Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic exposure of humans to benzene (BZ) causes acute myelogenous leukemia. These studies determined whether BZ, or its reactive metabolite, hydroquinone (HQ), affect differentiation of myeloblasts. BZ or HQ administered to C57BL/6J mice specifically induced terminal granulocytic differentiation of myeloblasts. The ability of the compounds to induce differentiation of the myeloblast was tested directly using the murine interleukin 3 (IL-3)-dependent myeloblastic cell line, 32D.3 (G) and the human HL-60 promyelocytic leukemic cell line. Treatment of HL-60 myeloblasts with BZ activated protein kinase C and upregulated the 5-lipoxygenase (LPO) pathway for the production of leukotriene D4 (LTD4), an essential effector of granulocytic differentiation. Differentiation was prevented by sphinganine, a kinase C inhibitor, as well as by LPO inhibitors and LTD4 receptor antagonists. BZ and HQ also induced differentiation in 32D.3 (G) myeloblasts. Both compounds interact with cellular signaling pathways activated by granulocyte colony-stimulating factor (G-CSF) and thus replace the requirement for G-CSF. IL-3 induces a growth response, whereas G-CSF provides both growth and differentiation signals. BZ does not induce growth in the absence of IL-3, but provides a differentiation signal. Both HQ and LTD4 induce differentiation and synergize with IL-3 for growth, however, neither support growth in the absence of IL-3. BZ-induced 32D cells showed a gradual progression of progenitor differentiation to granulocytes similar to that seen with G-CSF or LTD4. HQ blocks differentiation at the myelocyte stage; only a small percentage of progenitors proceed to granulocytes. BZ, like G-CSF, upregulates LTD4 production, whereas HQ obviates the requirement for LTD4 by activating the LTD4 receptor.
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PMID:Benzene and its metabolite, hydroquinone, induce granulocytic differentiation in myeloblasts by interacting with cellular signaling pathways activated by granulocyte colony-stimulating factor. 754 15

Ninety minutes after i.v. injection of Escherichia coli lipopolysaccharide (LPS) (1 mg/kg) into rats, phorbol 12-myristate 13-acetate (PMA)-stimulated superoxide anion (O2-) secretion was enhanced in suspensions of in vivo LPS-treated alveolar macrophages (AM phi) when compared with saline (SAL)-treated AM phi. The purpose of this investigation was to dissect the in vitro mechanism of PMA-stimulated O2- generation in both LPS and SAL-treated rat AM phi, with a panel of inhibitors of protein kinase C (PKC), protein serine-threonine phosphatase(s) (PSP), protein tyrosine kinase(s) (PTK) and phosphatase(s) (PTP), phospholipase A2 (PLA2), cyclooxygenase (CO) and 5-lipoxygenase (5-LO). The following agents blocked PMA-stimulated O2- generation in both LPS- and SAL-treated AM phi (expressed as percentage of control): 1) PKC inhibitors: staurosporine: 100 nM, 7.0% (LPS) and 5.6% (SAL); sphingosine: 10 microM, 21% (LPS) and 10.5% (SAL); 2) PTK inhibitor: genistein: 100 microM, 44% (LPS) and 31% (SAL); 3) PTP inhibitors: phenylarsine oxide, 10 microM, 12.1% (LPS) and 18% (SAL); diamide, 1000 microM, 10.1% (LPS) and 10.5% (SAL); and 4) PLA2 inhibitors: manoalide: 1 microM, 29.3% (LPS) and 5.2% (SAL); scalaradial: 1 microM, 7.7% (LPS) and 7.1% (SAL); and WAY 125,984: 10 microM, 17.1% (LPS) and 14.5% (SAL). In addition, it was observed that exogenously added arachidonic acid (AA)-stimulated O2- generation in a time- and dose-dependent manner in both LPS and SAL-treated AM phi. The following inhibitors enhanced or did not affect PMA-stimulated O2- generation in LPS- and SAL-treated AM phi (expressed as percentage of of control): 1) PSP inhibitors: okadaic acid: 0.5 microM, 117% (LPS) and 153% (SAL); calyculin A: 1 microM, 112% (LPS) and 101% (SAL); 2) CO and 5-LO inhibitors: indomethacin: 10 microM, 107% (LPS) and 90% (SAL); WY 50, 295: 1 microM, 99% (LPS) and 103% (SAL); and 3) the PTP inhibitor orthovanadate upon prolonged preincubation. In both in vivo LPS- or SAL-primed AM phi, PMA-stimulated O2- generation appears to be modulated by PKC, PLA2, AA, PTK, PTP and PSP. No modulatory role was evident for either CO or 5-LO metabolites. These findings might bear on the design of therapeutic approaches for the modulation of O2- release by AM phi in the early stages of sepsis and adult respiratory distress syndrome.
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PMID:Modulation of superoxide generation in in vivo lipopolysaccharide-primed rat alveolar macrophages by arachidonic acid and inhibitors of protein kinase C, phospholipase A2, protein serine-threonine phosphatase(s), protein tyrosine kinase(s) and phosphatase(s). 761 27

1. The M1 selective muscarinic agonist, McNeil A 343, enhanced the electrically evoked release of noradrenaline from postganglionic sympathetic nerves in mouse atria. This has been found previously to be due to activation of muscarinic receptors of the M1 subtype, probably located on sympathetic nerve terminals. The present study investigated the signal transduction mechanisms involved in the release-enhancing effects of McNeil A 343. The release of noradrenaline from mouse atria was assessed by measuring the electrically-induced (3 Hz, 60 s) outflow of radioactivity from atria which had been pre-incubated with [3H]-noradrenaline. 2. 8-Bromo cyclic AMP in the presence of IBMX was used to enhance maximally S-I noradrenaline release through cyclic AMP-dependent mechanisms. However, the facilitatory effect of McNeil A 343 (10 microM) was not different from the effect in the absence of these drugs, suggesting that McNeil A 343 enhances noradrenaline release independently of the cyclic AMP system. Furthermore, the release-enhancing effect of McNeil A 343 (10 microM) on noradrenaline release was also not altered by the 5-lipoxygenase inhibitor, BW A4C. 3. The facilitatory effect of McNeil A 343 was not altered in the presence of drugs (trifluoperazine, W7, and calmidazolium) which inhibit calmodulin-dependent processes, suggesting that the mechanisms of action of McNeil A 343 does not depend on calmodulin. 4. It was considered likely that the facilitatory effect of McNeil A 343 on noradrenaline release may be due to activation of protein kinase C, since activators of protein kinase C enhance noradrenaline release. The facilitatory effect of McNeil A 343 was abolished by the non-selective protein kinase C inhibitor,K-252a. To investigate further the involvement of protein kinase C, mouse atria were chronically incubated (9-O h) with the protein kinase C activator, 4 beta-phorbol dibutyrate (1.0 microM) in order to down-regulate protein kinase C activity. In protein kinase C-down-regulated atria, the facilitatory effect of McNeil A 343 (30 microM) was abolished. Incubation with 4 alpha-phorbol dibutyrate which does not affect protein kinase C did not reduce the facilitatory effect of McNeil A 343. This provides evidence that activation of protein kinase C is involved in the signal transduction process of McNeil A 343.
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PMID:Evidence that M1 muscarinic receptors enhance noradrenaline release in mouse atria by activating protein kinase C. 769 61

Preincubation of human neutrophils with phorbol esters or soluble diglycerides enhances subsequent f-Met-Leu-Phe (fMLP)-stimulated arachidonate mobilization and leukotriene B4 (LTB4) synthesis. We have recently reported that 1,3-dioctanoylglycerol (1,3-diC8) is equipotent with 1,2-sn-dioctanoylglycerol (1,2-diC8) as priming agent, thus suggesting that the priming effects of diacylglycerols are protein kinase C (PKC) independent (Rosenthal et al., 1993, Biochim. Biophys. Acta 1177:79-86). In order to further investigate this question, the present study has directly compared the effects of oleoylacetylglycerol (OAG) and the PKC activator, phorbol 12-myristate 13-acetate (PMA), on agonist-stimulated lipid metabolism. The results indicate that both OAG and PMA dose dependently enhance f-Met-Leu-Phe (fMLP)-stimulated release of [3H]arachidonate. Optimal concentrations of OAG (5 microns) and PMA (10 nM) are equipotent in increasing fMLP-stimulated arachidonate mobilization as quantitated either with total radioactivity or by mass measurements of free arachidonate. By contrast OAG is sixfold more effective than PMA in enhancing synthesis of 5-lipoxygenase (5-LO) metabolites by mass and two to threefold more effective than PMA in enhancing synthesis of [3H]eicosanoids. Furthermore, OAG, but not PMA, enhances fMLP-stimulated synthesis of platelet-activating factor. By contrast, PMA directly stimulates [3H]arachidonate mobilization, while OAG (20 microM) does not; despite these differences, the combined effects of PMA + OAG on subsequent agonist-stimulated arachidonate release are not greater than those of PMA alone. In cells challenged with subthreshold concentrations (< 0.1 microM) of the calcium ionophore A23187, both OAG and PMA stimulate [3H]arachidonate release but not [3H]LTB4 synthesis. These findings suggest that OAG does not directly activate 5-LO, but instead couples arachidonate mobilization to leukotriene synthesis in a PKC-independent manner.
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PMID:Separation of agonist-stimulated arachidonate mobilization from subsequent leukotriene B4 synthesis in human neutrophils: different effects of oleoylacetylglycerol and phorbol myristate acetate as priming agents. 807 90

1. Kinins exert a contractile effect on rabbit aortic rings via the stimulation of B1 receptors. Des-Arg9-bradykinin (BK) is more potent than BK on this receptor type. The mode of action of des-Arg9-BK on rabbit aortic tissue has been studied by both the aortic ring contractility assay and a cellular model using cultured aortic smooth muscle cells (SMCs). 2. The des-Arg9-BK-induced contractions in rabbit aortic rings were unaffected by pretreatments with nifedipine, indomethacin, REV-5901 (a 5-lipoxygenase blocker) and LY-83583 (a guanylyl cyclase inhibitor); however, the protein kinase inhibitors H-7 and H-9 significantly reduced the maximal effect of des-Arg9-BK. 3. The contractile responses to des-Arg9-BK in calcium-free Krebs solution were slightly but not significantly attenuated in amplitude, as compared to paired control tissues bathed in Krebs solution, and sustained plateaus of contraction were observed in the absence of Ca2+. However, Ca2+ replenishment further increased the kinin-induced contraction measured in Ca(2+)-free bathing fluid. 4. Despite the lack of evidence of a mediating role for prostaglandin in the mechanical response to des-Arg9-BK, the kinin stimulated the release of prostacyclin from rabbit aorta rings measured as immunoreactive 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). 5. Smooth muscle cells (SMCs) derived from the rabbit aorta exhibit functional responses to des-Arg9-BK in acute release of 6-keto-PGF1alpha and of inositol phosphate turnover which were inhibited by pretreatment with the B1 receptor antagonist, Lys[Leu8]des-Arg9-BK, but not by the B2 receptor antagonist, Hoe-140. Preincubation of the cells with interleukin- 1 (IL-1) 20 h before stimulation with the kinin had no effect on basal inositol phosphate turnover, but potentiated the acute effect of des-Arg9-BK.6. These results suggest that second mesengers derived from the action of phospholipase C are produced by SMCs when B1 receptors are activated in rabbit aortic tissue. Intracellular calcium stores are primarily mobilized by des-Arg9-BK, although receptor-controlled calcium influx has not been ruled out, and may contribute to initiate the contractile responses. The maintenance of the contractile state involves protein kinase C activity and is consistent with a current model of SMC function. The cell model retains some of the cardinal properties of B1 receptor-mediated vascular responses: endothelium independent PGI2 release and up-regulation by the cytokine IL-1. PGI2 is not involved in the mechanical response, possible because the rabbit aorta is refractory to this prostaglandin.
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PMID:Vascular mode of action of kinin B1 receptors and development of a cellular model for the investigation of these receptors. 810 48

Chronic exposure of humans to benzene (BZ) affects hematopoietic progenitor cells in intermediate stages of differentiation which can lead to aplastic anemia and/or acute myelogenous leukemia and some of its variant forms. We studied the effects of BZ and hydroquinone (HQ), a toxic bone marrow metabolite, on the human HL-60 promyelocytic leukemic cell line. Because the HL-60 cell is bipotential and can be induced to differentiate to monocytes or granulocytes it has been used in many studies as a surrogate for the granulocyte/macrophage committed cell, GM-CFU. Treatment of HL-60 cells with BZ specifically induced differentiation along the granulocytic lineage as measured by morphology, induction of superoxide production and chloroacetate esterase activity and the appearance of the L12-2 surface antigen. Differentiation was induced via the activation of protein kinase C and the phosphorylation of several proteins known to be involved in HL-60 cell differentiation. Subsequent to kinase C activation, arachidonic acid was released from membrane phospholipids and the 5-lipoxygenase pathway was activated for the production of leukotriene D4 (LTD4) required for granulocytic differentiation. BZ induction of granulopoiesis was prevented by preincubation of HL-60 cells with inhibitors of protein kinase C, 5-lipoxygenase, gamma-glutamyl transpeptidase required for the conversion of LTC4 to LTD4, or LTD4 receptor antagonists. Treatment of HL-60 cells with tetraphorbol myristate acetate (TPA), 1 alpha, 25-dihydroxyvitamin D3 (1,25-(OH2)D3) or interleukin-1 (IL-1) induced HL-60 cells to differentiate to monocytes/macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effects of benzene and hydroquinone on myeloid differentiation of HL-60 promyelocytic leukemia cells. 812 4

Activation of neutrophils may contribute to lung injury in the adult respiratory distress syndrome. We added rabbit neutrophils to the pulmonary circulation of salt-perfused and ventilated isolated rabbit lungs. These neutrophils were activated by adding synthetically pure melittin to the perfusate. This led to lung injury as measured by filtration coefficient under no-flow conditions. We also activated neutrophils in vitro before addition to the pulmonary circulation. These preactivated neutrophils also produced lung injury, indicating a primary action of melittin on neutrophils rather than on lung. The injury was prevented by aristolochic acid, which is an inhibitor of phospholipase A2 (PLA2), and independently by catalase, which is scavenger of hydrogen peroxide (H2O2). Aristolochic acid also appeared to act primarily on neutrophils since addition to neutrophils in vitro prevented injury from in vitro activation by melittin. Aristolochic acid did not appear to act as a free radical scavenger since it did not prevent injury from neutrophils activated by phorbol myristate acetate (PMA). PMA is a direct activator of protein kinase C in neutrophils and leads to formation of H2O2 with consequent lung injury. We conclude that activation of neutrophils by melittin leads to oxidant lung injury possibly from activation of PLA2. Since PLA2 does not directly produce a second messenger, such as diacylglycerol or inositol triphosphate, it is likely that other actions of PLA2 produce an intermediary mediator. We previously showed that an inhibitor of eicosanoid synthesis prevents lung injury from exogenous PLA2. This suggests that the formation of leukotriene B4 (LTB4), a 5-lipoxygenase product of arachidonic acid, may contribute to the oxidant lung injury from melittin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increase in filtration coefficient from actions of melittin on neutrophils in isolated rabbit lungs. 814 48

In this study, we compared the effects of interleukin-1 beta and tumor necrosis factor (TNF) on in vitro rat gastric fundus motility. Interleukin-1 beta produced rapid, concentration-dependent relaxation of rat gastric fundus strips, similar to that seen with TNF, with a maximal effect at 30 U/ml and an estimated EC50 at 0.9 U/ml. The relaxant effects of interleukin-1 beta and TNF were not influenced by the inhibition of cyclooxygenase or nitric oxide-synthase activities. Interleukin-1 beta- and TNF-induced gastric relaxations were concentration dependently inhibited by BW 755c, which inhibits both cyclooxygenase and lipoxygenase, BW A4, which selectively inhibits the 5-lipoxygenase pathway, and SC 41930, a selective leukotriene B4 receptor antagonist, providing pharmacological evidence that leukotriene B4 is involved in the relaxant effects of both cytokines. The interleukin-1 beta- and TNF-induced activation of 5-lipoxygenase pathway did not appear to be triggered by phospholipase A2. An alternative pathway could involve the following steps: (i) activation of phospholipase C and the formation of diacylglycerol; (ii) diacylglycerol-induced activation of protein kinase C; (iii) formation of free arachidonic acid from diacylglycerol by diacylglycerol-lipase. This mechanism is suggested by the finding that leukotriene B4 is able to mimic cytokine-induced strip relaxation only in the presence of phorbol 12-myristate 13-acetate, which selectively activates protein kinase C.
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PMID:Evidence that interleukin-1 beta and tumor necrosis factor inhibit gastric fundus motility via the 5-lipoxygenase pathway. 816 47

Recent evidence suggests that phospholipase A2 (PLA2)-derived lipid mediators may regulate a number of neutrophil responses including degranulation and adhesion. In view of the potential role of PLA2 in stimulus-secretion coupling, we examined the relationship between PLA2 activation and the surface expression of CD11b/CD18 (MAC-1) in human polymorphonuclear leukocytes (hPMNL), including the functional consequences of PLA2 inactivation on MAC-1-dependent adhesion. The selective inhibition of PLA2 by the marine natural products manoalide (MLD) and scalaradial (SLD) blocks [3H]arachidonic acid (AA) release in calcium ionophore A23187-stimulated neutrophils, and also inhibits secretion of specific and azurophilic granule constituents. Additional studies demonstrate that MLD, SLD, and other less potent PLA2 inhibitors such as 4-bromophenacylbromide and nordihydroguiaretic acid inhibit the surface expression of MAC-1 (IC50: MLD, 0.33 microM; SLD, 0.23 microM; 4-bromophenacylbromide, 2.8 microM; NDGA, 3.5 microM) at concentrations similar to those at which they inhibit [3H]AA release. Inhibitors of cyclooxygenase, 5-lipoxygenase, protein kinase C, or calcium channel antagonists have no effect on MAC-1 expression. PLA2 inactivation also prevents MAC-1 up-regulation in hPMNL stimulated with FMLP, IL-8, TNF-alpha, PMA, or platelet activating factor. In FMLP-stimulated hPMNL, under conditions in which no secondary granule constituents are secreted, MAC-1 and alkaline phosphatase up-regulation from intracellular granules is inhibited by MLD and SLD. Functional assays also demonstrate that MLD and SLD block MAC-1-dependent adhesion of activated neutrophils to keyhole limpet hemocyanin at concentrations that block the surface expression of MAC-1. [3H]AA release and MAC-1 expression in MLD and SLD-treated hPMNL could be recovered in the presence of 1 mM hydroxylamine in a time-dependent fashion, consistent with reported data that MLD and SLD inactivate PLA2 through Schiff base formation. In summary, these data emphasize the role of PLA2 as a key regulator of MAC-1 expression in models of neutrophil adhesion.
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PMID:Regulation of CD11b/CD18 expression in human neutrophils by phospholipase A2. 822 53

Early accumulation of polymorphonuclear leukocytes (PMN) in the liver after in vivo exposure to Escherichia coli lipopolysaccharide (LPS) and concomitant in vitro phorbol myristate acetate (PMA)-stimulated superoxide anion (O2-) generation has recently been described in a rat model of endotoxemia. The purpose of this investigation was to study the role of phospholipase A2 (PLA2), arachidonic acid (AA), its metabolites, and protein kinase C (PKC) in the mechanism of PMA-stimulated O2- generation of liver infiltrated PMN as compared to circulating blood PMN. Rat PMN were isolated after a 1.5-h infusion of saline or LPS from the blood (SAL-PMN) or the liver (LPS-PMN), respectively. The following results were observed in both SAL-PMN and LPS-PMN: 1) Inhibitors of cyclooxygenase (indomethacin) and 5-lipoxygenase [eicosatetraynoic acid, WY 50,295 tromethamine and VZ 65, 4-(11-hydroxy-1,9-undecadiin)-brenzcatechin] pathways did not inhibit O2- generation; 2) the potent marine PLA2 inhibitor Manoalide inhibited O2- generation in a dose-dependent manner (IC50 = 0.5 microM); 3) exogenously added AA enhanced PMA-stimulated O2- generation in a time- and dose-dependent manner and partially reversed the effect of Manoalide in LPS-PMN; 4) staurosporine, a putative PKC inhibitor, blocked PMA-stimulated O2- generation completely in the absence of AA and 79% in the presence of AA. It was concluded that LPS-induced liver sequestration of PMN does not alter the role PLA2, AA and PKC play in PMA-stimulated O2- generation. These findings should have implications on the design of novel therapeutic approaches for the modulation of O2- release in the pathogenesis of LPS hepatotoxicity.
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PMID:Modulation of superoxide anion generation by manoalide, arachidonic acid and staurosporine in liver infiltrated neutrophils in a rat model of endotoxemia. 822 68


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