as well as triggering cytotoxicity and apoptosis. The metabolic active cleavage product of SMase, ceramide, is a novel multifunctional lipid second messenger capable of inducing various signaling systems. Both cytokines, TNF and IL-1, stimulate a neutral,plasma membrane-associated SMase that leads to stimulation of a protein kinase and eventually to activation of the mitogen-activated protein (MAP) kinase cascade and phospholipase A2. Ceramide is also capable of stimulating a cytosolic protein phosphatase. PKC plays a role in activation of the nuclear transcription factor AP-1, and the DAG-regulated acidic SMase is involved in transducing TNF signals to the cell nucleus via activation of the nuclear transcription factor NF-kappa B.
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PMID:The role of diacylglycerol and ceramide in tumor necrosis factor and interleukin-1 signal transduction. 796 60

Tumor necrosis factor (TNF) is one of the most potent physiological inducers of the nuclear transcription factor kappa B (NF-kappa B). A key event in the activation of NF-kappa B is the rapid release of the inhibitory subunit I kappa B-alpha. Various inhibitors of serine-like proteases are shown to block TNF-mediated NF-kappa B activation as well as the disappearance of I kappa B-alpha immunoreactivity in primary murine T lymphocytes and in various human leukemic cell lines. The protease inhibitors did not block TNF-induced activation of either phosphatidylcholine-specific phospholipase C or acidic sphingomyelinase (SMase), indicating that the putative protease operates rather downstream of TNF signal transduction processes. I kappa B-alpha degradation could be directly induced by addition of sphingomyelinase or synthetic ceramide to a cell-free system, indicating a stringent coupling of SMase to the NF-kappa B activation pathway. SMase-induced I kappa B-alpha degradation was suppressed by the protease inhibitor dichloroisocoumarin. Together, the data suggest that a TNF-responsive sphingomyelinase triggers the rapid degradation of I kappa B-alpha through a serine-like protease, which appears to be crucial to the control of NF-kappa B activation.
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PMID:Sphingomyelinase activates proteolytic I kappa B-alpha degradation in a cell-free system. 818 52

Tumor necrosis factor-alpha (TNF-alpha), a known pro-inflammatory cytokine, has been suggested to play a role in the pathogenesis of inflammatory bowel disease (IBD) by mediating damage to the intestinal epithelial cells. The present study demonstrates that TNF-alpha potentiates release and metabolism of 14C-labeled arachidonic acid (14C-AA) in cultured intestinal epithelial cells (INT 407). Although TNF-alpha on its own was but a weak stimulator of cellular 14C-AA turnover, it significantly potentiated the release of 14C-AA and 14C-labeled prostaglandin E2(14C-PGE2) after stimulation with three known phospholipase A2 activators: phospholipase. C from Clostridium perfringens, the calcium ionophore A23187, and the phorbol ester 4-beta-phorbol-12-myristate-13-acetate (PMA). The phospholipase A2 inhibitor quinacrine significantly reduced both AA and PGE2 release after combined stimulation with phospholipase C and TNF-alpha. In contrast to its effect on the AA turnover, TNF-alpha did not affect the phospholipase C-stimulated production of platelet-activating factor (PAF-acether). Taken together, these findings indicate that a) TNF-alpha potentiates phospholipase A2-stimulated AA release from cultured intestinal epithelial cells; b) TNF-alpha may stimulate phospholipase A2-dependent AA release without affecting the formation of PAF-acether and c) pretreatment with TNF-alpha potentiates the formation of PGE2 after stimulation with phospholipase A2 activators. In summary, the present investigation points to the possibility that TNF-alpha may stimulate intestinal epithelial cells to produce biologically active AA metabolites and that this stimulation may be modulated by components of the intestinal luminal content, like bacterial toxins.
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PMID:Tumor necrosis factor-alpha potentiates phospholipase A2-stimulated release and metabolism of arachidonic acid in cultured intestinal epithelial cells (INT 407). 848 66

Tumor necrosis factor (TNF) is a pleiotropic mediator of inflammation that has been implicated in the pathogenesis of devastating clinical syndromes including septic shock. We have investigated the role of a TNF-responsive phosphatidylcholine-specific phospholipase C (PC-PLC) for the cytotoxic and proinflammatory activity of TNF. We show here that the cytotoxicity signaled for by the so-called "death domain" of the p55 TNF receptor is associated with the activation of PC-PLC. The xanthogenate tricyclodecan-9-yl (D609), a specific and selective inhibitor of PC-PLC, blocked the cytotoxic action of TNF on L929 and Wehi164 cells. In vivo, D609 prevented both adhesion molecule expression in the pulmonary vasculature and the accompanying leukocyte infiltration in TNF-treated mice. More strikingly, D609 protects BALB/c mice from lethal shock induced either by TNF, lipopolysaccharide, or staphylococcal enterotoxin B. Together these findings imply PC-PLC as an important mediator of the pathogenic action of TNF, suggesting that PC-PLC may serve as a novel target for anti-inflammatory TNF antagonists.
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PMID:Function of the p55 tumor necrosis factor receptor "death domain" mediated by phosphatidylcholine-specific phospholipase C. 876 Aug 26

Tumor necrosis factor-alpha (TNF-alpha) influences hormone synthesis of many ovarian cell types and can also exert cytotoxic effects, possibly by increasing the synthesis of prostaglandins. The purpose of the present study was to characterize the mechanism of TNF-alpha-stimulated prostaglandin; F2 alpha (PGF2 alpha) production in cultured bovine luteal cells. Inhibitors of RNA and protein synthesis (actinomycin D and cycloheximide, respectively) completely blocked TNF-alpha-stimulated PGF2 alpha production. The phospholipase A2 inhibitor, aristolochic acid, prevented TNF-alpha-stimulated, but not basal, PGF2 alpha production, whereas the phospholipase C inhibitor, compound 48/80, was without effect. The addition of arachidonic acid to cultures did not overcome the inhibitory effects of cycloheximide or aristolochic acid. In conclusion, TNF-alpha-stimulated prostaglandin production by bovine luteal cells is dependent upon the stimulation of phospholipase A2 through mechanisms which require synthesis of RNA and protein.
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PMID:Mechanism of action of TNF-alpha-stimulated prostaglandin production in cultured bovine luteal cells. 894 4

Tumor necrosis factor-alpha induces oligodendrocytes apoptosis, and is known to stimulate the hydrolysis of sphingomyelin to form the lipid mediator, ceramide. These data encouraged us to determine whether ceramide itself is able to induce apoptosis in oligodendrocytes. For this purpose the cell-permeable ceramide analog, C2-ceramide was used. Treatment of bovine oligodendrocyte cell cultures with this compound induced cell death in a time- and concentration-dependent manner. The induction of cell death was specifically associated with the action of C2-ceramide and could not be elicited by dioctanoylglycerol (DC8) or phorbol 12-myristate 13-acetate (PMA). Treatment of the cultures with neutral sphingomyelinase, which increased the hydrolyses of endogenous sphingomyelin, resulted in oligodendrocyte death, whereas exposure of the cells to phospholipase C and A2 did not. C2-ceramide treatment caused DNA fragmentation. Morphologic analysis of the cells showed that C2-ceramide treatment resulted in a loss of their processes, reduction of cell volume, chromatin condensation, and formation of apoptotic bodies. These results indicate that ceramide can induce oligodendrocyte apoptosis, and suggest that sphingolipid metabolism plays a key role in the regulation of this process.
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PMID:Induction of oligodendrocyte apoptosis by C2-ceramide. 913 Feb 66


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