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)

The role of polymorphonuclear leukocytes (PMN) in stemming systemic infection is executed mainly by the utilization of molecular O2 leading to the production of reactive oxygen intermediates (ROI). PMN-derived ROI also serve as intra- and extracellular second messengers providing both positive and negative feedback on cellular autoregulation. We investigated the effect of endogenous ROI on two signal transducing pathways: the receptor (R)-G-protein-phospholipase D (PLD) and receptor (R)-G-protein-phospholipase C pathways responsible for the subsequent interleukin-8 (IL-8)-induced PMN respiratory burst. Purified human PMN were primed with LPS adhered to plastic surfaces and stimulated with IL-8 with or without the presence of each of five different selective ROI scavengers/antioxidants: DMSO, N(a)N3, L-alanine, catalase, or superoxide dismutase. Total IL-8 surface receptor expression was assessed by 125I-IL-8 and 125I-labeled mAbs against IL-8R type A and B binding assays; PLD activation was assessed by measuring formation of phosphatidyl ethanol (PEt) in the presence of ethanol; PLC activation was measured by quantitative conversion of [32P]ATP-labeled phosphatidic acid (PA) into diacylglycerol (DAG); expression of G alpha-inhibitory subunit was assessed by SDS-PAGE and immunoblotting with polyclonal Abs against this subunit. Production of O2-, H2O2, HClO, and myeloperoxidase (MPO) in the experimental model was confirmed in a separate set of experiments. The overall impact of antioxidants on each component of the transducing tripartite complex was stimulatory; however, N(a)N3 and SOD exhibited the most ubiquitous effect with consistent up-regulation by N(a)N3 of IL-8R expression, whereas even trace amounts of externally added authentic MPO significantly down-regulated the functional activity of both effector enzymes. These results demonstrate a multiple site-specific targeting of the signal-transducing complex by endogenous PMN-derived ROI and an overall protective effect of ROI scavengers/antioxidants.
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PMID:Endogenous PMN-derived reactive oxygen intermediates provide feedback regulation on respiratory burst signal transduction. 926 41

Bacterial products such as LPS have been shown to activate monocytes and to increase CD14 expression, while anti-inflammatory cytokines, i.e., IL-4, down-regulate CD14. Furthermore, activation of monocytes increases survival, whereas deactivation evokes apoptosis (programmed cell death, PCD). This correlation among activation, CD14 expression, and the lifespan of the cells prompted us to investigate the role of CD14 in monocyte apoptosis. The effects of LPS and IL-4 on the expression of CD14, indicated by binding of Leu M3 Ab, and PCD of monocytes were studied simultaneously and in a kinetic fashion by multiparameter flow cytometry. Monocyte PCD was determined by binding of FITC-conjugated annexin V, which indicates apoptotic cell death in early stages, and was confirmed using well-established detection methods, i.e., DNA electrophoresis, electron microscopy, or colorimetric DNA staining. The present study shows that the LPS-induced increase in CD14 expression rescued monocytes from apoptosis, whereas IL-4 treatment first down-regulated CD14 expression and consecutively evoked apoptosis. CD14-/annexin V- monocytes were not apoptotic as confirmed by DNA electrophoresis, whereas CD14-/ annexin V+ monocytes showed clear apoptotic features. Kinetic studies ruled out that monocytes first bound annexin V and later lost the CD14 Ag. Other molecules, such as HLA-A, -B, and -C Ags, were not down-regulated during apoptosis. Enzymatic removal of membrane-bound CD14 by phosphatidylinositol-specific phospholipase C evoked PCD similarly to IL-4. These results suggest that regulation of CD14 receptor expression is an early effector mechanism mediating life or death of monocytes. Down-regulation or removal of the receptor triggers apoptosis, whereas up-regulation promotes survival.
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PMID:Regulation of human monocyte apoptosis by the CD14 molecule. 931 15

Several genes involved in the determination of Listeria monocytogenes pathogenesis have been identified. Among them, plcA gene encodes phosphatidylinositol-specific phospholipase C (PI-PLC), plcB gene encodes a broad-range phospholipase C (PC-PLC), and actA encodes a protein contributing to actin assembly in infected cells. The interaction of L. monocytogenes wild type (LO 28) strain and two derivative mutants, plcA- (BUG 206) and actA-/plcB- (LUT 12), with macrophages and T lymphocytes was investigated in a mouse model of listeriosis. Both mutants showed evidence of attenuation. The plcA- mutant, but not the plcB- mutant, expressed an increase in susceptibility to the anti-listerial activity of macrophages. Both mutants showed a decreased ability to induce IL-12 production by bone marrow macrophages when co-stimulated with E. coli LPS or IFN-gamma. In vivo, L. monocytogenes plcA- mutant was found to be a more effective stimulator of T cells than the wild LO 28 strain.
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PMID:The host response to Listeria monocytogenes mutants defective in genes encoding phospholipases C (plcA, plcB) and actin assembly (actA). 944 25

A critical feature of sepsis-induced adult respiratory distress syndrome (ARDS) is the release of cytokines (such as interleukin [IL]-6, IL-8, and tumor necrosis factor [TNF]) from endotoxin (lipopolysaccharide [LPS])-activated alveolar macrophages (AM). Nuclear factor kappa B (NF-kappaB) is activated in AM from patients with ARDS, and it is essential for the transcription of many cytokine genes. In these studies, we evaluated the regulation of LPS-induced cytokine release and the activation of NF-kappaB in human AM. We found that the activation of NF-kappaB and the release of IL-6, IL-8, and TNF from AM exposed to LPS was protein kinase C-independent and tyrosine kinase- and phosphatidylcholine-specific phospholipase C-dependent. We also found that LPS-induced activation of NF-kappaB was enhanced in AM cultured in serum or in the presence of LPS-binding protein, simulating conditions in the lung that are present in ARDS. In addition, LPS triggered the activation of several different NF-kappaB complexes in AM, and different forms of NF-kappaB bound to the IL-6, IL-8, and TNF promoter sequences. These observations suggest that physiologic abnormalities present in the lungs of patients with ARDS facilitate the activation of NF-kappaB and local release of cytokines.
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PMID:Lipopolysaccharide-induced NF-kappaB activation and cytokine release in human alveolar macrophages is PKC-independent and TK- and PC-PLC-dependent. 949 Jun 56

IL-13 is known to suppress the production of inflammatory cytokines such as TNF. Whether IL-13 also modulates the biologic effects of TNF is not known. In the present report we examined the effect of IL-13 on TNF-induced activation of nuclear transcription factors NF-kappa B and activation protein-1 (AP-1) and apoptosis. Pretreatment of cells with IL-13 blocked TNF-induced NF-kappa B activation, nuclear translocation of p65 subunit, and degradation of I kappa B alpha. IL-13 also inhibited NF-kappa B activation by LPS, okadaic acid, H2O2, and ceramide. TNF-induced NF-kappa B-dependent gene transcription was also blocked by IL-13. TNF-induced activation of another nuclear transcription factor, AP-1, was suppressed by IL-13. The activation of N-terminal c-Jun kinase and mitogen-activated protein kinase kinase, implicated in the regulation of AP-1 and NF-kappa B, was also down-regulated by IL-13. TNF-mediated cytotoxicity and activation of caspase-3 were abolished by IL-13. The inhibitory effects of IL-13 on TNF were sensitive to H-7, neomycin, and wortmannin, suggesting that the pathway consisting of protein kinase C, phosphatidylinositol 3-kinase, and phospholipase C must be involved in IL-13 signaling. Thus, overall, these results demonstrate that IL-13 is a potent inhibitor of TNF-mediated activation of NF-kappa B, AP-1, and apoptosis, which may contribute to its previously described immunosuppressive and anti-inflammatory effects.
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PMID:IL-13 suppresses TNF-induced activation of nuclear factor-kappa B, activation protein-1, and apoptosis. 974 47

Protein A of S. aureus exhibits a wide array of immunopotentiating activities. Since the role of nitric oxide (NO) in bioregulation has been well envisaged; we studied the effect of Protein A on NO production by immunocytes both in vivo and in vitro. Our data indicate that PA at a comparable dose of LPS (lipopolysaccharide) increases the NO levels in the serum of Swiss albino mice by about 12-fold from its basal level. The peak level is reached at about 12 hours after i.p. inoculation of PA. However, NO concentration returns to the basal value 15 hours posttreatment. Splenic lymphocytes and peritoneal macrophages showed appreciable increase in NO production when cultured with PA in vitro. Interestingly, inhibitors of tyrosine kinase, phospholipase C, and protein kinase C (PKC) inhibited NO production in splenic lymphocytes. Thus, it appears that these enzymes participate in the signaling cascade induced by PA, which culminates in the production of NO downstream of PKC. It is possible that PA-induced NO production may have relevance with the anti-tumor and anti-parasitic properties of PA, described earlier.
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PMID:Protein A induces NO production: involvement of tyrosine kinase, phospholipase C, and protein kinase C. 975 46

We have shown that, in murine J774 macrophages, binding of UTP to pyrimidinoceptors stimulates phosphoinositide (PI) breakdown and an increase in [Ca2+]i. In this study, UTP modulation of the expression of inducible nitric-oxide synthase (iNOS) was investigated. Although UTP alone had no effect, stimulation of J774 cells with a combination of UTP (10-300 microM) and LPS (0.1-3 microgram/ml) resulted in a potentiated increase in nitrite levels. In parallel, the amount of iNOS protein induced by LPS was also potentiated by UTP treatment. The UTP potentiating effect was attenuated by U73122, suggesting involvement of the downstream signaling pathways of phosphatidylinositide turnover. The tyrosine kinase inhibitor genistein inhibited both the LPS-induced nitrite response and the UTP potentiation. Conversely, two protein kinase C inhibitors, Ro 31-8220 and Go 6976, and a phosphatidylcholine-specific phospholipase C inhibitor, D609, inhibited LPS-stimulated nitrite induction, but did not affect the potentiating effect of UTP, which was also unaffected by pretreatment with phorbol 12-myristate 13-acetate for 8 h. Furthermore, the UTP-induced potentiation was abolished by BAPTA/AM or KN-93 (a selective inhibitor of Ca2+/calmodulin-dependent protein kinase (CaMK)). Nitrite potentiation and iNOS induction were prominent when UTP was added simultaneously with LPS, with the potentiating effect being lost when UTP was added 3 h after treatment with LPS. Pyrrolidinedithiocarbamate (3-30 microM), an inhibitor of NF-kappaB, caused a concentration-dependent reduction in the nitrite response to LPS and UTP. In electrophoretic mobility shift assays, LPS produced marked activation of NF-kappaB and AP-1, which was potentiated by UTP. LPS-induced degradation of IkappaB-alpha as well as the phosphorylation of IkappaB-alpha were also increased by UTP. Moreover, the UTP-potentiated activation of NF-kappaB and AP-1 and the degradation and phosphorylation of IkappaB-alpha were inhibited by KN-93. Taken together, these data demonstrate that nucleotides, especially UTP, can potentiate the LPS-induced activation of NF-kappaB and AP-1 and of iNOS induction via a CaMK -dependent pathway and suggest that the UTP-dependent up-regulation of iNOS may constitute a novel element in the inflammatory process.
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PMID:Pyrimidinoceptor-mediated potentiation of inducible nitric-oxide synthase induction in J774 macrophages. Role of intracellular calcium. 979 89

The signaling pathway for protein kinase C (PKC) activation and the role of PKC isoforms in LPS-induced nitric oxide (NO) release were studied in RAW 264.7 macrophages. The tyrosine kinase inhibitor genestein attenuated LPS-induced NO release and inducible nitric oxide synthase (iNOS) expression, as did the phosphoinositide-specific phospholipase C (PI-PLC) inhibitor U73122 and the phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor D609. LPS stimulated phosphatidylinositol (PI) hydrolysis and PKC activity in RAW cells; both were inhibited by genestein. The PKC inhibitors (staurosporine, calphostin C, Ro 31-8220, or Go 6976) or long-term 12-O-tetradecanoylphorbol 13-acetate (TPA) treatment also resulted in inhibition of LPS-induced NO release and iNOS expression. Western blot analysis showed expression of PKC-alpha, -betaI, -delta, -eta, and -zeta in RAW cells; down-regulation of PKC-alpha, -betaI, and -delta, but not -eta, was seen after long-term TPA treatment, indicating the possible involvement of one or all of PKC-alpha, -betaI, and -delta, but not -eta, in LPS-mediated effects. Treatment with antisense oligonucleotides for these isoforms further demonstrated the involvement of PKC-alpha, -betaI, and delta, but not -eta, in LPS responses. Stimulation of cells with LPS for 1 h caused activation of NF-kappaB in the nuclei by detection of NF-kappaB-specific DNA-protein binding; this was inhibited by genestein, U73122, D609, calphostin C, or antisense oligonucleotides for PKC-alpha, -betaI, and -delta, but not -eta. These data suggest that LPS activates PI-PLC and PC-PLC via an upstream tyrosine kinase to induce PKC activation, resulting in the stimulation of NF-kappaB DNA-protein binding, then initiated the expression of iNOS and NO release. PKC isoforms alpha, betaI, and delta were shown to be involved in the regulation of these LPS-induced events.
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PMID:Antisense oligonucleotides targeting protein kinase C-alpha, -beta I, or -delta but not -eta inhibit lipopolysaccharide-induced nitric oxide synthase expression in RAW 264.7 macrophages: involvement of a nuclear factor kappa B-dependent mechanism. 983 7

Mycoplasma fermentans-derived membrane lipoproteins (LAMPf) have been demonstrated to stimulate monocytic cells and to induce the secretion of proinflammatory cytokines by a mechanism involving the triggering of protein tyrosine kinase and mitogen-activated protein kinase cascades. Herein, we have examined the effects of LAMPf on the activation of a series of transcription factors potentially involved in cytokine gene expression. LAMPf was capable of inducing NF-kappa B, activated protein 1 (AP-1), and c-fos activation in macrophages and of stimulating NF-kappa B and AP-1 transactivation. Furthermore, we have delineated the contribution of each mitogen-activated protein kinase pathway to the LAMPf-mediated activation of AP-1, c-fos, and NF-kappa B. Whereas the selective extracellular signal-regulated kinase pathway inhibitor PD-98059 did not affect the LAMPf-mediated transactivation of AP-1, c-fos, or NF-kappa B, the specific p38 inhibitor SB203580 abrogated this activity. A c-Jun N-terminal kinase-dominant negative was shown to block the activation of AP-1 without altering NF-kappa B or c-fos activation by LAMPf. In addition, D609, a selective inhibitor of phosphatidylcholine-specific phospholipase C, was shown to block both translocation and transactivation of either NF-kappa B or AP-1 in response to LAMPf. Although LAMPf-mediated macrophage activation is CD14 independent, we could not distinguish between the intracellular mechanisms leading to the macrophage activation triggered by either LPS or LAMPf. This suggests that macrophages display a common signaling machinery leading to the secretion of proinflammatory cytokines in response to different bacterial products. The comprehension of these mechanisms may help to better understanding the bacterial pathogenesis and to elucidate general mechanisms of macrophage activation leading to cytokine secretion.
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PMID:Signal transduction pathways involved in the activation of NF-kappa B, AP-1, and c-fos by Mycoplasma fermentans membrane lipoproteins in macrophages. 997 95

This study uses human alveolar macrophages to determine whether activation of a phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) is linked to activation of the p42/44 (ERK) kinases by LPS. LPS-induced ERK kinase activation was inhibited by tricyclodecan-9-yl xanthogenate (D609), a relatively specific inhibitor of PC-PLC. LPS also increased amounts of diacylglycerol (DAG), and this increase in DAG was inhibited by D609. LPS induction of DAG was, at least in part, derived from PC hydrolysis. Ceramide was also increased in LPS-treated alveolar macrophages, and this increase in ceramide was inhibited by D609. Addition of exogenous C2 ceramide or bacterial-derived sphingomyelinase to alveolar macrophages increased ERK kinase activity. LPS also activated PKC zeta, and this activation was inhibited by D609. LPS-activated PKC zeta phosphorylated MAP kinase kinase, the kinase directly upstream of the ERK kinases. LPS-induced cytokine production (RNA and protein) was also inhibited by D609. As an aggregate, these studies support the hypothesis that one way by which LPS activates the ERK kinases is via activation of PC-PLC and that activation of a PC-PLC is an important component of macrophage activation by LPS.
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PMID:A phosphatidylcholine-specific phospholipase C regulates activation of p42/44 mitogen-activated protein kinases in lipopolysaccharide-stimulated human alveolar macrophages. 1007 52


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