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 mononuclear cell surface protein IA4, recently classified as CD82, was originally identified in our laboratory by the IA4 monoclonal antibody (mAb), because of its high expression on three lymphoblastoid, LAK-susceptible, variant cell lines. We have characterized CD82 as a new activation/differentiation marker of mononuclear cells. This protein belongs to the new family of TST proteins (tetra spans transmembrane), which includes CD9, CD37, CD53, CD63, and CD81 (TAPA-1). Here we demonstrate that cross-linking of IA4 mAbs induces an increase of intracellular free calcium in U937 cells and tyrosine phosphorylation of various proteins. Our data indicate that the intracellular calcium increase is initiated by a phospholipase C (PLC)-induced PtdIns(1,4,5)P3 second messenger followed by a more stable change, linked to extracellular calcium entry. This transducing signal was dependent on dual engagement of both CD82 and Fc receptors. Surface cross-linking of CD82 together with Fc receptors (FcRs) induces a specific long-lasting increase of intracellular calcium, whereas FcR cross-linking alone induces only a transient calcium mobilization. These results suggest that, upon cross-linking of CD82, a multimolecular complex including CD82 and FcR could be induced that is able to trigger signal transduction. We have previously shown that CD82 membrane expression is up-regulated during differentiation of human monocytes. Using U937 cells, we demonstrate here that several cytokines [interleukin-1 beta (IL-1 beta), IL-4, IL-6, IL-13, interferon-gamma, tumor necrosis factor alpha] could significantly up-regulate the surface expression of CD82 antigen, by contrast with FcR surface expression, which was up-regulated only after IFN-gamma treatments. Based on our finding of a strict dependence of CD82 activation on FcR stimulation, we suggest a putative role of CD82 in enhancing FcR-mediated activation of cells from the monocyte/macrophage lineage.
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PMID:CD82, tetra-span-transmembrane protein, is a regulated transducing molecule on U937 monocytic cell line. 779 Jul 79

Endothelin (ET) produced by endothelial cells has recently been found to be a potent vasoconstricting hormone. In this paper, ET isopeptides, both ET-1 and ET-3, were shown to be potent stimulators of interleukin (IL)-6 production by a rat aortic endothelial cell clone, WAE-1. Semi-quantitative polymerase chain reaction analysis indicated that augmentation of IL-6 production is due to an increase in IL-6 messenger RNA level. Ligand binding assay indicated that most of the [125I]ET-1 binding sites correspond to ET receptor type A (ETAR). However, ET receptor type B (ETBR) was shown to be also present on this cell line by reverse transcription polymerase chain reaction using ETBR-specific primers and by ligand binding assay using [125I]ET-3, although the protein receptor level is much lower than that of ETAR. ET-1, but not ET-3, induced inositol 1,4,5-triphosphate production and an increase in intracellular Ca2+ concentration with similar dose response. These data suggest that ET-1 stimulates IL-6 production through ETAR-phospholipase C activation axis, whereas ET-3 stimulates IL-6 production through different signaling pathway. The results shown in this paper raise the possibility that ET plays a role in inducing inflammation in endothelium.
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PMID:Endothelin-induced interleukin-6 production by rat aortic endothelial cells. 782 23

Phospholipase C-mediated release of inositol trisphosphate, followed by an increase in free intracellular calcium, is an important signal transduction pathway for several membrane receptors. In the present investigation, the coupling of various receptors to phospholipase C was studied in the human keratinocyte line HaCaT. Inositol trisphosphate formation was determined by anion-exchange chromatography, and the release of intracellular calcium was analysed with the fluorescence probe Fura-2 AM. Activation of HaCaT keratinocytes with bradykinin resulted in a time- and dose-dependent release of inositol trisphosphate and intracellular calcium, with an EC50 value of 50 nM for bradykinin-induced inositol trisphosphate formation. The mediators and cytokines IL-1, IL-4, IL-6, IL-8, EGF and TGF alpha, as well as bombesin, prolactin, carbachol, substance P and retinoic acid, did not activate this pathway. The inability of the mediators examined to activate phospholipase C may be due to lack of the respective cognate receptors or to the use of other signal transduction pathways.
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PMID:Inositol phosphate formation and release of intracellular free calcium by bradykinin in HaCaT keratinocytes. 830 79

The alternative CD2-mediated pathway of T cell activation, which is independent of MHC/peptide recognition by the TCR/CD3 complex, is dependent upon two signals being received by the CD2 molecule. The natural ligand for CD2 is CD58, but controversy exists over alternative or additional ligands that could deliver the second signal in vivo. We have used rat retinal pigment epithelial cells (RPE), which lack temperature-insensitive ligands for CD2 adhesion, to study Ag-independent T cell activation. Rat RPE cells expressed high levels of CD59 and low levels of another potential CD2 ligand, CD48, both in vitro and in the in vivo model of experimental autoimmune uveoretinitis. When increasing numbers of syngeneic T cells were added to microwell cultures of rat RPE cells, the T cells, even in the absence of any exogenous stimulant in the cultures, underwent spontaneous proliferation. This effect required metabolically active RPE cells, and was IL-2 driven and enhanced in the presence of indomethacin. Proliferation was modulated by phosphatidylinositol-phospholipase C treatment of the RPE, and blocked by mAbs to CD59. Ab cross-linking of CD48 but not CD59 on the RPE was found to induce messenger RNA expression for IL-1 beta, which together with constitutively expressed IL-6 are required costimulatory factors for T cell activation through CD2. This is the first demonstration in a fully syngeneic system that bi-directional signaling involving CD59 and CD48 molecules expressed by physiologically normal, nonhematopoietic, cells can trigger T lymphocyte activation and proliferation through autocrine IL-2 production in the absence of Ag.
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PMID:CD59 and CD48 expressed by rat retinal pigment epithelial cells are major ligands for the CD2-mediated alternative pathway of T cell activation. 862 4

A short synthetic peptide (Pa) containing a structural motif ("2-6-11" motif) present in a number of human extracellular matrix proteins was found to stimulate the production of cytokines IL-1alpha, IL-1beta, IL-6, and TNFalpha by human peripheral blood mononuclear cells. We have now investigated the signal transduction pathway involved in the elicitation of these immunomodulating properties on isolated human monocytes. Our results show that active peptide Pa provoked phosphoinositide hydrolysis, intracellular calcium elevation, and cAMP accumulation. Herbimycin A, an inhibitor of protein tyrosine kinases (PTK), markedly reduced these effects of peptide Pa. We have also found that this peptide stimulated CREB, NF-kappaB, and AP-1 DNA-binding activity. With the help of inhibitors of PTK (herbimycin A), phospholipase C (neomycin sulfate), protein kinase C (bis-indolyl maleimide), protein kinase A (H89), and the calmodulin antagonist W-7, as well as cholera toxin, an agent that increases intracellular cAMP, we showed that cytokine (IL-1alpha, IL-1-beta, IL-6, and TNFalpha) production could be modified by the signal transduction pathway triggered by peptide Pa on monocytes.
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PMID:Signaling pathway triggered by a short immunomodulating peptide on human monocytes. 902 64

Sulfasalazine is widely used in rheumatoid arthritis and inflammatory bowel diseases. The mechanisms of its activity have not been elucidated. In leukocytes, sulfasalazine and its analogue, CL 42A, inhibited the formation of leukotrienes and possibly of the second messenger compounds at the level of phospholipase C. Partial inhibition of interleukin-lbeta (IL-1beta), IL-6 and tumor necrosis factor-alpha (TNF-alpha) was also found. Since the synthesis of eicosanoids is induced by phospholipase A2 and since secretory phospholipase A2 (sPLA2) is proinflammatory, we investigated the impact of sulfasalazine and related compounds on mRNA, protein synthesis, and release of sPLA2 from osteoblasts. Sulfasalazine and CL 42A markedly inhibited extracellular release of sPLA2. The impact of sulfasalazine was evident at 50 microM (P < 0.001) and maximal at 400 microM, and that of CL 42A at 10 microM (P < 0.001) and 200 microM, respectively. Split products of sulfasalazine, 5-aminosalicylic acid (400 microM) and sulfapyridine (400 microM), had no impact. The effect of sulfasalazine and CL 42A was evident regardless of whether the cells were stimulated with IL-1beta/TNF-alpha, lipopolysaccharide/forskolin, or dibutyryl-cAMP. Sulfasalazine and CL 42A did not alter the level of sPLA2 mRNA. Exposure of stimulated fetal rat calvaria osteoblasts (FRCO) to sulfasalazine did not show accumulation of the intracellular sPLA2 protein as tested by western blot; however, enzymatic activity of PLA2 in disrupted cells was definitely increased. Thus, the impact is on the post-transcriptional release of sPLA2 rather than on the synthesis. There was also an increase in the extracellular release of prostaglandin E2 from FRCO exposed to sulfasalazine or to CL 42A. In contrast, sulfasalazine had no effect on the extracellular release of gelatinase from the cells or on mRNA of cytosolic PLA2 or cyclooxygenase 2. We conclude that the anti-inflammatory activity of sulfasalazine may be related, in part, to the selective inhibition of the extracellular release of proinflammatory sPLA2.
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PMID:Inhibition of extracellular release of proinflammatory secretory phospholipase A2 (sPLA2) by sulfasalazine: a novel mechanism of anti-inflammatory activity. 925 65

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

Protein tyrosine phosphorylation and other biochemical events have been shown to occur after cross-linking of Fc epsilonRI in rodent mast cells. To investigate the mechanism of Fc epsilonRI signal transduction in human mast cells, we used human cultured mast cells (HCMC) generated from cord blood cells in the presence of recombinant human stem cell factor and IL-6. We found that on cross-linking of Fc epsilonRI: 1) HCMC released histamine; 2) rapid tyrosine phosphorylation of multiple cellular substrates, including Syk, HS1, c-Cbl, ERK-1, and ERK-2, was observed; 3) intracellular Ca2+ and inositol phosphate production were increased within the first minute after Fc epsilonRI cross-linking; and 4) genistein, a tyrosine kinase inhibitor, inhibited both protein tyrosine phosphorylation and histamine release in a dose-dependent manner. These results were consistent with previous studies in rodent mast cells. In contrast, no tyrosine phosphorylation of phospholipase C gamma1 and Btk (Bruton's tyrosine kinase) were observed in our experimental conditions. These results suggest that the greater part of the early and late signaling events in HCMC is similar to those obtained with rodent mast cells and indicated that the requirement of tyrosine phosphorylation in the activation process of each of the signaling molecules might be different in HCMC and rodent mast cells. Our finding indicates that HCMC may be useful for analysis of Fc epsilonRI-mediated signal transduction in human mast cells.
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PMID:Early and late events in Fc epsilon RI signal transduction in human cultured mast cells. 955 Mar 84

1. We recently demonstrated the presence of phospholipase C-coupled bradykinin (BK) B2-receptors in human primary and SV40 virus-immortalized corneal epithelial (CEPI) cells. 2. The aims of the present studies were to demonstrate the specific binding of [3H]-BK to CEPI cell membranes and to study its pharmacological characteristics. In addition, we wished to study the functional coupling of the BK receptors to various physiological and pathological mechanisms in the CEPI cells, including phosphoinositide (PI) turnover, intracellular Ca2+-mobilization ([Ca2+]i), cell proliferation (via [3H]-thymidine incorporation), and the release of various cytokines, collagenase-1 (matrix metalloproteinase-1) and prostaglandin E2 (PGE2). 3. Specific [3H]-BK binding comprised 83 +/- 2% of the total binding, and was of high affinity (Kd = 1.66 +/- 0.52 nM, n = 5), saturable (Bmax = 640 +/- 154 fmol g(-1) wet weight) and reversible. Competition studies yielded the following affinity values for BK and a number of BK-related peptides: Hoe-140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]BK; icatibant): Ki = 0.17 +/- 0.07 nM; BK: Ki = 1.0 +/- 0.11 nM; [Tyr8]-BK: Ki = 12.9 +/- 2.3 nM; [des-Arg9]-BK: Ki > 9,200 nM (all n = 3-5)). 4. BK potently stimulated PI turnover (EC50 = 2.3 +/- 0.3 nM; n = 7) and [Ca2+]i mobilization (EC50 = 8-20 nM) in CEPI cells and both responses were inhibited in a concentration-dependent manner by 100 nM-10 microM Hoe-140, a selective B2-receptor antagonist, and also inhibited by the selective phospholipase C (PLC) inhibitor, U73122 (1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1 H-pyrrole-2,5-dione) (IC50 = 3.0 +/- 1.6 microM). BK-induced [Ca2+]i mobilization was reduced by about 30% in the presence of 4 mM EGTA, but was not significantly affected by 100 nM nifedipine. 5. BK (0.1 nM-10 microM) significantly (P<0.05-0.001) stimulated [3H]-thymidine incorporation into CEPI cellular DNA. However, while interleukin-1alpha (IL-1alpha; 10 ng ml(-1)) potently stimulated the release of IL-6, IL-8 and granulocyte macrophage colony-stimulating factor from CEPI cells, BK (0.1 nM-10 microM) was without effect. 6. Whilst phorbol-12-myristate-13-acetate (PMA; 3 microg ml(-1)) and 10% foetal bovine serum (positive control agents) significantly stimulated the release of both MMP-1 and PGE2 from CEPI cells, BK (0.1 nM-10 microM) was without any significant effect under these conditions. 7. In conclusion, these data indicate that the CEPI cells express high-affinity [3H]-BK binding sites representing B2-subtype BK receptors coupled to PI turnover and [Ca2+]i mobilization which appear to stimulate [3H]-thymidine incorporation into cellular DNA. In contrast, BK failed to elicit the release of PGE2, various cytokines and MMP-1 from CEPI cells. These results suggest that BK may have a potential role in corneal epithelium wound healing by stimulating cell proliferation.
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PMID:Effects of bradykinin on signal transduction, cell proliferation, and cytokine, prostaglandin E2 and collagenase-1 release from human corneal epithelial cells. 955 96

In vivo, vascular walls are exposed to mechanical stretch, which may promote atherogenesis. This study was designed to investigate the effect of mechanical stretch on the production and gene expression of cytokines in endothelial cells (ECs) of human umbilical veins. ECs were cultured on flexible silicone membranes and exposed to cyclic mechanical stretch. Although the secretion levels of interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6, granulocyte (G) -colony stimulating factor (CSF), G and macrophage (M) -CSF, and M-CSF were not affected by cyclic stretch over 24 hours, the levels of IL-8 and monocyte chemotactic and activating factor (MCAF)/monocyte chemoattractant protein-1 (MCP-1) were significantly increased by cyclic stretch. Northern blot analysis indicated that the mRNA levels of IL-8 and MCAF/MCP-1 were upregulated by cyclic stretch as a function of its intensity. Cytochalasin D, which disrupts the actin cytoskeleton, abolished the stretch-induced gene expression of IL-8 and MCAF/MCP-1. In contrast, neither inhibition of stretch-activated ion channels nor disruption of microtubules affected the induction of these chemokines by cyclic stretch. Northern blot analysis using enzyme inhibitors showed that phospholipase C, protein kinase C, and tyrosine kinase were involved in the stretch-induced gene expression of IL-8 and MCAF/MCP-1, whereas cAMP- or cGMP-dependent protein kinase was not. In conclusion, cyclic stretch enhanced the secretion and gene expression of IL-8 and MCAF/MCP-1 in a stretch-dependent fashion, and the integrity of the actin cytoskeleton and activities of phospholipase C, protein kinase C, and tyrosine kinase may be essential in the process of stretch-induced gene induction of IL-8 and MCAF/MCP-1.
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PMID:Cyclic stretch upregulates production of interleukin-8 and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in human endothelial cells. 963 28


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