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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet-activating factor is a potent proinflammatory lipid mediator which directly stimulates neutrophil chemotaxis, degranulation, aggregation, and superoxide radical (O2-) production. PAF also modifies or 'primes' neutrophil responses to other agents. Although a relatively weak direct oxidative agonist, PAF markedly enhances O2- release evoked by phorbol myristate acetate (PMA) and the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), increasing the maximal rate of O2- production by a calcium-dependent mechanism. PAF also increases protein kinase activity in the membrane fraction of neutrophils. In search of a mechanism for oxidative priming by PAF, we investigated the role of PAF in modifying PMA-induced activation/translocation of protein kinase C (PKC) in human neutrophils. In the presence of PAF and PMA both PKC and calcium-, phospholipid-independent protein kinase activities in particulate fractions increase markedly over activities detected in the presence of PMA alone. The increase in particulate protein kinase activities requires the presence of cytochalasin B and is calcium-dependent. The PKC-enhancing effect of PAF may be involved in the mechanism whereby the phospholipid 'primes' neutrophils for augmented oxidative responses to some stimuli but the exact role of PKC in neutrophil oxidative metabolism remains to be defined.
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PMID:Priming of neutrophil oxidative responses by platelet-activating factor. 196 14

We investigated the regulation of the adhesiveness of the human promonocytic cell line U-937, differentiated along the monocytic pathway either by 1,25-(OH)2-cholecalciferol or a combination of retinoic acid and dibutyryl cAMP. Adhesion to untreated polystyrene plastic was induced by inflammatory agents like PAF, fMLP or LTB4. The response to PAF first appeared after 48hr of differentiation and was inhibited by PAF antagonists and protein kinase C inhibitors indicating involvement of the phosphatidyl-inositol pathway in the stimulating effect. On the other hand, all the c-AMP raising agents tested inhibited PAF-induced cell adhesion, whatever their target membrane receptors, the Gs transducing protein, the catalytic unit of adenylate cyclase or cAMP phosphodiesterase. Direct stimulation of protein kinase A by Br8-cAMP had a similar effect. Moreover, PAF was able to increase cAMP levels. This suggests the existence of a cAMP based negative control mechanism limiting the action of PAF.
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PMID:The adhesiveness of monocytic U937 cells is stimulated by pro-inflammatory agents and inhibited by adenosine 3':5'-cyclic monophosphate. 215 91

We have shown previously that both 1,2-diacylglycerol (AAG) and 1-O-alkyl-2-acylglycerol (EAG) prime neutrophil release of arachidonic acid via uncharacterized phospholipases A2. Therefore, we investigated the actions of EAG and AAG specifically on neutrophil cytosolic (cPLA2) and secretory (sPLA2) phospholipase A2s. We hypothesized that AAG as a protein kinase activator would activate cPLA2 via phosphorylation events. EAG is antagonistic to the AAG activation of PKC, thus it was not expected to act via phosphorylation of cPLA2. Neutrophils were primed with either AAG or EAG and then stimulated with fMLP. When neutrophils were primed with 5-20 microM 1,2-diacylglycerol, a shift was observed in cPLA2 migration on SDS-PAGE gels, consistent with phosphorylation of the protein. This gel shift was not seen after exposure to EAG. AAG also caused a parallel increase in enzymatic activity of cPLA2 that was not seen with EAG. We also investigated whether either diglyceride would cause similar priming or direct secretion of sPLA2. Both AAG and EAG directly caused significant secretion of neutrophil sPLA2. EAG also increased the release of sPLA2 in cells subsequently stimulated with fMLP. Thus, AAG activated cPLA2 and stimulated secretion of sPLA2. In contrast, EAG did not activate cPLA2, but directly activated secretion of sPLA2. We also demonstrated that human synovial fluid sPLA2 increased AA release from resting and fMLP-stimulated neutrophils. Given that diglycerides prime for release of AA, PAF, and LTB4, these current data support the hypothesis that such priming may be mediated by phosphorylation dependent (cPLA2) or phosphorylation independent (e.g. secretion of sPLA2) events.
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PMID:Differential activation of human neutrophil cytosolic phospholipase A2 and secretory phospholipase A2 during priming by 1,2-diacyl- and 1-O-alkyl-2-acylglycerols. 979 28

An aqueous fraction (10-300 micrograms/mL) of the ethanol extract of the leaves of Cissampelos sympodialis Eichl inhibited N-formyl-Met-Leu-Phe (fMLP)-induced release of lysozyme and myeloperoxidase from human neutrophils. Inhibition by the fraction, as well as by dibutyryl-cAMP and prostaglandin E2, was substantially greater when the cells were pretreated with the phosphodiesterase (PDE) inhibitor isobutyl methyl xanthine (IBMX) indicating that the effect may be mediated by cAMP. Measurement of intracellular cAMP levels showed that the fraction (30-100 micrograms/mL) increased the nucleotide levels in IBMX-pretreated neutrophils which was unaffected by propranolol. Cyclic AMP dependent protein kinase A activity was also increased by the fraction (1.5-100 micrograms/mL). Superoxide anion generation induced by fMLP in cytochalasin B-treated cells primed with PAF was not inhibited by the aqueous fraction. The results indicate that the aqueous fraction of Cissampelos sympodialis inhibits neutrophil degranulation by a cAMP-dependent mechanism which may be relevant to the use of the plant as an anti-asthmatic agent in folk medicine.
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PMID:Effects of the aqueous fraction of the ethanol extract of the leaves of Cissampelos sympodialis Eichl. in human neutrophils. 1018 43

Emedastine difumarate (emedastine) is an antiallergic drug found among the derivatives which has a series of benzimidazole frames. It has been reported that emedastine can significantly inhibit the migration of eosinophils elicited by classical chemoattractants, including LTB4 or PAF. However, the effect of emedastine on the selective migration of eosinophils that have been stimulated with CC chemokines has not been examined. Emedastine at concentrations of 10 nM or higher strongly inhibited the eosinophil migration elicited by CC chemokines, including eotaxin, RANTES and MCP-3. Preincubation of the eosinophils with emedastine did not alter the expression of the CCR3 receptor, although a decrease in the concentration of intracellular calcium ions was observed after stimulation with 100 ng/ml of eotaxin. Herbimycin A, genistein, staurosporin and emedastine were all able to inhibit the eotaxin-elicited migration. Tyrosine kinase activity in the cytosol supernatant of eosinophils obtained after stimulation with eotaxin significantly decreased when the eosinophils were preincubated with emedastine. In addition, protein kinase A and protein kinase C activities in eotaxin-stimulated EoL-1 cell supernatants decreased significantly with emedastine pretreatment. These findings suggest that emedastine inhibits CC chemokine-elicited eosinophil migration by decreasing the activities of tyrosine kinase or protein kinases but does not alter CCR3 expression.
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PMID:Effect of emedastine difumarate on CC chemokine-elicited eosinophil migration. 1140 68

Mucin production and secretion by specialized epithelial cells is a common mechanism used by mammals to protect the underlying mucosae against various injuries (pollutants, pathogens, pH). The expression of mucin genes is cell- and tissue-specific but is submitted to variations during cell differentiation, inflammatory process, and is altered during carcinogenesis. The molecular mechanisms responsible for the control of mucin transcription and expression are beginning to be understood as mucin gene promoters and regulatory regions are characterized. The four gel-forming mucin genes, MUC2-MUC5AC-MUC5B-MUC6, are clustered on the p15 arm of chromosome 11. Common regulatory mechanisms (PKA, PKC, PKG and Ca2+ signaling, Sp1/Sp3) may account for the capability of mucous-secreting cells to express several mucin genes simultaneously. In response to an insult or during carcinogenesis, the normal pattern of expression is altered and results from specific answers of the cell by activating different intracellular signaling pathways. 11p15 mucin genes are regulated at the transcriptional level by pro-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha), pleiotropic cytokines (IL-4, IL-13, IL-9), bacterial exoproduct (LPS), growth factors (EGF, TGF-alpha), lipid mediator (PAF), retinoids and hormones. To date, the only downstream cascade known to activate mucin gene transcription is the Src/Ras/MAPK/pp90rsk cascade, which leads to the activation of the transcription factor NF-kappaB. Mucin gene transcription is also regulated by ATF-1, CREB and RAR-alpha transcription factors. Finally, repression of mucin transcription in cancer cells is under the control of the epigenetic mechanism of methylation. As transcriptional regulation of mucin genes begins to be unraveled, it becomes clear that many signaling pathways are involved. Our understanding of mucin gene transcriptional regulation, which awaits more data (identification of the signaling cascades and active cis-elements within promoters and introns), will most certainly lead to the use of mucin genes as molecular markers in cancer and molecular tools in human gene therapy, and to the synthesis of new therapeutic agents in inflammatory diseases of the epithelium.
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PMID:Transcriptional regulation of the 11p15 mucin genes. Towards new biological tools in human therapy, in inflammatory diseases and cancer? 1157 73

Herpetomonas muscarum muscarum is a flagellate parasite of the family Trypanosomatidae, whose cell differentiation can be triggered by the lipid mediator, PAF. In this study we demonstrate for the first time that PAF effect relies on the activation of casein kinase 2 (CK2). The classical antagonist of PAF receptor, WEB 2086, abrogated PAF-enhanced CK2 activity. CK2 activation by PAF was also inhibited when parasite extracts were assayed in the presence of modulators of PKC, MAPK, and both Ser/Thr and Tyr phosphatases. Finally, a cell permeable inhibitor of CK2 (DRB) suppressed PAF-induced cell differentiation in a dose-dependent manner.
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PMID:Platelet-activating factor (PAF) activates casein kinase 2 in the protozoan parasite Herpetomonas muscarum muscarum. 1205 63

Development of the barley powdery mildew fungus involves the sequential formation of a primary germ tube, an appressorial germ tube, and an appressorium. Previously, we have shown that the cAMP pathway controls the emergence of the two germ tubes. Following identification of two MAP kinase genes in an EST database from developing conidia we studied the role of the MAP kinase pathway and its interaction with the cAMP pathway. Fungal MAP kinase activity increased rapidly during mildew development, reaching a maximum between 2 and 8h after inoculation. Sphingosine or PAF-16, activators of the MAP kinase pathway, increased activity and appressorial development whilst an inhibitor, PD 98059, decreased both. Studies on the interaction between the cAMP and MAPK pathways revealed that several effectors of the MAPK pathway had no effect on cAMP levels. However upstream effectors of the cAMP pathway, such as cholera toxin and pertussis toxin (activators of G(alpha) proteins) increased MAPK activities whereas downstream effectors such as forskolin (adenylyl cyclase activator) or H89 (PKA inhibitor) had no effect. Combined application of forskolin and sphingosine produced a rise in appressorial germ tube and appressorial formation higher than when either pathway was stimulated individually. These results suggest that the two pathways cooperate in appressorial development.
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PMID:Evidence that the appressorial development in barley powdery mildew is controlled by MAP kinase activity in conjunction with the cAMP pathway. 1274 67

1. Histamine is generally regarded as a pro-inflammatory mediator in diseases such as allergy and asthma. A growing number of studies, however, suggest that this autacoid is also involved in the downregulation of human polymorphonuclear leukocyte (PMN) functions and inflammatory responses through activation of the Gs-coupled histamine H(2) receptor. 2. We report here that histamine inhibits thapsigargin- and ligand (PAF and fMLP)-induced leukotriene (LT) biosynthesis in human PMN in a dose-dependent manner. 3. The suppressive effect of histamine on LT biosynthesis was abrogated by the histamine H(2) receptor antagonists cimetidine, ranitidine, and tiotidine. In contrast, the histamine H(1), H(3), and H(4) receptor antagonists used in this study were ineffective in counteracting the inhibitory effect of histamine on the biosynthesis of LT in activated human PMN. 4. The inhibition of LT biosynthesis by histamine was characterized by decreased arachidonic acid release and 5-lipoxygenase translocation to the nuclear membrane. 5. Incubation of PMN with the cAMP-dependent protein kinase (PKA) inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide prevented the inhibitory effect of histamine on LT biosynthesis, suggesting an important role for PKA in this effect of histamine on LT biosynthesis in PMN. 6. These data provide the first evidences that, similarly to adenosine and prostaglandin E(2), histamine is a potent suppressor of LT biosynthesis, and support the concept that histamine may play a dual role in the regulation of inflammation.
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PMID:Histamine-induced inhibition of leukotriene biosynthesis in human neutrophils: involvement of the H2 receptor and cAMP. 1474 9

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84


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