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)

Murine macrophages activated by interferon (IFN)-gamma and bacterial lipopolysaccharide (LPS) produce large amounts of nitric oxide (NO), which is a critical mediator for a variety of biological functions. The expression of this inducible NO synthase (iNOS) involves a protein kinase C (PKC)-dependent pathway, but the mechanism for the PKC activation in this system is unclear. Through analysis of diacylglycerol (DAG) synthesis and choline metabolism in activated macrophages, direct evidence is provided that NO synthesis involves the activation of an unusual phosphatidylcholine-specific phospholipase C (PC-PLC) and not a phosphatidylinositol-specific phospholipase C (PI-PLC) or phospholipase D (PLD).
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PMID:The role of a phosphatidylcholine-specific phospholipase C in the production of diacylglycerol for nitric oxide synthesis in macrophages activated by IFN-gamma and LPS. 751 Sep 53

In the past few years, a number of experimental observations have provided more insight into the mechanisms of action of tumor necrosis factor (TNF)/lymphotoxin (LT) ligand-receptor system. This system consists of three ligands, TNF, LT alpha (LT alpha) and LT beta (LT beta), and three membrane-associated receptors, p55, p75 and LT beta-receptor (LT beta-R). Like TNF, LT alpha is a secreted protein which in solution forms a homotrimer molecule, with a conformation similar to that of TNF. LT beta is a transmembrane protein that provides the membrane anchor for the attachment to the cell surface of the heteromeric complex of LT alpha and LT beta. This complex retains a structure related to TNF and LT alpha homotrimers, with the homology regions interacting in a heterotypic fashion. The LT alpha 1:LT beta 2 heteromer has been found to be a predominant form of surface LT. The biological effects of TNF and LT alpha homotrimers are mediated by p55 and p75 receptors, while the heteromeric complex of LT alpha/LT beta transduces its cellular signal via LT beta-R. Membrane-associated receptor affinities as well as final biological effects of TNF/LT can be modulated by the influence of naturally occurring soluble receptors, derived from the cell surface by proteolytic cleavage. The multimerization of receptor cytoplasmic domains upon TNF/LT ligation is postulated to activate the intracellular signal-transduction pathways. One of them is the activation of phospholipase A2 (PL-A2) resulting in the production of arachidonic acid (AA) and other metabolites, including leukotriens, phosphatidycholine-specific phospholipase C (PC-PLC) with subsequent production of diacylglycerol (DAG) and activation of protein kinase C (PKC). As a third signaling pathway, TNF/LT employ the sphingomyelinase (SMase)-mediated hydrolysis of membrane sphingomyelin (SM) to ceramide. The final link in the TNF/LT signaling is activation of nuclear transcription factors, such as NF-kappa B, AP-1, interferon regulatory factors-1 and -2 (IRF-1, IRF-2), and NF-GMa. Since induction of AP-1, IRF-1 and IRF-2 as well as NF-GMa proceeds through translational event, the posttranslational TNF/LT-driven activation of NF-kappa B remains the only cellular event identified so far that serves as a direct target in their signaling cascade.
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PMID:Mechanisms of action of the tumor necrosis factor and lymphotoxin ligand-receptor system. 757 92

Enhanced secretion of PGF2 alpha from endometrial explants in vitro in response to oxytocin is associated with augmented activities of phospholipase A2, phospholipase C and prostaglandin endoperoxide H synthase (PGS). In early pregnancy, maintenance of the corpus luteum is associated with an absence of pulsatile PGF2 alpha secretion; an increase in endometrial inhibitors of phospholipase A2 and PGS contribute to the antiluteolytic alterations of PGF2 alpha secretion. Linoleic acid is a competitive inhibitor of arachidonic acid metabolism by PGS, and microsomal concentrations of free linoleic acid are increased in the endometrium of pregnant cattle. The trophoblast produces large quantities of interferon tau (IFN-tau). Inhibition of increases in endometrial oestradiol receptor mRNA and protein are associated with intrauterine administration of recombinant (r) ovine (o) IFN-tau in sheep. Intrauterine injections of ovine (b) IFN-tau in cattle (days 14-17) altered endometrial function so that secretion of PGF2 alpha from cultured endometrial epithelial cells was reduced. Antiluteolytic effects were not expressed in 20% of cows receiving IFN-tau or rbIFN-alpha I1 indicating that an inadequate endometrial responsiveness may contribute to embryo mortality. IFN-tau may activate a signal transduction system similar to that induced by other type I IFNs; activation of an intracellular tyrosine kinase ultimately leads to activation of an IFN-stimulated response element to induce gene transcription. Biological responses associated with pregnancy and IFN-tau treatment are integrated into a multifactorial antiluteolytic model. Strategies to enhance embryo survival could include supplementation with rIFN-tau and alterations in endometrial responsiveness to this cytokine through dietary manipulation of lipid metabolism.
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PMID:Maternal recognition of pregnancy. 762 10

Primary cultures of luteal cells have been used to determine both acute and chronic effects of cytokines on luteal cell function and viability. Gonadotrophin-stimulated progesterone production is inhibited by interleukin 1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), or gamma-interferon (IFN-gamma), the last two cytokine being more effective than IL-1. In contrast, all three cytokines are potent stimulators of prostaglandin production by these cells. The mechanism by which prostaglandin synthesis is enhanced may differ slightly for each cytokine. In luteal cells, TNF-alpha appears to act primarily through stimulation of phospholipase A2, whereas IL-1 beta may activate phospholipase C and prostaglandin endoperoxide synthase (PGS) in addition to phospholipase A2. The mechanism of action of IFN-gamma has not yet been determined. In addition to the observed functional effects, cytokines may also promote cell death during luteal regression. Although the three cytokines mentioned have little or no effect on viability of cultured luteal cells when administered separately, combined treatment with TNF-alpha and IFN-gamma results in a substantial decrease in the number of viable cells. Inhibition of cytokine-stimulated prostaglandin production does not alter the cytotoxic effect of these cytokines. Expression of major histocompatibility (MHC) class I molecules on luteal cells is enhanced, and MHC class II molecules are induced, by exposure to IFN-gamma. This is especially intriguing, as MHC class II expression increases before luteal regression in vivo, and is suppressed in early pregnancy. In summary, evidence is rapidly accumulating that supports the hypothesis that the function or structural integrity of luteal cells may be modulated by resident immune cells. Future research will probably address how these local events are hormonally controlled, and if they can be modified to regulate corpus luteum function.
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PMID:Involvement of immune cells in regulation of ovarian function. 762 27

The expression of Fc gamma receptor III (Fc gamma RIII) on a human eosinophilic leukemia cell line, EoL-1, was examined and compared with its expression on normal blood eosinophils. Surface Fc gamma RIII expression on EoL-1 cells could be induced in vitro with a combination of dibutyryl cAMP (dbcAMP) and gamma-interferon (IFN-gamma), but not with IFN-gamma or dbcAMP alone. Pretreatment of EoL-1 cells with dbcAMP induced EoL-1 cells to express Fc gamma RIII when stimulated with IFN-gamma, but EoL-1 cells pretreated with IFN-gamma and then stimulated with dbcAMP failed to express Fc gamma RIII. Cyclic AMP was shown to play a role in the effect of dbcAMP. Both the treatment with phosphatidyl-inositol-specific phospholipase C (PI-PLC) and the restriction enzyme digestion of Fc gamma RIII cDNA showed that the Fc gamma RIII on EoL-1 cells was a phosphatidylinositol-linked form. On the other hand, freshly isolated blood eosinophils constitutively expressed few, if any, Fc gamma RIII, and IFN-gamma induced Fc gamma RIII expression on them in vitro. Dibutyryl cAMP did not induce Fc gamma RIII expression and even suppressed the IFN-gamma-induced Fc gamma RIII expression on normal eosinophils. The EoL-1 cell line appears to be a useful in vitro model for the expression and function of the phosphatidylinositol-linked form of Fc gamma RIII on eosinophils.
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PMID:Induction of phosphatidylinositol-linked Fc gamma receptor III expression on an eosinophilic cell line, EoL-1, by dibutyryl cyclic AMP and interferon-gamma. 839 82

The early molecular mechanisms activated by the treatment of human lymphocytes with human interferon beta have been studied. These identify an early increase with respect to control, in diacylglycerol (DG) levels as response to interferon treatment. Such a DG production was derived from the rapid and sequential activation of phosphoinositide specific phospholipase C and phospholipase D pathway. This suggests that a synergistic involvement of phosphatidylinositol-bis-phosphate (PIP2) hydrolysis and phosphatidylcholine (PC) breakdown provide early molecular events upon the interaction between interferon beta and its cell surface receptors. This finally leads to the slowing down of cell growth.
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PMID:Interferon beta mediated intracellular signalling traffic in human lymphocytes. 858 79

Added to HeLa cells previously exposed to recombinant human interferon (IFN)-gamma for 20 h, thyroid hormone [L-thyroxine (T4)] in physiological concentrations potentiates the antiviral action of IFN-gamma by more than 100-fold in 4 h. We examined protein kinase activities for their contributions to the mechanism of this posttranslational effect of thyroid hormone. Added concurrently with thyroid hormone, the protein kinase C (PKC) inhibitor CGP-41251 (5 nM) blocked T4 potentiation of IFN-gamma action. Coincubated with CGP-41251, phorbol 12-myristate 13-acetate (PMA) reversed the effect of the inhibitor on thyroid hormone action. U-73122 (10 nM), a phospholipase C inhibitor, also blocked hormone potentiation. KT-5720 (500 nM), a protein kinase A (PKA) inhibitor, completely inhibited the T4 effect, whereas 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) restored hormone action in the presence of KT-5720. In the absence of T4, 8-BrcAMP and PMA, added together to cells in the 4-h paradigm, fully reproduced hormone potentiation of the antiviral effect of IFN-gamma. Incubated individually with IFN-gamma-treated cells, the two agonists had no potentiating action. Thyroid hormone apparently must activate both PKA and PKC in the nongenomic pathway of IFN-gamma action to enhance antiviral activity in HeLa cells.
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PMID:Potentiation by thyroxine of interferon-gamma-induced antiviral state requires PKA and PKC activities. 889 32

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

To identify the role in periodontal inflammatory diseases of human gingival fibroblasts (HGF), the major constituents of gingival tissue, the expression of CD14, a possible lipopolysaccharide (LPS) receptor, and the release of soluble CD14 (sCD14) by HGF were examined. Among the HGF samples from the nine donors tested, more than 50% of the HGF from five donors expressed CD14 but less than 20% of HGF from the other four donors did so, as determined by flow cytometric analysis. The CD14 expression on the cell surface was correlated with the expression of CD14 mRNA. The HGF and skin and lung fibroblasts tested expressed no CD18, which indicates that fibroblasts do not possess other LPS receptors, such as CD11b/CD18 and CD11c/CD18. The CD14 expression by the HGF was decreased after subculturing and was highest at the confluent stage of culture. The treatment of high-CD14-expressing (CD14(high)) HGF with phosphatidylinositol-phospholipase C reduced CD14 expression; this result and the increase in a 55-kDa CD14 indicate that the membrane CD14 (mCD14) on the HGF may be a 55-kDa glycosylphosphatidylinositol-anchored protein. CD14(high) HGF spontaneously released 48- and 57-kDa sCD14. The total release of sCD14 by the HGF was augmented by gamma interferon and Escherichia coli LPS in accordance with the increased expression of mCD14. The CD14(high) HGF secreted interleukin-8 in response to LPS, and the secretion was completely inhibited by anti-CD14 antibody. These results suggest that (i) HGF consist of populations that are heterogeneous on the basis of different levels of expression of CD14 and (ii) CD14(high) HGF secrete inflammatory cytokines in response to LPS via CD14.
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PMID:Heterogeneous expression and release of CD14 by human gingival fibroblasts: characterization and CD14-mediated interleukin-8 secretion in response to lipopolysaccharide. 963 64

During wound healing, fibroblasts are recruited from the surrounding tissue to accomplish repair. The requisite migration and proliferation of the fibroblasts is promoted by growth factors including those that activate the epidermal growth factor receptor (EGFR). Counterstimulatory factors in wound fluid are postulated to limit this response; among these factors is the ELR-negative CXC chemokine, interferon inducible protein-10 (IP-10). We report here that IP-10 inhibited EGF- and heparin-binding EGF-like growth factor-induced Hs68 human dermal fibroblast motility in a dose-dependent manner (to 52% and 44%, respectively, at 50 ng/ml IP-10), whereas IP-10 had no effect on either basal or EGFR-mediated mitogenesis (96 +/- 15% at 50 ng/ml). These data demonstrate for the first time a counterstimulatory effect of IP-10 on a specific induced fibroblast response, EGFR-mediated motility. To define the molecular basis of this negative transmodulation of EGFR signaling, we found that IP-10 did not adversely impact receptor or immediate postreceptor signaling as determined by tyrosyl phosphorylation of EGFR and two major downstream effectors phospholipase C-gamma and erk mitogen-activated protein kinases. Morphological studies suggested which biophysical steps may be affected by demonstrating that IP-10 treatment resulted in an elongated cell morphology reminiscent of failure to detach the uropod; in support of this, IP-10 pretreatment inhibited EGF-induced cell detachment. These data suggested that calpain activity may be involved. The cell permeant agent, calpain inhibitor I, limited EGF-induced motility and de-adhesion similarly to IP-10. IP-10 also prevented EGF- induced calpain activation (reduced by 71 +/- 7%). That this inhibition of EGF-induced calpain activity was secondary to IP-10 initiating a cAMP-protein kinase A-calpain cascade is supported by the following evidence: (a) the cell permeant analogue 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) prevented EGF-induced calpain activity and motility; (b) other ELR-negative CXC chemokines, monokine induced by IFN-gamma and platelet factor 4 that also generate cAMP, inhibited EGF-induced cell migration and calpain activation; and (c) the protein kinase A inhibitor Rp-8-Br-cAMPS abrogated IP-10 inhibition of cell migration, cell detachment, and calpain activation. Our findings provide a model by which IP-10 suppresses EGF-induced cell motility by inhibiting EGF-induced detachment of the trailing edges of motile cells.
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PMID:IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal growth factor receptor-mediated calpain activity. 1040 74


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