Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Simultaneous stimulation of human monocytes/macrophages or THP1 cells with LPS and an antibody specific for the activation marker CD69 induces apoptosis. Here we demonstrate the involvement of multiple independent signals that are necessary for apoptosis induction. Thus, inhibitors of phospholipase A2 and lipoxygenase prevent apoptosis induction. Similarly, the ADP-ribosylating G-protein-reactive pertussis toxin (PTX) but not a mutant toxin lacking the ADP-ribosylating moiety (mPTX) prevents apoptosis induction. Furthermore, inhibition of NO generation abrogates completely the induction of apoptosis by LPS/CD69 ligation. These three pathways can be dissociated from each other in the sense that interventions on the arachidonic acid metabolism or G proteins do not inhibit the generation of NO and that exogenous NO cannot reverse the inhibition of cell death by inhibitors of phospholipase A2 or PTX. In addition, both PTX and mPTX affect arachidonic acid mobilization only partially, indicating that the apoptosis-inhibitory effect of PTX (which is not shared by mPTX) cannot be explained by its effect on phospholipase A2 activation. Both LPS and anti-CD69 are sufficient on their own to activate cells, as determined by TNF production, NO generation, or arachidonic acid metabolism, but neither LPS nor anti-CD69 can induce apoptosis on their own. Thus, apoptosis induction in this system involves at least three independent signal transduction systems--(i) arachidonic acid metabolism, (ii) NO, and (iii) PTX-sensitive events--each of which is necessary but insufficient to induce monocyte/macrophage apoptosis. These findings underline the complex control of activation-induced apoptosis in cells of the myelomonocytic lineage.
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PMID:CD69-induced monocyte apoptosis involves multiple nonredundant signaling pathways. 896 80

The biochemical signaling mechanisms involved in transducing the effects of interferon-gamma (IFN-gamma) on human leukemia-derived HL-60 cell differentiation are not completely understood. Recent studies established the existence of a sphingomyelin (SM) cycle that operates in response to the action of IFN-gamma on HL-60 cells, but the mechanisms by which IFN-gamma induces the SM hydrolysis remain unexplored. In this study, biochemical events mediating IFN-gamma effects on SM turnover and their specificity and role in HL-60 differentiation were investigated. The activation of the SM cycle by IFN-gamma occurred rapidly, with a decrease of approximately 20% in the SM level observed after 60 minutes with a concomitant increase in ceramide level. Treatment of HL-60 cells with IFN-gamma did not influence the 1,2-diacylglycerol concentration, intracellular Ca2+ concentration, or phospholipase D activity. IFN-gamma stimulated a rapid release of arachidonic acid (AA) from HL-60 cells; the effect was abolished by the pretreatment of cells with pertussis toxin, suggesting a role for a pertussis-toxin-sensitive G protein in IFN-gamma-mediated activation of phospholipase A2 (PLA2). At 4 to 120 hours after the stimulation of the cells with IFN-gamma, a significant increase in the particulate and soluble PLA2 activity was observed, corresponding to an increase in the level of immunoreactive cPLA2 in both cytosol and membrane fractions. The treatment of cells with tyrosine kinase inhibitor herbimycin A completely abolished the effect of IFN-gamma on PLA2 activity in membrane and cytosolic fractions, but had no effect on IFN-gamma-mediated early AA release suggesting dual mechanism of PLA2 activation. Melittin, potent activator of PLA2, and AA mimicked the effect of IFN-gamma on SM hydrolysis. Pretreatment of HL-60 cells with the PLA2 inhibitor, bromophenacyl bromide (BPB), or pertussis toxin abolished the effect of IFN-gamma on SM hydrolysis; exogenous addition of AA overcame the effects of BPB and pertussis toxin. Long-term exposure (5 days) of HL-60 cells to IFN-gamma caused an increase in nitroblue tetrazolium (NBT)-reducing and nonspecific esterase (NSE) activity and induced expression of Fc gamma RI (CD64) without significant effects on cell number, adherence, or phagocytic activity. The treatment of cells with AA or melittin induced NBT, NSE, and CD64 expression to the level similar to that observed with IFN-gamma, and no further increase was observed with the combination of IFN-gamma and AA or IFN-gamma and melittin. Treatment of HL-60 cells with indomethacin, an inhibitor of cyclo-oxygenase, and nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, had no effects on IFN-gamma-mediated induction of CD64 expression. These studies indicate a key role for the phospholipase A2/AA pathway, as an early biochemical signal elicited by the occupation of IFN-gamma-receptor, in mediating IFN-gamma induction of the SM cycle and phenotypic changes associated with differentiation of HL-60 along monocytic lineage.
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PMID:Arachidonic acid mediates interferon-gamma-induced sphingomyelin hydrolysis and monocytic marker expression in HL-60 cell line. 897 80

The purpose of this study was to elucidate likely signal transduction pathways in activated bovine neutrophils, by comparing the effects of various inhibitors on the bovine neutrophil respiratory burst and degranulation in vitro. The protein kinase C(PKC) inhibitors staurosporine, and chelerythine, and the beta-adrenergic receptor antagonist DL-propranolol, markedly inhibited opsonized zymosan (OZ) stimulated luminol-dependent chemiluminescence (LDCL). The G-protein inhibitor pertussis toxin (PT), the protein tyrosine inhibitor genistein, and the calcium channel blocker verapamil also reduced LDCL in a dose-dependent manner. In contrast, the lipoxygenase inhibitor zileuton had only a slight effect, and the cyclooxygenase inhibitor indomethacin had no effect on LDCL. The effects of these inhibitors on degranulation was also examined. Staurosporine, propranolol, and pertussis toxin significantly decreased primary granule (beta-glucosaminidase) release in response to OZ. These inhibitors also significantly reduced both phorbol myristate acetate (PMA)-induced primary and secondary granule (lactoferrin) release. Regulation of secondary granule (lactoferrin) release was complex, as it was significantly depressed by propranolol, enhanced by PT and unaffected by staurosporine. These findings suggest that PKC, beta-adrenergic receptors, G-proteins, protein tyrosine kinase(s) and Ca(2+) uptake, may all be involved in some part of the process of bovine neutrophil activation. Moreover, stimulation of LDCL and degranulation may be mediated through distinct signal transduction pathways.
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PMID:Regulation of luminol-dependent chemiluminescence and degranulation by bovine neutrophils stimulated with opsonized zymosan. 915 84

We have investigated the possible interaction (cross talk) between the phospholipase A2 (PLA2) and inositol 1,4,5-trisphosphate/protein kinase C (PKC) signaling pathways in rat lactotroph-enriched cell cultures. Melittin, a bee venom peptide, stimulated release of [3H]arachidonic acid ([3H]AA) from [3H]AA-labeled enriched lactotrophs in a dose-dependent manner. Moreover, melittin and exogenous AA induced a redistribution of PKC catalytic activity and PKC alpha and beta immunoreactivity from the soluble to the particulate fraction in resting and substance P (SP)-stimulated cells. Melittin had no effect on phospholipase C (PLC) activity. Pretreatment of cell cultures with the PLA2 inhibitors quinacrine and aristolochic acid resulted in a dose-dependent inhibition of melittin-stimulated PKC isozyme translocation as did the inhibitor of lipoxygenase, nordihydroguaiaretic acid, whereas the cyclooxygenase inhibitor indomethacin had no effect. SP and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) dose-dependently increased levels of [3H]AA released from cells. Pretreatment of cell cultures with quinacrine reduced the effect of SP on [3H]AA formation. After long-term treatment (24 h) of cells with TPA, the effect of TPA on [3H]AA production was not different from control, whereas SP still displayed [3H]AA-releasing abilities although not at full scale. Pretreatment of cells with thapsigargin, U 73122, methoxyverapamil, and RHC 80267, an inhibitor of diacylglycerol lipase, all resulted in reduced SP-stimulated [3H]AA liberation. Treatment of cell cultures with pertussis toxin (PTX) reduced the release of [3H]AA induced by SP, whereas PTX had no effect on SP-stimulated generation of 3H-inositol phosphates. On the basis of these results, it is concluded that (1) the PLA2 pathways interfere with the phosphoinositide-PLC signaling system at the level of PKC isozymes alpha and beta, the product responsible for this interaction being either AA or a metabolite produced by the action of lipoxygenase; (2) SP and TPA are able to activate the PLA2 pathway at a level at or beyond PLA2, and this effect is mediated, in part, through PKC alpha and beta species and (for SP) intracellular Ca2+ recruited from internal stores as well as from external sources; and (3) SP also activates PLA2 through a PTX-sensitive pathway distinct from the one coupled to phosphoinositide-PLC, which is PTX insensitive.
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PMID:Cross talk between substance P and melittin-activated cellular signaling pathways in rat lactotroph-enriched cell cultures. 923 37

Basal and fatty-acid-modulated G-protein function was studied in 1-3-day-pre-term, fetal guinea-pig, type II (fATII) pneumocyte apical membrane. Unstimulated (tonic) high-affinity GTPase activity (measured as [gamma-32P]GTP hydrolysis rate) was high and 77% pertussis toxin-insensitive. Alteration of this activity was used as a marker of G-protein regulation. Arachidonic acid (AA) showed a dose-dependent (IC50 = 48+/-8 microM) inhibition of activity at concentrations significantly below critical micellar concentrations; this effect was mimicked by other polyunsaturated fatty acids (IC50 for linoleic acid = 47 +/- 2 microM; IC50 for oleic acid = 106 +/- 11 microM). Saturated fatty acids showed no effect. The effect of AA on ouabain-insensitive ATPases in the same preparation was significantly lower, suggesting a specificity of the GTPase modulation effect. AA modulation of GTPase activity was not attenuated by blocking eicosanoid metabolism with inhibitors of 5'-lipoxygenase, cyclo-oxygenase and P-450. In order to explore further the mechanism of AA-G-protein interaction, the effect of AA on the time course and equilibrium binding of [35S]GTP[S] to apical membrane was studied. Consistent with our GTPase assay data, AA inhibited binding with an IC50 value of 71+/-1 microM; stearic acid did not mimic this effect. This is the first report of unsaturated-fatty-acid-specific modulation of lung G-protein function: since AA also up-regulates perinatal lung alveolar Na+ transport, we suggest this lipid/G-protein switch helps maintain pulmonary fluid homoeostasis around birth.
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PMID:Direct modulation of G-proteins by polyunsaturated fatty acids: a novel eicosanoid-independent regulatory mechanism in the developing lung. 930 21

The effect of angiotensin II (Ang II) to activate c-Jun amino-terminal kinase (JNK) was studied in a Chinese hamster ovary fibroblast cell line overexpressing the rat vascular type-1a Ang II receptor (CHO-AT1a). Ang II treatment induced a time-dependent activation of JNK. Ang II (10(-7) mol/L) activated JNK activity, with a peak at 30 minutes (9.39 +/- 2.52-fold, n = 7, P < .02 versus control), which was maintained until 3 hours (2.7 +/- 0.65-fold, n = 3, P < .02 versus control). Ang II-induced JNK activation at 30 minutes was inhibited by a specific lipoxygenase (LO) pathway inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (1 mumol/L) by 87.5% (n = 4, P < .01 versus Ang II-induced JNK activity). The direct addition of 12-HETE also induced a time-dependent JNK activation. 12-HETE (10(-7) mol/L) activated JNK activity, with a peak at 10 minutes (3.43 +/- 0.87-fold, n = 6, P < .02 versus control), which remained elevated until 1 hour. These results suggest that the LO pathway is a mediator of Ang II-induced JNK activation. 15-HETE can also activate JNK at 5 minutes, but this activity was reduced at 30 minutes and could not be seen at 1 hour, indicating that the time course was different from that seen with 12-HETE. N-Acetylcysteine (NAC), an antioxidant, was used to perturb intracellular reactive oxygen intermediate (ROI) levels to assess the role of endogenous ROIs in regulating JNK activity. Pretreatment of cells with 500 mumol/L NAC for 1 hour attenuated approximately 50% of Aug II-induced JNK activation, suggesting that ROIs, at least partially, mediate Ang II-induced JNK activation. Furthermore, 12-HETE-induced JNK activation was reduced by approximately 90% by NAC. Finally, pertussis toxin completely blocked 12-HETE-induced JNK activation, suggesting that Gi-protein signaling participates in 12-HETE-induced effects. These results suggest that LO activation plays a role in mediating Ang II-induced JNK activation in part by altering the redox tone and Gi-protein signaling of cells.
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PMID:Evidence that angiotensin II and lipoxygenase products activate c-Jun NH2-terminal kinase. 935 37

Angiotensin II (Ang II) elicits an Ang II type 2 (AT2) receptor-mediated increase in delayed-rectifier K+ current (IK) in neurons cultured from newborn rat hypothalamus and brainstem. This effect involves a pertussis toxin (PTX)-sensitive Gi protein and is abolished by inhibition of serine and threonine phosphatase 2A (PP-2A). Here, we determined that Ang II stimulates [3H]arachidonic acid (AA) release from cultured neurons via AT2 receptors. This effect of Ang II was blocked by inhibition of phospholipase A2 (PLA2) and by PTX. Because AA and its metabolites are powerful modulators of neuronal K+ currents, we investigated the involvement of PLA2 and AA in the AT2 receptor-mediated stimulation of IK by Ang II. Single-cell reverse transcriptase (RT)-PCR analyses revealed the presence of PLA2 mRNA in neurons that responded to Ang II with an increase in IK. The stimulation of neuronal IK by Ang II was attenuated by selective inhibitors of PLA2 and was mimicked by application of AA to neurons. Inhibition of lipoxygenase (LO) enzymes significantly reduced both Ang II- and AA-stimulated IK, and the 12-LO metabolite of AA 12S-hydroxyeicosatetraenoic acid (12S-HETE) stimulated IK. These data indicate the involvement of a PLA2, AA, and LO metabolite intracellular pathway in the AT2 receptor-mediated stimulation of neuronal IK by Ang II. Furthermore, the demonstration that inhibition of PP-2A abolished the stimulatory effects of Ang II, AA, and 12S-HETE on neuronal IK but did not alter Ang II-stimulated [3H]-AA release suggests that PP-2A is a distal event in this pathway.
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PMID:Angiotensin II type 2 receptor stimulation of neuronal delayed-rectifier potassium current involves phospholipase A2 and arachidonic acid. 942 10

AA stimulates integrin-dependent neutrophil adhesion, a critical early step in acute inflammation. However, neither the signaling pathway(s) of AA-stimulated adhesion, nor whether AA acts directly or through the generation of active metabolites, has been elucidated. Previously, we have observed a tight association between neutrophil Erk activation and homotypic adhesion in response to chemoattractants acting through G protein-linked receptors. We now report a similar association between homotypic adhesion and Erk activation in response to AA. Erk activation was cyclooxygenase independent and required AA metabolism to 5(S)- hydroperoxyeicosatetraenoic acid (5-HpETE) via 5-lipoxygenase, but not the further lipoxygenase-dependent metabolism of 5-HpETE to leukotrienes. AA stimulation of Erk was accompanied by Raf-1 activation and was sensitive to inhibitors of Raf-1 and Mek. Whereas activation of Erk by AA was pertussis toxin sensitive, [3H]-AA binding to neutrophils was not saturable, suggesting that an AA metabolite activates a G protein. Consistent with this hypothesis, Erk activation by 5(S)-hydroxyeicosatetraenoic acid (5-HETE; lipoxygenase-independent metabolite of 5-HpETE) was also pertussis toxin sensitive. These data suggest that a 5-lipoxygenase metabolite of AA, e.g., 5-HETE, is released from AA-treated cells to engage a plasma membrane-associated, pertussis toxin-sensitive, G protein-linked receptor, leading to activation of Erk and adhesion via the Raf-1/Mek signal transduction pathway.
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PMID:Integrin-dependent homotypic adhesion of neutrophils. Arachidonic acid activates Raf-1/Mek/Erk via a 5-lipoxygenase- dependent pathway. 964 70

This investigation examined which signal pathways are of relevance in growth factor-stimulated bone cell mitogenesis. Platelet-derived growth factor (PDGF) and insulin-like growth factor-II (IGF-II) were potent mitogens for both the MG-63 osteoblast cell line and for primary cultures of human osteoblasts (HObs). The mitogenic action of both IGF-II and PDGF was attenuated by pertussis toxin (Ptx), by indomethacin, and by the lipoxygenase inhibitors BW755C74 and BW4AC. A combination of Ptx and indomethacin caused much greater inhibition but failed to abolish mitogenesis completely. PDGF significantly elevated inositol phosphates levels in both cell types; IGF-II had no effect on this pathway. In MG-63 cells, we demonstrated tyrosine phosphorylation of high-molecular-weight substrates elicited by both PDGF and IGF-II. Genistein inhibited the phosphorylation and mitogenic response to PDGF, but had no effect on IGF-II-induced tyrosine phosphorylation or mitogenesis. Another inhibitor of tyrosine kinases, methyl 2,5-dihydroxycinnamate, (MDHC), inhibited PDGF-stimulated mitogenesis effectively in both cell types but only blocked IGF-II-induced mitogenesis in MG-63 cells. The specificity of these inhibitors suggests that particular tyrosine kinases may regulate growth factor-induced stimulation of bone cells.
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PMID:Signal pathways that transduce growth factor-stimulated mitogenesis in bone cells. 966 26

Pituitary adenylate cyclase activating polypeptide (PACAP) is a high-affinity ligand for at least two types of G-protein coupled receptors, the PACAP type 1 and type 2 receptor. In this study it is demonstrated that the C-terminal PACAP-fragment PACAP(6-27) stimulates serotonin release from rat peritoneal mast cells with higher potency (EC50: 0.2 vs. 2.0 microM) than the PACAP receptor ligand PACAP(1-27). PACAP-induced degranulation of rat peritoneal mast cells was abolished by pertussis toxin and by benzalkonium chloride (IC50: 9.1 microg/ml) indicating the involvement of heterotrimeric G-proteins of the Gi-type. The PACAP effect was also reduced by inhibitors of the phosphatidylinositol specific phospholipase C ((U73122), IC50: 4 microM; (ET-18-O-CH3), IC50: 18 microM), by D609, a specific inhibitor of the phosphatidylcholine specific phospholipase C (IC50: 41 microM), by the protein kinase C-inhibitor staurosporine (IC50: 0.6 microM) and by the lipoxygenase inhibitor nordihydroguaiaretic acid (NGDA) but not by indomethacin. It is concluded that PACAP peptides stimulate secretion in rat peritoneal mast cells in a PACAP receptor-independent manner, probably via direct activation of heterotrimeric G-proteins of the Gi-type; these G-proteins may lead to a sequential activation of different signaling cascades (see above), which may converge at the level of one or more staurosporine-sensitive protein kinase.
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PMID:Pituitary adenylate cyclase activating polypeptide induces multiple signaling pathways in rat peritoneal mast cells. 971 72


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