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)

Infection with human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is necessary for the development of KS. The HHV-8 lytic-phase gene ORF74 is related to G protein-coupled receptors, particularly interleukin-8 (IL-8) receptors. ORF74 activates the inositol phosphate/phospholipase C pathway and the downstream mitogen-activated protein kinases, JNK/SAPK and p38. We show here that ORF74 also activates NF-kappaB independent of ligand when expressed in KS-derived HHV-8-negative endothelial cells or primary vascular endothelial cells. NF-kappaB activation was enhanced by the chemokine GROalpha, but not by IL-8. Mutation of Val to Asp in the ORF74 second cytoplasmic loop did not affect ligand-independent signaling activity, but it greatly increased the response to GROalpha. ORF74 upregulated the expression of NF-kappaB-dependent inflammatory cytokines (RANTES, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor) and adhesion molecules (VCAM-1, ICAM-1, and E-selectin). Supernatants from transfected KS cells activated NF-kappaB signaling in untransfected cells and elicited the chemotaxis of monocytoid and T-lymphoid cells. Expression of ORF74 conferred on primary endothelial cells a morphology that was strikingly similar to that of spindle cells present in KS lesions. Taken together, these data, demonstrating that ORF74 activates NF-kappaB and induces the expression of proangiogenic and proinflammatory factors, suggest that expression of ORF74 in a minority of cells in KS lesions could influence uninfected cells or latently infected cells via autocrine and paracrine mechanisms, thereby contributing to KS pathogenesis.
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PMID:Activation of NF-kappaB by the human herpesvirus 8 chemokine receptor ORF74: evidence for a paracrine model of Kaposi's sarcoma pathogenesis. 1150 11

Intestinal mucosal immunity is modulated by cytokine release from intestinal cells, but little is known about the relation between nutrient absorption and cytokine release. In this study, we examined how exposure to fatty acids affects the production of growth-regulated oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) and interleukin (IL)-6 in rat intestinal epithelial cells (IEC). The long-chain fatty acids, oleic, linoleic and arachidonic acids, and the middle-chain fatty acid octanoic acid were administered to subconfluent cultures of IEC-6 cells alone, or in combination with IL-1beta and transforming growth factor (TGF)-beta. The GRO/CINC-1 and IL-6 concentrations in culture media were determined by sandwich enzyme immunoassay. In epithelial cells, GRO/CINC-1 and IL-6 mRNA expression were examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and mitogen-activated protein kinase (MAPK) activities determined by immunoblotting. Administration of long-chain fatty acids significantly increased the GRO/CINC-1 and IL-6 secretion into culture media, and this secretion was markedly increased (P < 0.05) in the presence of IL-1beta or TGF-beta. Octanoic acid had no effect on GRO/CINC-1 or IL-6 production. Furthermore, treatment with long-chain fatty acids significantly enhanced the GRO/CINC-1 and IL-6 expression that was induced by IL-1beta or TGF-beta. MAPK activity was significantly enhanced by treatment with long-chain fatty acids. Inhibitors of phospholipase C, protein kinase C or MAPK significantly reduced the fatty acid-induced increase in GRO/CINC-1 secretion, whereas a calcium/calmodulin inhibitor did not attenuate the secretion. These results suggest that long-chain fatty acids enhance cytokine release under conditions of inflammatory stimulation in the intestinal mucosa.
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PMID:Fatty acids enhance GRO/CINC-1 and interleukin-6 production in rat intestinal epithelial cells. 1169 23

Streptolysin O (SLO), archetype of a cholesterol-binding bacterial cytolysin, forms large pores in the plasma membrane of mammalian cells. We have recently reported that when a limited number of pores are generated in a cell, they can be sealed in a Ca++-dependent process. Here, we show that resealing is followed by the release of IL-6 and IL-8 from keratinocytes and from endothelial cells, both relevant targets for SLO attack. Production of cytokines by these cells was preceded by activation of transcription factor nuclear factor kappaB, which thus emerges as a common denominator of stress responses to various pore-forming agents, including alpha-toxin of Staphylococcus aureus and complement. Furthermore, we show that activation and cytokine release in response to an agent that forms a pore in the plasma membrane do not depend on paracrine effects, because supernatants of cells perforated by SLO did not activate bystander cells. The study provides definitive evidence that a transient transmembrane pore suffices to trigger productive transcriptional activation in a target cell.
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PMID:Resealing of large transmembrane pores produced by streptolysin O in nucleated cells is accompanied by NF-kappaB activation and downstream events. 1174 25

Staphylococcus aureus alpha-toxin is a pore-forming bacterial exotoxin that has been implicated as a significant virulence factor in human staphylococcal diseases. In primary cultures of rat pneumocyte type II cells and the human A549 alveolar epithelial cell line, purified alpha-toxin provoked rapid-onset phosphatidylinositol (PtdIns) hydrolysis as well as liberation of nitric oxide and the prostanoids PGE(2), PGI(2), and thromboxane A(2). In addition, sustained upregulation of proinflammatory interleukin (IL)-8 mRNA expression and protein secretion occurred. "Priming" with low-dose IL-1beta markedly enhanced the IL-8 response to alpha-toxin, which was then accompanied by IL-6 appearance. The cytokine response was blocked by the intracellular Ca(2+)-chelating reagent 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, the protein kinase C inhibitor bis-indolyl maleimide I, as well as two independent inhibitors of nuclear factor-kappaB activation, pyrrolidine dithiocarbamate and caffeic acid phenethyl ester. We conclude that alveolar epithelial cells are highly reactive target cells of staphylococcal alpha-toxin. alpha-Toxin pore-associated transmembrane Ca(2+) flux and PtdIns hydrolysis-related signaling with downstream activation of protein kinase C and nuclear translocation of nuclear factor-kappaB are suggested to represent important underlying mechanisms. Such reactivity of the alveolar epithelial cells may be relevant for pathogenic sequelae in staphylococcal lung disease.
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PMID:Mediator generation and signaling events in alveolar epithelial cells attacked by S. aureus alpha-toxin. 1179 25

The recently cloned scaffolding molecule Gab2 can assemble multiple molecules involved in signaling pathways. Bone marrow-derived mast cells isolated from Gab2(-/-) mice have defective signaling probably due to the lack of the activation of phosphatidylinositol-3 kinase (PI3-kinase). In this study, we investigated the role of Gab2 using the rat basophilic leukemia 2H3 cell line mast cells. Fc epsilon RI aggregation induced the tyrosine phosphorylation of Gab2 and translocation of a significant fraction of it from the cytosol to the plasma membrane. As in other cells, Gab2 was found to associate with several signaling molecules including Src homology 2-containing protein tyrosine phosphatase 2, Grb2, Lyn, and phospholipase C gamma (PLC gamma). The association of Gab2 with Lyn and PLC gamma were enhanced after receptor aggregation. Overexpression of Gab2 in rat basophilic leukemia 2H3 cell line cells inhibited the Fc epsilon RI-induced tyrosine phosphorylation of the subunits of the receptor, and the phosphorylation and/or activation of Syk and mitogen-activated protein kinase. Downstream events such as calcium mobilization, degranulation, and induction of TNF-alpha and IL-6 gene transcripts were decreased in Gab2 overexpressing cells, although Akt phosphorylation as a measure of PI3-kinase activation was unaffected. These results suggest that in addition to the positive effects mediated by PI3-kinase that are apparent in Gab2(-/-) mast cells, Gab2 by interacting with Lyn and PLC gamma may have negative regulatory effects on Fc epsilon RI-induced mast cell signaling and functions.
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PMID:The adapter molecule Gab2 regulates Fc epsilon RI-mediated signal transduction in mast cells. 1197 Oct 18

This study was performed to investigate the in vivo effects of staphylococcal alpha-toxin on phagocytosis and the secretion of proinflammatory cytokines at local sites of intraperitoneal toxin-challenged mice. A dosage of 45 hemolytic units (HU) of alpha-toxin induced a marked increase in the peritoneal neutrophil count. The toxin caused a 52% decrease in phagocytosis by peritoneal macrophages, compared with that of control mice receiving Staphylococcus aureus particles alone. However, no effect on phagocytosis in neutrophils was observed. A dosage of 45 HU toxin and the synergistic activity of S. aureus particles strongly induced interleukin (IL) 6 secretion but only mildly induced IL-1alpha secretion. The toxin did not induce the secretion of tumor necrosis factor-alpha (TNF-alpha). Interestingly, S. aureus culture supernatant induced the secretion of TNF-alpha in cultured macrophages. These results suggest that alpha-toxin damages the primary host defense system by inducing the oversecretion of IL-1alpha and IL-6, but not TNF-alpha, via a mechanism that requires the synergistic action of bacterial components.
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PMID:Staphylococcal alpha-toxin synergistically enhances inflammation caused by bacterial components. 1198 63

Anaplasma phagocytophila, an obligately intracellular bacterium of granulocytes, causes human granulocytic ehrlichiosis. Within 2 h after addition of A. phagocytophila, interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and IL-6 mRNAs are induced in human peripheral blood leukocytes (PBLs) or monocytes in vitro. However, neutrophils generate only IL-1beta mRNA. In the present study, signaling pathways for induction of these three cytokines were examined. TNF-alpha and IL-6 mRNA expression by PBLs was inhibited with SB 203580 (a p38 mitogen-activated protein kinase [MAPK] inhibitor), MG-132 (a proteasome inhibitor), and SN-50 (an NF-kappaB inhibitor). Activation of p38 MAPK and NF-kappaB mRNAs in monocytes was detectable within 15 to 30 min after addition of A. phagocytophila. Expression of these two cytokine mRNAs in PBLs and monocytes was also dependent on protein kinase C (PKC), protein kinase A (PKA), and protein tyrosine kinase (PTK). IL-1beta mRNA expression by neutrophils was not dependent on p38 MAPK, and p38 MAPK was not activated in neutrophils incubated with A. phagocytophila. IL-1beta mRNA induction by PBLs, monocytes, and neutrophils was dependent on PKC and PKA. Neutrophil expression of IL-1beta mRNA was dependent on transglutaminase, phospholipase C, and PTK, all of which are also required for internalization of A. phagocytophila. However, monocyte expression of IL-1beta mRNA was less dependent on these enzymes. These results suggest that A. phagocytophila transduces different signals between its host neutrophils and monocytes for proinflammatory cytokine generation.
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PMID:Roles of p38 mitogen-activated protein kinase, NF-kappaB, and protein kinase C in proinflammatory cytokine mRNA expression by human peripheral blood leukocytes, monocytes, and neutrophils in response to Anaplasma phagocytophila. 1211 21

The effects of low concentrations of extracellular ATP on cytosolic Ca(2+), membrane potential, and transcription of IL-6 were studied in monocyte-derived human macrophages. During inflammation or infection many cells secrete ATP. We show here that application of 10 microM ATP or 10 microM UTP induces oscillations in cytosolic Ca(2+) with a frequency of approximately 12 min(-1) and oscillations in membrane potential. RT-PCR analysis showed expression of P2Y(1), P2Y(2), P2Y(11), P2X(1), P2X(4), and P2X(7) receptors, large-conductance (KCNMA1 and KCNMB1-4), and intermediate-conductance (KCNN4) Ca(2+)-activated K(+) channels. The Ca(2+)oscillations were unchanged after removal of extracellular Ca(2+), indicating that they were mainly due to movements of Ca(2+) between intracellular compartments. Comparison of the effects of different nucleotides suggests that the Ca(2+) oscillations were elicited by activation of P2Y(2) receptors coupled to phospholipase C. Patch-clamp experiments showed that ATP induced a transient depolarization, probably mediated by activation of P2X(4) receptors, followed by membrane potential oscillations due to opening of Ca(2+)-activated K(+) channels. We also found that 10 microM ATP gamma S increased transcription of IL-6 approximately 40-fold within 2 h. This effect was abolished by blockade of P2Y receptors with 100 microM suramin. Our results suggest that ATP released from inflamed, damaged, or metabolically impaired cells represents a "danger signal" that plays a major role in activating the innate immune system.
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PMID:Extracellular ATP induces oscillations of intracellular Ca2+ and membrane potential and promotes transcription of IL-6 in macrophages. 1519 22

We investigated the effects of bradykinin (BK) on the production of interleukin (IL)-6 and prostaglandin PGE(2), whose molecules are capable of stimulating the development of osteoclasts from their hematopoietic precursors as well as the signal transduction systems involved, in human osteoblasts (SaM-1 cells). BK receptors B1 (B1R) and B2 (B2R) were expressed in SaM-1 and osteosarcoma (SaOS-2, HOS, and MG-63) cells. Treatment of SaM-1 cells with BK increased the synthesis of both IL-6 and PGE(2) and the increase in both was blocked by HOE140 (B2R antagonist), but not by Des-Arg(9)-[Leu(8)]-BK (B1R antagonist). U-73122, a phospholipase C (PLC) inhibitor, suppressed BK-induced IL-6 and PGE(2) synthesis in SaM-1 cells. In addition, BK caused an increase in the intracellular Ca(2+) concentration ([Ca(2+)]i), which was inhibited by pretreatment with HOE140 or 2-aminoethoxydiphenyl borate (2-APB), an inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) blocker. Furthermore, both SB203580 (an inhibitor of p38 mitogen-activated protein kinase [MAPK]) and PD98059 (an inhibitor of MEK, upstream of ERK) attenuated the BK-induced IL-6 and PGE(2) synthesis. BK treatment resulted in the phosphorylation of p38 MAPK and extracellular signal-regulated kinase (ERK)1/2, and 2-APB could suppress BK-induced phosphorylation of ERK1/2. These findings suggest that BK increased both IL-6 and PGE(2) synthesis in osteoblastic cells via B2R and that PLC, IP(3)-induced [Ca(2+)]i, MEK, and MAPKs were involved in the signal transduction in these cells.
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PMID:Activation of osteoblastic functions by a mediator of pain, bradykinin. 1534 32

Neuromedin U (NmU), originally isolated from porcine spinal cord and later from other species, is a novel peptide that potently contracts smooth muscle. NmU interacts with two G protein-coupled receptors designated as NmU-1R and NmU-2R. This study demonstrates a potential proinflammatory role for NmU. In a mouse Th2 cell line (D10.G4.1), a single class of high affinity saturable binding sites for (125)I-labeled NmU (K(D) 364 pM and B(max) 1114 fmol/mg protein) was identified, and mRNA encoding NmU-1R, but not NmU-2R, was present. Competition binding analysis revealed equipotent, high affinity binding of NmU isopeptides to membranes prepared from D10.G4.1 cells. Exposure of these cells to NmU isopeptides resulted in an increase in intracellular Ca(2+) concentration (EC(50) 4.8 nM for human NmU). In addition, NmU also significantly increased the synthesis and release of cytokines including IL-4, IL-5, IL-6, IL-10, and IL-13. Studies using pharmacological inhibitors indicated that maximal NmU-evoked cytokine release required functional phospholipase C, calcineurin, MEK, and PI3K pathways. These data suggest a role for NmU in inflammation by stimulating cytokine production by T cells.
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PMID:Neuromedin U elicits cytokine release in murine Th2-type T cell clone D10.G4.1. 1558 45


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