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)

Expression of the aminophospholipid phosphatidylserine (PS) on the surface of apoptotic lymphocytes and lipid-symmetric erythrocytes triggers their phagocytosis by macrophages. Phagocytosis by both activated and unactivated macrophages, which utilize different recognition systems, can be blocked by certain monoclonal antibodies directed against the LPS receptor, CD14. Here we investigate the requirement for CD14 in the phagocytosis of both apoptotic thymocytes and lipid-symmetric erythrocytes by both activated and unactivated macrophages. We show that phagocytosis of lipid-symmetric erythrocytes by both activated and unactivated macrophages is completely abolished when CD14 is removed from macrophages by cleaving its glycosylphosphatidylinositol tether with phospholipase C. This treatment also substantially reduces phagocytosis of apoptotic lymphocytes by both types of macrophages. Unactivated LR-9 mouse macrophages which are deficient in CD14 expression are completely unable to phagocytose either apoptotic thymocytes or lipid-symmetric erythrocytes. These results argue that CD14 is an absolute requirement for the phagocytosis of lipid-symmetric erythrocytes by both activated and unactivated macrophages, despite their different recognition systems, that CD14 contributes at least substantially to the phagocytosis of apoptotic lymphocytes by both activated and unactivated macrophages, and that activated macrophages may also possess an alternate, CD14-independent mechanism for phagocytosis of apoptotic lymphocytes.
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PMID:CD14 is a component of multiple recognition systems used by macrophages to phagocytose apoptotic lymphocytes. 1038 56

The interaction between bacteria and macrophages is central to the outcome of Salmonella infections. Salmonella can escape killing by these phagocytes and survive and multiply within them, giving rise to chronic infections. Cytokines produced by infected macrophages are involved in the early gastrointestinal pathology of the infection as well as in the induction and maintenance of the immune response against the invaders. Jun N-terminal kinases (JNK) are activated by inflammatory stimuli and play a role in cytokine production. We have investigated the signaling routes leading to JNK activation in Salmonella-infected macrophages and have discovered that they differ radically from the mechanisms operating in epithelial cells. In particular, activation of the JNK kinase stress and extracellular-activated kinase 1 (SEK1) and of JNK in macrophages occurs independently of actin rearrangements and of the GTPases Cdc42 and Rac, essential mediators in other cells. Activation of JNK is effected by a novel pathway comprising tyrosine kinase(s), phosphoinositide 3-kinase and, likely, atypical protein kinase C zeta. SEK1 is stimulated by a distinct mechanism involving phosphatidylcholine-phospholipase C and acidic sphingomyelinase. Dominant-negative SEK1 can block JNK activation by LPS, but not by Salmonella. These data demonstrate that SEK1 and JNK are activated independently in Salmonella-infected macrophages and offer experimental support for the concept that incoming signals can direct the selective coupling of downstream pathways to elicit highly specific responses. Inhibitors of stress kinase pathways are receiving increasing attention as potential anti-inflammatory drugs. The precise reconstruction of stimulus-specific pathways will be instrumental in predicting/evaluating the effects of the inhibitors on a given pathological condition.
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PMID:Distinct mechanisms target stress and extracellular signal-activated kinase 1 and Jun N-terminal kinase during infection of macrophages with Salmonella. 1052 95

Local TNF-alpha production in different organs may affect HIV replication and pathogenesis. Alveolar macrophages (AMs) obtained by bronchoalveolar lavage from asymptomatic HIV-seropositive and HIV-seronegative individuals did not spontaneously release TNF-alpha, but LPS stimulation of these cells significantly increased TNF-alpha production. We tested whether NF-kappa B affects TNF-alpha production by AMs using N-tosyl-<cmd SC>l<cmd /SC> -phenylalanine chloromethylketone (TPCK) or N-benzoyl-<cmd SC>l<cmd /SC> -tyrosine ethyl ester (BTEE), which inhibit the degradation of I kappa B, or tricyclodecan-9-yl-xanthogenate-potassium (D609), which inhibits phospholipase C. Alveolar macrophages were exposed to LPS alone and with the chemical protease inhibitors TPCK, BTEE, and D609. NF-kappa B DNA binding induced by LPS treatment of AMs was inhibited by TPCK, BTEE, and D609. These agents also inhibited TNF-alpha mRNA and TNF-alpha protein production. After 24 h, the levels of TNF-alpha mRNA reached equilibrium, as assessed by RT-PCR. The levels of NF-kappa B mRNA remained constant under all conditions. The levels of I kappa B-alpha mRNA were similar after 30, 60, and 180 min, but the I kappa B-beta mRNA concentration was initially low and increased over time under all conditions. I kappa B-alpha and I kappa B-beta protein production was not affected by the chemical protease inhibitors. Our data show that TNF-alpha production by LPS-stimulated AMs from asymptomatic HIV-seropositive and -seronegative individuals is regulated via the phospholipase C pathway and by NF-kappa B DNA binding activity without obvious changes in I kappa B-alpha or I kappa B-beta protein concentrations.
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PMID:NF-kappa B modulates TNF-alpha production by alveolar macrophages in asymptomatic HIV-seropositive individuals. 1064 Jul 79

We have identified new activating receptors of the Ig superfamily expressed on human myeloid cells, called TREM (triggering receptor expressed on myeloid cells). TREM-1 is selectively expressed on blood neutrophils and a subset of monocytes and is up-regulated by bacterial LPS. Engagement of TREM-1 triggers secretion of IL-8, monocyte chemotactic protein-1, and TNF-alpha and induces neutrophil degranulation. Intracellularly, TREM-1 induces Ca2+ mobilization and tyrosine phosphorylation of extracellular signal-related kinase 1 (ERK1), ERK2 and phospholipase C-gamma. To mediate activation, TREM-1 associates with the transmembrane adapter molecule DAP12. Thus, TREM-1 mediates activation of neutrophil and monocytes, and may have a predominant role in inflammatory responses.
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PMID:Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. 1079 49

We previously reported that macrophage activators such as LPS, IL-2, and IL-4 down-modulate the M-CSFR via a mechanism involving protein kinase C and phospholipase C. In this study, we showed that M-CSFR is shed from macrophage surface and identified the protease responsible for M-CSFR cleavage and down-modulation. The shedding of M-CSFR elicited by phorbol esters (tetradecanoylphorbol myristate acetate (TPA)) or LPS in murine BAC.1-2F5 macrophages was prevented by cation chelators, as well as hydroxamate-based competitive inhibitors of metalloproteases. We found that the protease cleaving M-CSFR is a transmembrane enzyme and that its expression is controlled by furin-like serine endoproteases, which selectively process transmembrane metalloproteases. M-CSFR down-modulation was inhibited by treating cells in vivo, before TPA stimulation, with an Ab raised against the extracellular, catalytic domain of proTNF-converting enzyme (TACE). TACE expression was confirmed in BAC.1-2F5 cells and found inhibited after blocking furin-dependent processing. Using TACE-negative murine Dexter-ras-myc cell monocytes, we found that in these cells TPA is unable to down-modulate M-CSFR expression. These data indicated that TACE is required for the TPA-induced M-CSFR cleavage. The possibility that the cleavage is indirectly driven by TACE via the release of TNF was excluded by treating cells in vivo with anti-TNF Ab. Thus, we concluded that TACE is the protease responsible for M-CSFR shedding and down-modulation in mononuclear phagocytes undergoing activation. The possible physiological relevance of this mechanism is discussed.
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PMID:TNF-alpha-converting enzyme cleaves the macrophage colony-stimulating factor receptor in macrophages undergoing activation. 1116 Jan 99

Recently, it has been shown that ATP and TNF-alpha synergize in the activation and maturation of human dendritic cells (DC); the effect of ATP was reproduced by hydrolysis-resistant derivatives of ATP and was blocked by suramin, suggesting the involvement of a P2 receptor, but the particular subtype involved was not identified. In this report we confirm that ATP and various derivatives synergize with TNF-alpha and LPS to induce the maturation of human monocyte-derived DC, as revealed by up-regulation of the CD83 marker and the secretion of IL-12. The rank order of potency of various analogs (AR-C67085 > adenosine 5'-O-(3-thiotriphosphate) = 2'- and 3'-O-(4-benzoyl-benzoyl) ATP > ATP > 2-methylthio-ATP) was close to that of the recombinant human P2Y11 receptor. Furthermore, these compounds activated cAMP production in DC, in a xanthine-insensitive way, consistent with the involvement of the P2Y11 receptor, which among P2Y subtypes has the unique feature of being dually coupled to phospholipase C and adenylyl cyclase activation. The involvement of the P2Y11/cAMP/protein kinase A signaling pathway in the nucleotide-induced maturation of DC is supported by the inhibitory effect of H89, a protein kinase A inhibitor. Taken together, our results demonstrate that ATP activates DC through stimulation of the P2Y11 receptor and subsequent increase in intracellular cAMP.
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PMID:The P2Y11 receptor mediates the ATP-induced maturation of human monocyte-derived dendritic cells. 1139 Apr 64

The periparturient period of animals (and humans) is very stressful and influenced by the microecosystem of the gastrointestinal tract (GIT). Performance and productivity of animal husbandry depend on the health of animal mothers and their offspring. We investigated the influence of prebiotic amounts of lactulose in sows and their piglets. Two experimental trial sows received daily 30 ml lactulose, 71 field trial sows received daily 45 ml lactulose during their periparturient period (10 days before until 10 days after parturison). The weaners of trial sows received 15 ml lactulose per 1 kg baby food 10 days before and 10 days after weaning.The effect of lactulose was recorded by performance parameters like number of piglet born alive, losses until weaning, body mass of piglets, daily weight gain of weaners until 35 days after weaning. The effect of lactulose on GIT microflora was estimated by bacterial counts of faeces of sows (total aerobic bacteria, Gram-negative bacteria, Clostridium (C.) perfringens). In order to show a previously unknown effect of lactulose we investigated the levels of antibodies to phospholipase C (PLC) of C. perfringens in plasma of experimental sows and in colostral and ripe milk of field sows. Lactulose influenced the performance parameters of sows in a non-significant way. In case of weaners we recorded significant daily weight gains. Lactulose significantly influenced total aerobic bacterial counts, C. perfringens counts in faeces of sows 20 days after parturison. Under experimental conditions it was shown that trial sows and their piglets had higher IgG-antibody levels to C. perfringens PLCs than the control animals. Similar results were found under field conditions. Trial sows had significant higher IgG-anti LPS (J5) antibodies in milk 10 days after birth.
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PMID:Effects of lactulose on the intestinal microflora of periparturient sows and their piglets. 1242 Jan 13

We have previously shown that interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha mRNA levels in rat alveolar macrophages are increased in by endotoxin (lipopolysaccharide; LPS)- stimulation and further enhanced by culturing with low-Mg2+ medium. We have now investigated the mechanisms of underlying this enhancement by using some specific signal transduction inhibitors. The enhanced elevation of both mRNAs levels was suppressed by pretreatment with TMB-8 (which inhibits calcium release from the endoplasmic reticulum) or dexamethasone (which inhibits nuclear factor [NF]-kappaB and activator protein [AP]-1), but not with verapamil or nifedipine (which inhibits calcium channels). The enhancment of IL-1beta, but not TNF-alpha mRNA levels, was suppressed by pretreatment with W-7 (which inhibits calmodulin), whereas the enhancement of TNF-alpha mRNA levels was suppressed by pretreatment with U73122 (which inhibits phospholipase C). Curcumin (an inhibitor of AP-1), suppressed the increases in both mRNAs induced by low-Mg2+ medium alone, but had no suppressive effect on the levels of either mRNA after LPS-stimulation in low-Mg2+ medium. Pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB) prevented the elevation of TNF-alpha mRNA levels induced by low-Mg2+ medium without LPS-stimulation, but had no suppressive effect on IL-1beta mRNA levels. From these results, we conclude that the enhanced elevation of IL-1beta and TNF-alpha mRNA levels seen in LPS-stimulated alveolar macrophages in low-Mg2+ medium occurs partly via the same, and partly via different, signaling pathways.
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PMID:Mechanisms underlying the enhanced elevation of IL-1beta and TNF-alpha mRNA levels following endotoxin challenge in rat alveolar macrophages cultured with low-Mg2+ medium. 1263 66

We studied the cytoplasmic signalling pathways involved in the generation of nitric oxide (NO) after stimulation with adult excretory/secretory antigens (ESA) of Toxocara canis. The pathways of phospholipase A2 (PLA2) and phospholipase C (PLC) were considered as potentially involved in the synthesis of nitric oxide. We used inhibitors of these pathways at different levels. Several concentrations of lithium chloride, verapamil, TMB-8 and staurosporine were used to inhibit the PLC pathway. Inhibition of the PLA2 pathway was attempted with mepacrine, diethylcarbamazine or meloxicam. Lithium chloride, verapamil and TMB-8 reduced the production of NO induced by ESA in a concentration-dependent manner. Regarding the PLA2 pathway, a range of concentrations of mepacrine greatly reduced the production of NO induced by ESA. Meloxicam inhibition was always higher than 50%. Diethylcarbamazine showed a dose-dependent effect on the production of NO induced by the ESA. Our results suggest that both the PLC and the PLA2 pathways play an essential role in activating the production of macrophage NO triggered by the ESA of T. canis. This could indicate that NO production in our experimental conditions is due to both an increase of intracellular calcium and to the participation of the arachidonic acid cascade. The implications of these activations on the host-parasite relationship are discussed and compared with LPS-stimulated macrophages.
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PMID:Cytoplasmic signalling pathways in alveolar macrophages involved in the production of nitric oxide after stimulation with excretory/secretory antigens of Toxocara canis. 1269 4

Our previous data have demonstrated that LPS-stimulated alveolar macrophages produce higher levels of IL-1beta and TNF-alpha mRNA in low-Mg(2+) medium than in normal-Mg(2+) medium. In this study, we examined whether the increased mRNA levels are correlated with the release of both cytokines. LPS-stimulated alveolar macrophages released higher amounts of IL-1beta and TNF-alpha in low-Mg(2+) medium than in normal-Mg(2+) medium. The enhanced release of IL-1beta was completely suppressed by pretreatment with verapamil (a calcium entry blocker), U73122 (a phospholipase C inhibitor), W-7 (a calmodulin inhibitor), and curcumin (an activator-protein [AP]-1 inhibitor), and weakly suppressed by dexamethasone (which inhibits nuclear factor [NF]-kappaB and AP-1). On the other hand, the enhanced release of TNF-alpha was completely suppressed by U73122, and strongly suppressed by TMB-8 (which inhibits calcium release from the endoplasmic reticulum) and W-7, and weakly suppressed by pyrrolidine dithiocarbamate (a NF-kappaB inhibitor). From these results, we conclude that the enhanced release of IL-1beta and TNF-alpha from LPS-stimulated alveolar macrophages in low-Mg(2+) medium depends partly on the enhanced synthesis of both cytokines, and occurs partly via identical, and partly via different, signaling pathways.
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PMID:Enhanced release of IL-1beta and TNF-alpha following endotoxin challenge from rat alveolar macrophages cultured in low-mg(2+) medium. 1289 81


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