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 physicochemical nature of the human glomerular complement receptor was studied. Receptor activity was measured by determining the avidity of glomeruli of normal human renal tissue for fluorescein-labeled bacteria (S.typhi) coated with C3b. Maximal binding of C3b-coated bacteria to normal human glomeruli took place in phosphate-saline buffers of pH 6.5 and 0.08 to 0.15 mu ionic strength. Pretreatment of renal tissue with neuraminidase enhanced receptor activity. On the other hand, binding of C3b-coated bacteria to the glomeruli was diminished by pretreatment of the tissue with proteolytic enzymes, phospholipase C and certain lipid solvents. The binding of C3b-coated bacteria to the glomeruli was also diminished by pretreatment of the tissue with fluid-phase C3b, or by pretreatment of the bacteria with C3b inactivator. Normal human serum and purified fluid-phase C3 or the absence of magnesium and calcium ions had little effect on glomerular complement receptor activity.
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PMID:The nature of the receptor for complement (C3b) in the human renal glomerulus. 65 27

Avirulent mutant strains of Listeria monocytogenes which fail to produce phosphatidylinositol-specific phospholipase C, or which produce reduced amounts of hemolytic listeriolysin O, are incapable of causing progressive infection in normal mice. However, both strains can grow progressively in mice that have been rendered incapable of focusing neutrophils at sites of infection as a result of being treated with monoclonal antibody 5C6, specific for the type 3 complement receptor of myelomonocytic cells. In 5C6-treated mice, phospholipase C-negative and listeriolysin-defective mutant strains of L. monocytogenes, like the wild-type strain, give rise in the liver to large numbers of discrete foci of infected hepatocytes that retain their morphological integrity during the first 24 h, despite their large bacterial burden. In normal mice, in contrast, sites of infection in the liver are indicated by discrete focal accumulations of neutrophils that occupy the space originally occupied by infected hepatocytes. It is apparent that in normal mice neutrophils function to lyse infected hepatocytes and thereby to release L. monocytogenes for ingestion and killing by neutrophils themselves and by macrophages. However, whereas a proportion of wild-type organisms survive this early mechanism of defense to give rise to progressive infection, the phospholipase C-negative organisms are totally eliminated. On the basis of these and other results, it is suggested that virulence factors other than listeriolysin are needed by L. monocytogenes to counteract the early neutrophil-mediated mechanism of defense. Listeriolysin, itself, is an intrinsic virulence factor that allows L. monocytogenes to survive and multiply in a proportion of the fixed phagocytes of the liver (permissive phagocytes) and which enables the organism to go on to infect and replicate in adjacent hepatocytes. It was found that a mutant strain of L. monocytogenes incapable of producing any listeriolysin was incapable of establishing progressive infection, even in 5C6-treated mice.
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PMID:Roles of Listeria monocytogenes virulence factors in survival: virulence factors distinct from listeriolysin are needed for the organism to survive an early neutrophil-mediated host defense mechanism. 154 69

Complement receptor (CR)-mediated phagocytosis is associated with an increased accumulation of diglyceride (sn-1,2-diacylglycerol and/or 1-O-alkyl-2-acyl-glycerol) in human neutrophils. The C3bi-mediated increase in diglyceride (5-20 min) was only partially impaired when phosphoinositide-specific phospholipase C (PLC) activity was abolished by reduction of cytosolic free Ca2+. At an early time point (1 min), however, diglyceride production was barely detectable in control cells, whereas production was considerable in cells with a reduced cytosolic free Ca2+ concentration. C3bi stimulation of 32P-labeled neutrophils caused a rapid and significant breakdown of [32P]phosphatidylcholine (PC) which was not affected by inhibition of Ca(2+)-dependent phosphoinositide-specific PLC. Thus, PC hydrolysis could be involved in C3bi-induced diglyceride formation. Stimulation of cells labeled with [3H]1-O-alkyl-lyso-PC ([3H]alkyl-lyso-PC), resulted in an increased formation of [3H]1-O-alkyl-phosphatidic acid ([3H]alkyl-PA) and a later and slower formation of [3H]1-O-alkyl-diglyceride ([3H]alkyl-diglyceride); this suggests activation of phospholipase D (PLD). When these labeled cells were stimulated in the presence of 0.5% ethanol a marked accumulation of [3H]1-O-alkyl-phosphatidylethanol ([3H]alkyl-PEt) was observed in both controls and calcium-reduced cells, further strengthening the suggested involvement of PLD activity. In parallel with the sustained increase in diglyceride formation, CR-mediated phagocytosis was also associated with phosphorylation of a cellular protein kinase C substrate (MARCKS). Therefore it seems reasonable to suggest a causal relationship between C3bi-induced PLD activation, which results in diglyceride formation, and activation of protein kinase C. In electropermeabilized cells which were incapable of ingesting particles, C3bi particles were still able to activate PLD and induce formation of diglyceride. This signaling event must therefore be triggered by binding of particles to the cell and not by the engulfment process. Most importantly, introduction of the protein kinase C inhibitor peptides, PKC(19-36) and PKC(19-31), into these permeabilized cells resulted in a clear reduction of the C3bi-induced production of diglyceride, indicating that CR-mediated activation of protein kinase C directly triggers a positive feedback mechanism for additional diglyceride formation. Taken together, these data further clarify the mechanisms of CR-mediated diglyceride formation and give added support to the concept that protein kinase C plays an important role in the phagocytic process.
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PMID:Complement receptor-mediated phagocytosis is associated with accumulation of phosphatidylcholine-derived diglyceride in human neutrophils. Involvement of phospholipase D and direct evidence for a positive feedback signal of protein kinase. 173 62

A luminol-dependent non-opsonized zymosan-induced chemiluminescence method for phagocytes in small quantities of whole blood (40 microliters; final dilution: 1:14) is described. It was characterized with reference to cellular and humoral components, and also applied to isolated neutrophils, eosinophils and monocytes. Normal values for whole blood chemiluminescence and for neutrophils, eosinophils and monocytes are presented. From the chemiluminescence characteristic of distinct phagocytes and their frequency distribution pattern in whole blood, it is concluded that whole blood chemiluminescence has its source predominantly in neutrophils. The question as to the origin of chemiluminescence in phagocytes of whole blood and isolated neutrophils is investigated. The results support the importance of the myeloperoxidase-H2O2-halide system, but also go beyond this. The release of arachidonic acid by phospholipase A2 and of diacylglycerol and inositol trisphosphate by phospholipase C, the metabolism of arachidonic acid by the cyclooxygenase and lipoxygenase pathway, the activation of membrane NADPH oxidase by diacylglycerol and the calcium mobilisation by inositol trisphosphate are necessary for the chemiluminescence reaction. Inhibition of either mechanism suppresses the chemiluminescence response. The interaction of non-opsonized zymosan with plasma opsonins, phagocyte Fc- and complement receptors, respectively, for the initiation of chemiluminescence, was investigated. Non-opsonized zymosan initiates a chemiluminescence response in blood phagocytes in the absence of opsonin from the interaction of the zymosan polysaccharide component glucan with the complement receptor type 3. In the presence of plasma this receptor type also mediates the major chemiluminescence response brought about by the zymosan-coated cleavage products of complement fraction three, iC3b and to a minor degree C3b, while immunoglobulin G-coated zymosan interaction with the Fc-receptor is in this case of minor importance.
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PMID:Mechanisms of non-opsonized zymosan-induced and luminol-enhanced chemiluminescence in whole blood and isolated phagocytes. 344 Aug 57

B lymphocytes must respond to low concentrations of antigen despite having low affinity antigen receptors during the primary immune response. CD19, a B cell-restricted membrane protein of the immunoglobulin superfamily that associates with the antigen receptor complex, may help the B cell meet this requirement. Cross-linking CD19 to membrane immunoglobulin (mIg) lowers, by two orders of magnitude, the number of mIg that must be ligated to activate phospholipase C (PLC) or to induce DNA synthesis. CD19 is coupled, via protein tyrosine kinases (PTKs), to PLC and phosphatidylinositol 3' kinase (PI3' kinase), and it interacts with the Src-type nonreceptor PTK lyn. It also associates with two other membrane proteins, CR2 (complement receptor type 2, CD21), which permits nonimmunologic ligation of CD19, and TAPA-1, a member of the tetraspan family of membrane proteins. CR2 binds fragments of C3 that are covalently attached to glycoconjugates. This indirectly enables CD19 to be cross-linked to mIg after preimmune recognition of an immunogen by the complement system. CR2 also can be ligated by CD23, a lectin-like membrane protein that resides on cells that may present antigen to B cells. TAPA-1 associates with several other membrane proteins on B and T cells, including MHC class II, CD4, and CD8, and it promotes Ca2(+)- and LFA-1-independent homotypic aggregation when ligated directly or indirectly through CD19 or CR2. This may facilitate interaction of the B cell with other cells essential for cellular activation. The formation of this membrane protein complex by representatives of three different protein families helps the B cell resolve its dilemma of combining broad specificity with high sensitivity.
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PMID:The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity. 754 9

This study investigates whether cell-derived glycosylphosphatidylinositol-linked complement control proteins CD55 and CD59 can be incorporated into HIV-1 virions and contribute to complement resistance. Virus was prepared by transfection of cell lines with pNL4-3, and primary isolates of HIV-1 were derived from patients' PBMCs. Virus was tested for sensitivity to complement-mediated virolysis in the presence of anti-gp160 antibody. Viral preparations from JY33 cells, which lack CD55 and CD59, were highly sensitive to complement. HIV-1 preparations from H9 and U937 cells, which express low levels of CD55 and CD59, had intermediate to high sensitivity while other cell line-derived viruses and primary isolates of HIV-1 were resistant to complement-mediated virolysis. Although the primary isolates were not lysed, they activated complement as measured by binding to a complement receptor positive cell line. While the primary isolates were resistant to lysis in the presence of HIV-specific antibody, antibody to CD59 induced lysis. Likewise, antibody to CD55 and CD59 induced lysis of cell line-derived virus. Western blot analysis of purified virus showed bands corresponding to CD55 and CD59. Phosphatidylinositol-specific phospholipase C treatment of either cell line-derived or primary isolates of HIV-1 increased sensitivity to complement while incubation of sensitive virus with purified CD55 and CD59 increased resistance to complement. These results show that CD55 and CD59 are incorporated into HIV-1 particles and function to protect virions from complement-mediated destruction, and they are the first report of host cell proteins functioning in protection of HIV-1 from immune effector mechanisms.
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PMID:Role of virion-associated glycosylphosphatidylinositol-linked proteins CD55 and CD59 in complement resistance of cell line-derived and primary isolates of HIV-1. 754 40

Complement protein C1q induces the production of superoxide (O2-) by neutrophils via an as yet unidentified receptor or receptor complex. Several strategies were therefore used to identify cell surface molecules involved in the response of neutrophils to C1q and its collagen-like domain (C1q-CLR). Treatment of neutrophils with phosphatidylinositol-specific phospholipase C effectively removed the phosphatidylinositol-linked surface molecules CD14 and CD16, yet did not reduce O2- production in response to C1q. Next, 17 monoclonal antibodies (mAbs) recognizing various neutrophil surface antigens were tested for their ability to inhibit C1q-CLR-mediated O2- production. Only two of the mAbs, 44a and IB4, which recognize CD11b/CD18 (complement receptor 3 or Mac-1), were inhibitory. In addition, neutrophils from a patient with leukocyte adhesion deficiency, which are CD18 deficient, did not produce O2- in response to C1q or C1q-CLR. Because CD11b/CD18 is recognized to play a role in cell adhesion, the role of adherence in C1q-mediated O2- production was explored. Adherence of neutrophils to C1q-CLR-coated surfaces occurred with kinetics, which usually paralleled those of O2- production, and was invariably abolished by the anti-CD11b mAb 44a. However, this mAb often only partially inhibited O2- production, indicating that an avid attachment of neutrophils to the C1q-CLR-coated surface is not required for O2- production.
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PMID:C1q triggers neutrophil superoxide production by a unique CD18-dependent mechanism. 764 12

We report that engagement of a particular epitope near the C-terminal region of complement receptor type 3 (CR3, CD11b/CD18) alpha-chain with CD11b mAb VIM12 induces granulocyte activation with a rise in cytosolic-free Ca2+, actin polymerization, an up-regulation of CR3 cell surface expression and enhanced adhesiveness. Induction of enhanced adhesiveness and homotypic aggregation of human granulocytes represents an active process. It is temperature and energy dependent, requires divalent cations, and an intact cytoskeleton. The mAb VIM12-induced enhanced adhesiveness seems to be mediated, at least in part, by activated CR3 molecules. It can be significantly inhibited, although not completely abolished, with blocking mAbs against adhesiotopes of CR3. VIM12-induced adhesion could be blocked with the serine/threonine inhibitors okadaic acid and calyculin A and with dibuturyl-cAMP but not with the protein kinase inhibitors herbimycin A and staurosporine. We further present evidence that the particular molecular region of CR3 recognized by mAb VIM12 might be involved in the reported intramembrane sugar-lectin type interaction and complex formation between transmembrane CR3 and glycosylphosphatidylinositol (GPI)-anchored Fc gamma RIIIB (CD16) molecules on human granulocytes. Binding of mAb VIM12 to CR3 on granulocytes enhances the release of GPI-anchored Fc gamma RIIIB molecules from granulocytes upon phosphoinositol-phospholipase C treatment. The sugar preparation N-acetyl-D-glucosamine, previously shown to dissociate CR3-Fc gamma RIIIB complex formation, inhibits mAb VIM12 binding. Engagement of CR3 with mAb VIM12 may thus mimic a biologically relevant intramembrane cooperation between two distinct receptor molecules on human granulocytes.
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PMID:Granulocyte activation via a binding site near the C-terminal region of complement receptor type 3 alpha-chain (CD11b) potentially involved in intramembrane complex formation with glycosylphosphatidylinositol-anchored Fc gamma RIIIB (CD16) molecules. 773 Jun 47

Human neutrophils preincubated with antibodies against complement receptor type 1 (CR1) (anti-CD35) and/or complement receptor type 3 (CR3) (anti-CD11b or anti-CD18) exhibited a reduced ability to engulf complement-opsonized yeast particles, whereas cellular adhesion of these particles was reduced only in the presence of anti-CD35 antibodies. These data support the idea that CR1 primarily promotes the adhesion of particles and CR3 mediates the subsequent engulfment. However, the effects of anti-CR1 and anti-CR3 antibodies on particle-induced diglyceride production correlate with the effects of these antibodies on the cellular uptake of the particles. Hence, it seems reasonable to suggest that CR1 also participates in mediating the signal(s) that induce particle uptake. This idea is further supported by the findings that cross-linking surface-bound anti-CD11b, anti-CD18 as well as anti-CD35 antibodies results in activation of phospholipase D (PLD), a signal closely associated with phagocytosis of complement-opsonized yeast particles in human neutrophils. The signaling property of CR1 was further revealed by the observation that cross-linking of surface-bound anti-CD35 triggered a rapid and transient mobilization of intracellular Ca2+, a signal most likely involved in the phagosome-lysosome fusion that occurs after the uptake of a particle. Pretreatment with PMA, which positively modulates CR-mediated engulfment of particles, was found to potentiate the CR3- and CR1-induced activation of PLD but impair the activation of phospholipase C, giving added support to the idea that PLD activation is the principal signal for the engulfment process. The activation of PLD was also increased by stimulating the cells with anti-CD18 or anti-CD35 antibodies prefixed on Staphylococcus aureus particles, instead of cross-linking cellular-bound antibodies, suggesting that the form of ligand presentation is a critical parameter of phagocytic signaling. Taken together, the present results demonstrate that both CR1 and CR3 can initiate transmembrane signaling in human neutrophils and, in particular, activation of PLD. This activation was also further recognized as an important signal regulating the engulfment of complement-opsonized particles.
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PMID:Signaling properties of CR3 (CD11b/CD18) and CR1 (CD35) in relation to phagocytosis of complement-opsonized particles. 832 30

The human erythrocyte CA receptor (E-CR) is the type 1 complement receptor (CR1), the most common form of which is a 220,000 Mr integral membrane glycoprotein composed of 30 short consensus repeats (SCRs). The E-CR of many nonhuman primates is a smaller receptor of unknown genetic origin. Recently, we identified a chimp cDNA, termed CR1b, which represented transcription of a homologue of the human genetic element, CR1-like. The purpose of this study was to identify CR1b in the baboon and, if present, determine whether it encodes the 65,000 Mr baboon E-CR. Baboon bone marrow cDNA was amplified by PCR using primers specific for the signal peptide-encoding region of human CR1 and the 3' region of chimp CR1b. This amplification yielded a CR1b sequence predicted to encode seven SCRs followed by a hydrophobic region, with an N terminus homologous to the N terminus of baboon E-CR. Expression of baboon CR1b yielded a membrane protein that reacted with an anti-CR1 mAb, was identical in size to baboon E-CR, and, like baboon E-CR, could bind baboon C3 linked to activated thiol-Sepharose (C3i-ATS), but not human C3i-ATS. Phosphatidylinositol-specific phospholipase C (PIPLC) released CR1b from Chinese hamster ovary cells and E-CR from baboon erythrocytes, demonstrating that both of these proteins are glycophosphatidylinositol linked to the membrane. Thus, the data indicate that baboon CR1b, a homologue of the human CR1-like genetic element, encodes a glycophosphatidylinositol-linked protein that is the baboon E-CR.
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PMID:The baboon erythrocyte complement receptor is a glycophosphatidylinositol-linked protein encoded by a homologue of the human CR1-like genetic element. 880 61


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