Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The signaling pathway for IFN-gamma-mediated induction of ICAM-1 expression was further studied in human NCI-H292 epithelial cells. The Tyr701 phosphorylation of signal transducer and activator of transcription 1 (STAT1) induced by interferon-gamma (IFN-gamma) and 12-O-tetradecanoylphorbol 13-acetate (TPA) was inhibited by the protein kinase C (PKC) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the Src kinase inhibitor PP2. An association between c-Src and STAT1 was increased by IFN-gamma and TPA, indicating the direct phosphorylation of STAT1 by PKC-dependent c-Src activation. Tyrosine phosphorylation of Janus kinases (JAK) 1/2 was induced by IFN-gamma but not by TPA. In addition, ICAM-1 promoter activity induced by IFN-gamma, but not that induced by TPA, was inhibited by the dominant-negative JAK1 and JAK2 mutants. IFN-gamma-induced tyrosine phosphorylation of phospholipase C (PLC)-gamma was inhibited by AG 490 (a JAK inhibitor), and the association between JAK1/2 and PLC-gamma was increased after IFN-gamma treatment, indicating the activation of PLC-gamma via JAK1/2 phosphorylation. ICAM-1 promoter activities induced by the overexpression of wild-type JAK1- and PLC-gamma2 were blocked by the PLCgamma2 mutant or the dominant-negative PKCalpha (Lys-->Arg), c-Src (Lys-->Met), or STAT1 (Y701M) mutants, but not by dominant-negative STAT3 (DN) mutants. These results confirmed that IFN-gamma activated PLC-gamma via JAK1/2 phosphorylation to induce PKC, c-Src, STAT1 activation, and ICAM-1 expression. The association between JAK1/2 and STAT1 was increased by IFN-gamma but not by TPA. It was inhibited by AG 490 but not by U73122, indicating the possible involvement of the JAK1/2-STAT1 pathway. All the results show that IFN-gamma induces ICAM-1 expression by two different pathways in NCI-H292 epithelial cells. One is the JAK1/2-dependent PLC-gamma pathway inducing the activations of PKCalpha, c-Src, and STAT1, and the other is the direct activation of STAT1 by JAK1/2.
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PMID:Differential role of Janus family kinases (JAKs) in interferon-gamma-induced lung epithelial ICAM-1 expression: involving protein interactions between JAKs, phospholipase Cgamma, c-Src, and STAT1. 1497 37

Interleukin (IL)-18 induces T cells and natural killer cells to produce not only interferon-gamma but also other cytokines by binding to the IL-18 receptor (IL-18R) alpha and beta subunits. However, little is known about how IL-18, IL-18Ralpha, and IL-18Rbeta form a high-affinity complex on the cell surface and transduce the signal. We found that IL-18 and IL-18Ralpha bind to glycosylphosphatidylinositol (GPI) glycan via the third mannose 6-phosphate diester and the second beta-GlcNAc-deleted mannose 6-phosphate of GPI glycan, respectively. To determine which GPI-anchored glycoprotein is involved in the complex of IL-18 and IL-18Ralpha, IL-18Ralpha of IL-18-stimulated KG-1 cells was immunoprecipitated together with CD48 by anti-IL-18Ralpha antibody. More than 90% of CD48 was detected as beta-GlcNAc-deleted GPI-anchored glycoprotein, and soluble recombinant human CD48 without GPI glycan bound to IL-18Ralpha, indicating that CD48 is associated with IL-18Ralpha via both the peptide portion and the GPI glycan. To investigate whether the carbohydrate recognition of IL-18 is involved in physiological activities, KG-1 cells were digested with phosphatidylinositol-specific phospholipase C before IL-18 stimulation. Phosphatidylinositol-specific phospholipase C treatment inhibited the phosphorylation of tyrosine kinases and the following IL-18-dependent interferon-gamma production. These observations suggest that the complex formation of IL-18.IL-18Ralpha. CD48 via both the peptide portion and GPI glycan triggers the binding to IL-18Rbeta, and the IL-18.IL-18Ralpha.CD48.IL-18Rbeta complex induces cellular signaling.
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PMID:Functional role played by the glycosylphosphatidylinositol anchor glycan of CD48 in interleukin-18-induced interferon-gamma production. 1576 Sep 5

Under chronic inflammatory conditions, monocytes/macrophages often exhibit a desensitized phenotype, which is characterized by attenuated reactive oxygen species (ROS) production in close association with depletion of protein kinase C alpha (PKC alpha). This behavior has been observed in monocytes derived from septic blood although the stimulus responsible for initiating these alterations remained obscure. Using RAW264.7 macrophages, we provide evidence that components of neither gram-negative nor gram-positive bacteria deplete PKC alpha, whereas the T(H)1 cytokine interferon-gamma (IFNgamma) does. As shown by western blot analysis, lipopolysaccharide, as well as lipoteichoic acid, did not alter PKC alpha expression, but IFNgamma dose-dependently decreased PKC alpha protein level. Taking into consideration that diacylglycerol and Ca2+ as established PKC alpha activators are released in response to phospholipase C activation, we pretreated cells with the phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor tricyclodecan-9-yl potassium xanthate (D609) and the phosphatidylinositol-specific phospholipase C inhibitor 1-(6-(17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122). In cells preincubated with D609, IFNgamma-mediated PKC alpha depletion was attenuated, whereas U73122 did not impair this process. Moreover, phorbol 12-myristate 13-acetate-initiated ROS formation, which was attenuated in macrophages pretreated with IFNgamma, was restored in the presence of the PC-PLC inhibitor. These results suggest that IFNgamma causes PC-PLC stimulation, diacylglycerol release, Ca2+ influx, and concomitant PKC alpha activation, which subsequently depletes PKC alpha. Strategies to antagonize IFNgamma might be helpful to prevent monocyte/macrophage desensitization.
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PMID:PKC alpha depletion in RAW264.7 macrophages following microbial/IFNgamma stimulation is PC-PLC-mediated. 1611 26

Cytokines mediate pancreatic islet beta-cell apoptosis and necrosis, leading to loss of insulin secretory capacity and type 1 diabetes mellitus. The cytokines, IL-1beta and interferon-gamma, induced terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining of rat islet cells within 48 h by about 25-30%, indicative of apoptosis and/or necrosis. Sphingosine 1-phosphate (S1P) at nanomolar concentrations significantly reduced islet cell cytokine-induced TUNEL staining. Similar effects were observed in INS-1 cells. The dihydro analog of S1P also reduced the percentage of TUNEL stained islet and INS-1 cells, whereas the S1P receptor antagonist BML-241 blocked the protective effects. Pertussis toxin did not affect the S1P protective response. In the presence of a phospholipase C antagonist, U73122, there was significant inhibition of the S1P protective effects against apoptosis/necrosis. S1P stimulated INS-1 cell protein kinase C activity. Carbamylcholine chloride acting through muscarinic receptors also inhibited cytokine-induced TUNEL staining in pancreatic islet cells. S1P and/or dihydro-S1P also antagonized cytokine-induced increases in cytochrome c release from mitochondria and caspase-3 activity in INS-1 cells, which are indicative of cell apoptosis vs. necrosis. S1P failed to affect nitric oxide synthase activity after 48 h. Thus, the evidence suggests that S1P acting on S1P receptors coupled to G(q) mediates protective effects on islet beta-cells against cytokine-induced apoptosis.
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PMID:Sphingosine 1-phosphate affects cytokine-induced apoptosis in rat pancreatic islet beta-cells. 1679 3

Although considered to be an extracellular pathogen, Staphylococcus aureus is able to invade a variety of mammalian, non-professional phagocytes and can also survive engulfment by professional phagocytes such as neutrophils and monocytes. In both of these cell types S. aureus promptly escapes from the endosomes/phagosomes and proliferates within the cytoplasm, which quickly leads to host cell death. In this report we show that S. aureus interacted with human monocyte-derived macrophages in a very different way to those of other mammalian cells. Upon phagocytosis by macrophages, S. aureus persisted intracellularly in vacuoles for 3-4 days before escaping into the cytoplasm and causing host cell lysis. Until the point of host cell lysis the infected macrophages showed no signs of apoptosis or necrosis and were functional. They were able to eliminate intracellular staphylococci if prestimulated with interferon-gamma at concentrations equivalent to human therapeutic doses. S. aureus survival was dependent on the alternative sigma factor B as well as the global regulator agr, but not SarA. Furthermore, isogenic mutants deficient in alpha-toxin, the metalloprotease aureolysin, protein A, and sortase A were efficiently killed by macrophages upon phagocytosis, although with different kinetics. In particular alpha-toxin was a key effector molecule that was essential for S. aureus intracellular survival in macrophages. Together, our data indicate that the ability of S. aureus to survive phagocytosis by macrophages is determined by multiple virulence factors in a way that differs considerably from its interactions with other cell types. S. aureus persists inside macrophages for several days without affecting the viability of these mobile cells which may serve as vehicles for the dissemination of infection.
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PMID:A potential new pathway for Staphylococcus aureus dissemination: the silent survival of S. aureus phagocytosed by human monocyte-derived macrophages. 1818 90

Extracellular nucleotides are involved in the development of vascular inflammation. However, little is known about whether effects of nucleotides are modulated under inflammatory states. We investigated effects of interferon-gamma (INF-gamma) on ATP-induced responses in vascular endothelial cells. Treatment of human umbilical vein endothelial cells (HUVECs) with IFN-gamma for 24 h resulted in an enhancement of the ATP-induced increase in intracellular Ca2+ concentration ([Ca2+]i) without affecting the UTP-induced one. The increased Ca2+ response to ATP in IFN-gamma-treated cells was dependent on the extracellular Ca2+, and was not inhibited by the phospholipase C inhibitor U73122. RT-PCR and Western blotting revealed that HUVECs dominantly expressed P2X4 receptor. IFN-gamma increased P2X4-receptor mRNA and protein, accompanied by an increase in ATP-triggered membrane current. IFN-gamma did not affect P2X4-receptor mRNA stability, but increased P2X4-receptor gene transcription in a cycloheximide-insensitive manner. IFN-gamma stimulated phosphorylation of signal transducer and activator of transcription-1 (STAT1). Epigallocatechin gallate (EGCG), an inhibitor of STAT1-mediated signaling, and AG490, a Janus kinase (JAK) inhibitor, impaired P2X4-receptor mRNA up-regulation by IFN-gamma. These results indicate that INF-gamma selectively increases P2X4-receptor gene expression, leading to an up-regulation of purinergic signaling in vascular endothelial cells.
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PMID:Selective up-regulation of P2X4-receptor gene expression by interferon-gamma in vascular endothelial cells. 1867 88


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