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)

CD95 ligand is a cytotoxic cytokine that induces apoptosis. Here we report that CD95-mediated apoptosis of human malignant glioma cells is associated with arachidonic acid (AA) release. Inhibitors of phospholipase A2, phospholipase C or diacylglycerol lipase have minor effects on AA release and fail to modulate apoptosis. Formation of two AA metabolites generated during CD95-dependent apoptosis is attenuated by the lipoxygenase inhibitor, nordihydroguaretic acid (NDGA). NDGA also blocks CD95 ligand-induced apoptosis. This effect is independent of antioxidant properties of NDGA. Lipoxygenase may thus play a critical role in CD95 ligand-induced apoptosis of human malignant glioma cells.
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PMID:Lipoxygenase inhibitors block CD95 ligand-mediated apoptosis of human malignant glioma cells. 919 95

To understand the pathogenesis of vasculitides, we analyzed how cytokine stimulation of HUVEC in vitro activates the cytotoxic capacity of polymorphonuclear (PMN) granulocytes. IL-1beta, IFN-gamma, or TNF-alpha caused highly significant dose and time-dependent HUVEC injury. TNF-alpha-treated HUVEC activated the PMN by means of phospholipase C-related event, since coincubations conferred PMN to react with a rise of cytosolic calcium concentrations, [Ca2+]i. Ab blockade of ICAM-1 on HUVEC inhibited 50 to 70% of the injury induced by these cytokines, whereas a mAb to E-selectin reduced 45 to 65% of IL-1beta- and TNF-alpha-, but not IFN-gamma-induced cytotoxicity. The role of nitric oxide (NO) was of significance since injury induced by each cytokine was reduced by 60 to 87% by specific NO-synthase inhibitors, as well as by scavenging extracellular NO by oxyhemoglobin. In contrast, injury induced by TNF-alpha was inhibited by neither superoxide dismutase or catalase, alpha1-antitrypsin, alpha2-macroglobulin, nor the platelet-activating factor receptor antagonist WEB-2086. Moreover, PMN from a patient with chronic granulomatous disease were fully capable of mediating cytotoxicity. The possibility that IL-8, produced by HUVEC in response to TNF-alpha, mediated activation of PMN was not corroborated since addition of an IL-8-blocking mAb did not modify HUVEC injury. Nonetheless, the IL-8 mAb (but not WEB-2086) blocked the rise of [Ca2+]i. Thus, in this in vitro model of vasculitis, the effect of IL-1beta, IFN-gamma, and TNF-alpha as promotors of cytokine-mediated neutrophil-dependent injury to HUVEC is a process dependent on expression of adhesion molecules and probably associated with NO produced in the system.
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PMID:Cytokine-induced neutrophil-mediated injury of human endothelial cells. 921 11

The cytokine transforming growth factor-beta (TGF-beta) has multiple effects on a wide variety of cell types. These effects include modulation of growth and regulation of gene transcription. In a few instances, TGF-beta has also been shown to regulate gene expression posttranscriptionally by altering message stability, but the pathway by which this activity is executed remains largely unknown. In the present work, we demonstrate that TGF-beta 1 has no effect on transcription of the elastin gene in cultured human fetal lung fibroblasts, but does stabilize elastin messenger RNA (mRNA), leading to a dramatic increase in the steady-state level of elastin mRNA. A corresponding increase in production of tropoelastin accompanies the increase in elastin mRNA. Through the use of specific inhibitors, we demonstrate that phosphatidylcholine (PC)-specific phospholipase C (PLC) and protein kinase C (PKC) are involved in mediating the elastin message stabilization. In contrast, G proteins and extracellularly regulated kinases do not appear to be involved. These results suggest that although the TGF-beta signaling pathway leading to message stabilization shares components with that modulating transcription, the message-stabilization pathway also contains diverse other elements.
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PMID:Stabilization of elastin mRNA by TGF-beta: initial characterization of signaling pathway. 922 2

CD5 is a 67-kDa surface glycoprotein found in association with the Ag receptor complex on both T and B lymphocytes. CD5 modulates Ag receptor-mediated immune responses, but the molecular mechanisms of its action remain unclear. In this respect, the assessment of the relative and unique contribution of CD5 in cell signaling events is a crucial point. We have used Jurkat variants and anti-CD5 mAbs to show that the CD5 signaling pathway is distinct from that used by the TCR/CD3 complex. We hereby identify two independent mechanisms of CD5-mediated diacylglycerol release by virtue of their different kinetics: 1) an early and transient diacylglycerol increase that results from the activation of a phosphatidylcholine-specific phospholipase C, and 2) a late and sustained increase that requires de novo phospholipid synthesis. Studies performed on a TCR/CD3-deficient Jurkat cell variant indicate that only the CD5-mediated phosphatidylcholine-specific phospholipase C activation is dependent on TCR/CD3 expression. Mutational analyses of CD5 demonstrate that both mechanisms are dependent on the integrity of the CD5 distal cytoplasmic region. Our results show that CD5 is a signaling molecule per se that uses mechanisms resembling those used by some cytokine receptors (such as IL-1 or TNF receptors) to modulate lymphocyte activation.
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PMID:The cytoplasmic domain of CD5 mediates both TCR/CD3-dependent and -independent diacylglycerol production. 937 26

The numbers of patients in intensive care units, with immunosuppression, and of elderly people increase in parallel with antibiotic-resistant microorganisms. Therefore the demand for an effective antisepsis increases. Moreover, it became evident that the pathophysiology and the outcome of infection are dependent on the properties of the microorganisms, e.g. synthesis of endo- and exotoxins, and on the host defense, the immune system. In addition to the microbicidal action, we studied the effects of povidone-iodine (PVP-I, Betaisodona) on the generation, release and activity of exotoxins (alpha-hemolysin, phospholipase C, lipase), as well as on granulocyte-derived tissue-destructive enzymes (elastase, beta-glucuronidase) and microbial-induced cytokine generation from human neutrophils. Our results clearly show that PVP-I does not only kill a wide range of bacteria but also inhibits the generation and release of bacterial exotoxins; furthermore, it also inactivates bacterial exotoxins as well as granulocyte-derived tissue-destructive enzymes and cytokines. These data support the usefulness and efficacy of PVP-I as an effective therapeutic agent to combat infection.
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PMID:Effects of Betaisodona on parameters of host defense. 940 54

The purpose of this study was to examine the efficacy of a vaccination protocol using recombinant bovine interleukin-2 (rBoIL-2) as an adjuvant with a Staphylococcus aureus vaccine. Holstein dairy cows were immunized with a S. aureus vaccine in conjunction with either saline solution (n = 3), Freund's incomplete adjuvant (FIA; n = 3) or rBoIL-2 (n = 3). Whey and serum were analysed for antibody titer to specific S. aureus antigens. Isolated blood mononuclear cells (BMC) were examined for their ability to proliferate and to produce interleukin-2 (IL-2) and interferon (IFN) after either mitogenic or antigenic stimulation in vitro. Efficacy of the vaccination protocols was assessed by challenging experimental animals intramammarily with 100 colony forming units of S. aureus. Regardless of treatment, all cows exhibited similar serum antibody titers to S. aureus pseudocapsule. Cows treated with saline exhibited a significant increase in serum alpha-toxin antibody titer when compared to levels observed in FIA and rBoIL-2-treated cows. However, cows receiving rBoIL-2 treatment exhibited significantly higher lacteal pseudocapsule antibody titer compared to the other adjuvant groups. Administration of rBoIL-2 did not enhance BMC proliferative responses to the mitogens concanavalin A (ConA), phytohemagglutinin (PHA), pokeweed mitogen (PWM) or interleukin-2 (IL-2) when compared to FIA or saline treated cows. Although cows receiving rBoIL-2 treatment exhibited enhanced cytokine production upon antigenic stimulation, efficacy of the vaccination protocol was inferior compared to the protection offered by saline treatment.
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PMID:Efficacy of a bovine Staphylococcus aureus vaccine using interleukin-2 as an adjuvant. 946 2

CD14 is a glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein which functions as a receptor on myeloid cells for ligands derived from microbial pathogens such as lipopolysaccharide (LPS). We have studied the importance of the GPI tail of CD14 in signalling with the promonocytic cell line THP-1 expressing recombinant CD14 in a GPI-anchored form (THP1-wtCD14 cells) or in a transmembrane form (THP1-tmCD14). We found that, like other GPI-anchored molecules, GPI-anchored CD14 was recovered mainly from a Triton X-100-insoluble fraction, whereas transmembrane CD14 was fully soluble in Triton X-100. LPS induced cell activation of THP1-wtCD14 and of THP1-tmCD14 (protein tyrosine kinase phosphorylation, NF-kappaB activation, and cytokine production) in a very similar manner. However, anti-CD14 antibody-induced cross-linking caused a rapid calcium mobilization signal only in GPI-anchored CD14 cells. Studies with pharmacologic inhibitors of intracellular signalling events implicate phospholipase C and protein tyrosine kinases in the genesis of this antibody-induced calcium signal. Our results suggest that GPI anchoring and CD14 targeting to glycolipid-rich membrane microdomains are not required for LPS-mediated myeloid cell activation. GPI anchoring may however be important for other signalling functions, such as those events reflected by antibody cross-linking.
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PMID:Cell activation mediated by glycosylphosphatidylinositol-anchored or transmembrane forms of CD14. 948 11

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

Two closely related IkappaBalpha kinases as well as the upstream kinase, NIK, which integrates interleukin-1beta (IL-1beta)- and tumor necrosis factor (TNF)-alpha-dependent activation of the transcription factor NF-kappaB have recently been described. However, in this emerging pathway the role of previously identified components of cytokine-induced NF-kappaB activation, namely phosphatidylcholine-specific phospholipase C and protein kinase C, remains unclear. We now show that, in A549 human alveolar epithelial cells, the activation of a stably transfected NF-kappaB-dependent reporter gene by TNF-alpha and IL-1beta is completely blocked by the phosphatidylcholine-specific phospholipase C inhibitor D609 and the protein kinase C inhibitor RO31-8220. However, IL-1beta-induced IkappaBalpha degradation as well as NF-kappaB nuclear translocation and DNA binding, as determined by Western blot and electro-mobility shift assay, respectively, are not affected by these inhibitors. A similar effect, although less pronounced, is observed with the p38 mitogen-activated protein kinase inhibitor SB 203580. On the basis of these data we propose the existence of a second signaling pathway induced by IL-1beta and TNF-alpha that is activated in parallel to the cascade leading to IkappaBalpha degradation and is specifically required for NF-kappaB-dependent transcriptional competency.
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PMID:IkappaBalpha degradation and nuclear factor-kappaB DNA binding are insufficient for interleukin-1beta and tumor necrosis factor-alpha-induced kappaB-dependent transcription. Requirement for an additional activation pathway. 950 55

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine and growth factor that has important roles in both pathological and physiological angiogenesis. VPF/VEGF induces vascular hyperpermeability, cell division, and other activities by interacting with two specific receptor tyrosine kinases, KDR/Flk-1 and Flt-1, that are selectively expressed on vascular endothelium. The signaling cascade that follows VPF/VEGF interaction with cultured endothelium is only partially understood but is known to result in increased intracellular calcium, activation of protein kinase C, and tyrosine phosphorylations of both receptors, phospholipase C-gamma (PLC-gamma) and phosphatidylinositol 3'-kinase. For many reasons, signaling events elicited in cultured endothelium may not mimic mediator effects on intact normal or tumor-induced microvessels in vivo. Therefore, we developed a system that would allow measurement of VPF/VEGF-induced signaling on intact microvessels. We used mouse mesentery, a tissue whose numerous microvessels are highly responsive to VPF/VEGF and that we found to express Flk-1 and Flt-1 selectively. At intervals after injecting VPF/VEGF i.p., mesenteries were harvested, extracted, and immunoprecipitated. Immunoblots confirmed that VPF/VEGF induced tyrosine phosphorylation of several proteins in mesenteric microvessels as in cultured endothelium: Flk-1; PLC-gamma; and mitogen-activated protein kinase. Similar phosphorylations were observed when mesentery was exposed to VPF/VEGF in vitro, or when mesenteries were harvested from mice bearing the mouse ovarian tumor ascites tumor, which itself secretes abundant VPF/VEGF. Other experiments further elucidated the VPF/VEGF signaling pathway, demonstrating phosphorylation of both PYK2 and focal adhesion kinase, activation of c-jun-NH2-kinase with phosphorylation of c-Jun, and an association between Flk-1 and PLC-gamma. In addition, we demonstrated translocation of mitogen-activated protein kinase to the cell nucleus in cultured endothelium. Taken together, these experiments describe a new model system with the potential for investigating signaling events in response to diverse mediators on intact microvessels in vivo and have further elucidated the VPF/VEGF signaling cascade.
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PMID:Vascular permeability factor/vascular endothelial growth factor-mediated signaling in mouse mesentery vascular endothelium. 951 16


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