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

Recent studies have shown that eosinophils are capable of generating and releasing cytokines, providing a novel biologic aspect of eosinophils for regulating allergic inflammation by an autocrine or paracrine mechanism. Eosinophils synthesize various cytokines; however, the physiologic stimuli that trigger eosinophils to generate cytokines have not been fully elucidated. We examined the effect of chemotactic agonists on eosinophil cytokine generation by employing the determination of IL-8 as the main parameter. Both C5a and FMLP stimulated eosinophils to release IL-8, whereas platelet-activating factor and C-C chemokines did not exert any significant effects. On a molar basis, C5a was two orders of magnitude more potent than FMLP. The generation of IL-8 by chemoattractants was absolutely dependent on the presence of cytochalasin B. Pertussis toxin completely attenuated C5a- and FMLP-induced IL-8 production, indicating the involvement of pertussis toxin-sensitive G-proteins in the signal-transduction process leading to these responses. Experiments of in situ hybridization and PCR amplification revealed that both C5a and FMLP promoted eosinophil IL-8 production through transcriptional gene activation. Pyrrolidine dithiocarbamate completely abrogated chemoattractant-induced IL-8 production, indicating the involvement of NF-kappa B in the cytoplasmic/nuclear signal-transduction process. Furthermore, chemoattractant-induced cytokine production was not limited to IL-8; C5a and FMLP but not platelet-activating factor induced significant secretion of granulocyte-macrophage-CSF from eosinophils. These results indicate that C5a and FMLP stimulate eosinophils to elaborate cytokines, which could be an important mechanism in the regulation of allergic inflammation.
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PMID:Chemotactic agonists induce cytokine generation in eosinophils. 752

We have previously reported that serum amyloid A (SAA) induces adhesion and chemotaxis of human monocytes and polymorphonuclear neutrophils, in vitro as well as in vivo. Since the mechanism of SAA signaling is unknown, we have investigated the possibility that SAA, like other chemoattractants such as the chemotactic peptide FMLP and chemokines, might induce migration of monocytes by G protein activation. We report here that preincubation of monocytes with pertussis toxin (PTx) inhibited SAA chemotaxis, while incubation with cholera toxin (CTx) did not. Staurosporine and H-7, both inhibitors of protein kinase C (PKC), significantly decreased rSAA-induced chemotaxis of monocytes, suggesting that PKC may be involved in the rSAA signaling pathway. Moreover, rSAA, at concentrations that were effective in chemoattracting monocytes, resulted in transient elevation of cytoplasmic calcium concentration ([Ca2+]i), and incubation of cells with PTx markedly inhibited the mobilization of Ca2+ in response to rSAA. This suggests that both chemotaxis and the rise in [Ca2+]i, are mediated by G proteins of the Gi class. The increase in [Ca2+]i, induced in monocytes by rSAA, was comparable to that elicited by FMLP, and was severalfold greater than that induced by optimal concentrations of chemokine beta-family members such as RANTES, MCAF/MCP-1, and MIP-1 alpha. The chemoattractants FMLP, RANTES, MIP-1 alpha, and MCAF/MCP-1, all failed to desensitize rSAA-induced Ca2+ influx and chemotaxis in monocytes. This suggests that SAA uses a distinct receptor that is coupled to PTx-sensitive G proteins.
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PMID:Serum amyloid A induces calcium mobilization and chemotaxis of human monocytes by activating a pertussis toxin-sensitive signaling pathway. 756 Nov 9

"Classical" chemoattractants, such as FMLP, C5a, or leukotriene B4, not only elicit directed motility but also activate neutrophils (degranulation, release of active oxygen species). Signal transduction after ligation of receptors for these classical chemoattractants is mediated by pertussis toxin (PT)-sensitive, heterotrimeric G proteins and the early production of lipid messengers via phospholipases. In contrast, we have previously shown that substance P (SP) and transforming growth factor-beta 1 (TGF-beta 1) are "pure" chemoattractants in that they elicit chemotaxis without activating neutrophils. Paradoxically, pure chemoattractants also activate G proteins (plasmalemmal GTPase activity) without eliciting increments in cytosolic calcium ([Ca]i) and thus inositol trisphosphate. We therefore determined lipid remodeling and signal transduction in response to pure chemoattractants. Increments in plasmalemmal GTPase activated by SP (0.1 microM) and TGF-beta 1 (40 fM), like that after FMLP, were PT-sensitive (SP = 6.6 +/- 2 pm/mg/min vs SP + PT = 1.1 +/- 0.9 over basal activity; TGF-beta 1 = 4.3 +/- 1.6 vs TGF-beta 1 + PT = 2.3 +/- 0.9). In parallel, treatment of PMN with PT (1 microgram/ml, 30 min) inhibited chemotaxis (under agarose) after FMLP (2175 +/- 176 (SEM) microns vs 726 +/- 267) and SP (411 +/- 99 microns vs 103 +/- 62 microns) and TGF-beta 1 (40 fM, 375 +/- 53 microns vs 83 +/- 47). However, G proteins coupled to receptors for SP and TGF-beta 1, unlike FMLP, did not appear to be linked to phospholipases in that neither increments in diacylglycerol were detected after receptor ligation (FMLP = 152 +/- 22% resting levels; SP = 101 +/- 5%; TGF-beta 1 = 105 +/- 4%) nor was alkylacylglycerol increased by exposure to SP or TGF-beta 1 (SP = 92 +/- 4%; TGF-beta 1 = 101 +/- 8%; FMLP = 226 +/- 40%). Moreover, polymorphonuclear leukocytes failed to generate phosphatidates (PA) of either species after SP (DA-PA = 79 +/- 9% resting at 60 s; EA-PA = 103 +/- 4%) or TGF-beta 1 (DA-PA = 101 +/- 5%; EA-PA = 98 +/- 9%) in contrast to FMLP (DA-PA = 155 +/- 22%; EA-PA = 149 +/- 16%). The data clearly contravene the current dogma that all chemoattractants use inositol trisphosphate and diglycerides as intracellular signals and suggest the presence of a unique subset of PT-sensitive G proteins, not coupled to "classical" phospholipases, transduce chemoattraction.
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PMID:Chemoattraction of neutrophils by substance P and transforming growth factor-beta 1 is inadequately explained by current models of lipid remodeling. 768 33

The activity of hemolytically inactive C5b67, designated iC5b67, was evaluated as an agonist for functional responses of human polymorphonuclear leukocytes (PMN). C5b67 was formed from purified human complement components and decayed in phosphate-buffered saline (PBS) until it had no lytic activity for sheep erythrocytes in a standard assay. iC5b67, at nanomolar concentrations, stimulated PMN chemotaxis and Ca2+ fluxes, but inhibited superoxide production and failed to upregulate CR1 and CR3. There was no significant contamination of the iC5b67 with C5a to explain these results. Neither isolated C5b6 nor C7 alone exhibited the activities of iC5b67, while insolubilized anti-C7 could remove the PMN agonist activity from the iC5b67 preparation. Binding studies to define a specific receptor for iC5b67 on PMN were hampered by the very hydrophobic nature of the ligand. 125I-iC5b67, by contrast to hemolytically active 125I-C5b67, was unable to insert in erythrocytes, suggesting that iC5b67 need not insert in the PMN membrane to induce signaling. Two lines of evidence suggest that iC5b67 and C5a and FMLP share common steps in intracellular signaling (1) pretreatment of PMN with iC5b67 deactivates PMN for C5a- and FMLP-induced chemotaxis; and (2) pretreatment of PMN with pertussis toxin inhibits iC5b67-induced chemotaxis. Thus, iC5b67 has important effects on the activity of PMN and G-proteins and Ca2+ are involved in the signaling.
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PMID:Hemolytically inactive C5b67 complex: an agonist of polymorphonuclear leukocytes. 772 85

Chemoattractants bind to seven transmembrane-spanning, G-protein-linked receptors on polymorphonuclear leukocytes (neutrophils) and induce a variety of functional responses, including activation of microtubule-associated protein (MAP) kinase. Although the pathways by which MAP kinases are activated in neutrophils are unknown, we hypothesized that activation of the Ras/Raf pathway leading to activation of MAP/ERK kinase (MEK) would be induced by the chemoattractant f-met-leu-phe. Human neutrophils exposed to 10 nM FMLP for 30 s exhibited an MAP kinase kinase activity coeluting with MEK-1. Immunoprecipitation of Raf-1 kinase after stimulation with FMLP revealed an activity that phosphorylated MEK, was detectable at 30 s, and peaked at 2-3 min. Immunoprecipitation of Ras from both intact neutrophils labeled with [32P]orthophosphate and electropermeabilized neutrophils incubated with [32P]GTP was used to determine that FMLP treatment was associated with activation of Ras. Activation of both Ras and Raf was inhibited by treatment of neutrophils with pertussis toxin, indicating predominant linkage to the Gi2 protein. Although phorbol esters activated Raf, activation induced by FMLP appeared independent of protein kinase C, further suggesting that Gi2 was linked to Ras and Raf independent of phospholipase C and protein kinase C. Dibutyryl cAMP, which inhibits many neutrophil functional responses, blocked the activation of Raf by FMLP, suggesting that interruption of the Raf/MAP kinase pathway influences neutrophil responses to chemoattractants. These data suggest that Gi2-mediated receptor regulation of the Ras/Raf/MAP kinase pathway is a primary response to chemoattractants.
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PMID:FMLP activates Ras and Raf in human neutrophils. Potential role in activation of MAP kinase. 804 Feb 99

Biomaterial-centered infection is an important cause of the failure of prosthetic implants and organs. Because neutrophils mediate host defense against infection, the effect of biomaterials on neutrophil superoxide release and the mechanism of that effect were investigated using three materials commonly employed in surgical practice. The graft materials were expanded polytetrafluorethylene (PTFE), polyurethane and woven dacron. Polystyrene, a commonly used laboratory support vessel, was also studied. Both polystyrene and polyurethane were activating, but serum inhibitable, whereas PTFE was nonactivating, and woven dacron was not activating unless serum was present. The signaling mechanisms used by these materials demonstrated time and material dependency. Pertussis toxin inhibition of G protein-dependent activation had little or no effect on biomaterial induced activation, whereas FMLP-induced activation of the same biomaterial-associated cells was inhibited. Protein kinase C inhibition with staurosporine greatly inhibited polystyrene-induced activation, but had only a partial effect with polyurethane and even less effect with the activation associated with serum-treated woven dacron. These studies demonstrated that biomaterial contact-induced neutrophil activation differed from that described for cells in suspension, and showed that activation mechanisms on one material cannot be extrapolated to mechanisms on other materials.
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PMID:Mechanisms of biomaterial-induced superoxide release by neutrophils. 807 53

In these studies we show that stimulation of O2- generation by Tumor necrosis factor-alpha (TNF), or antibodies against the common beta 2 chain of leukocyte integrins (CD18), or LFA-1 (CD11a) displays a common and unique pattern of sensitivity or insensitivity to inhibitors of different signalling pathways. Both ways of stimulating neutrophil O2- generation were blocked by wortmannin, an inhibitor of myosin light chain kinase (Nakanishi, S., et al., 1992., J. Biol. Chem. 267, 2157-2163), and three different inhibitors of protein tyrosine kinases. Neither staurosporine, a protein kinase C inhibitor, nor Pertussis toxin, at concentrations which inhibited O2- generation in response to PMA, and FMLP, respectively, had any effect.
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PMID:Effect of inhibitors of distinct signalling pathways on neutrophil Q2- generation in response to tumor necrosis factor-alpha, and antibodies against CD18 and CD11a: evidence for a common and unique pattern of sensitivity to wortmannin and protein tyrosine kinase inhibitors. 809 58

Differentiated HL60 cells respond to challenge with ligand by mobilizing intracellular second messengers, resulting in superoxide production, degranulation, and actin polymerization with subsequent chemotaxis and phagocytosis. The functional capabilities of undifferentiated HL60 cells have not been similarly characterized due to the absence of the cell surface receptors required to initiate these processes. To investigate these properties, undifferentiated HL60 cells were transfected with one of the better characterized neutrophil chemotactic receptors, the N-formyl peptide receptor (FPR). Expression of the recombinant FPR gene product in FPR-transfected HL60 cells and the absence of the endogenous FPR in vector-transfected HL60 cells was demonstrated by Northern blot and flow cytometric analyses. FPR-transfected HL60 cells retained their ability to undergo granulocytic differentiation with dibutyryl cAMP, as determined by FMLP- and PMA-stimulated superoxide production. Furthermore, incubation of FPR-transfected HL60 cells for 5 days in the presence of FMLP resulted in limited differentiation as evidenced by the expression of functional C5a receptors. Binding studies of FPR-transfected HL60 cells demonstrated the presence of two binding affinities with dissociation constants of 0.6 and 33 nM, similar to dibutyryl cAMP differentiated HL60 cells and human neutrophils but contrasting the single high affinity state of the FPR expressed in mouse L cell fibroblasts. FPR-transfected HL60 cells displayed FMLP-dependent calcium mobilization with an EC50 of 3 nM and actin polymerization with an EC50 of approximately 10 nM. Actin polymerization was not observed in FPR-transfected L cell fibroblasts or undifferentiated vector-transfected HL60 cells. Both calcium mobilization and actin polymerization were sensitive to treatment with pertussis toxin, indicating the requirement for a Gi-like protein. Stimulation of either undifferentiated or differentiated HL60 cells with ATP resulted in pertussis toxin-insensitive calcium mobilization but was ineffective in producing actin polymerization. The results described herein show for the first time that undifferentiated HL60 cells can respond to chemoattractant receptor stimulation with many of the properties of the mature neutrophil. Transfected HL60 cells will provide an excellent system to study the characteristics of chemotactic receptors as well as the functional properties of myeloid cells.
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PMID:Signal transducing properties of the N-formyl peptide receptor expressed in undifferentiated HL60 cells. 822 56

The infiltration of neutrophils which phagocytose and kill microorganisms is an important defense mechanism against infections of the airways. Bordetella pertussis is a human respiratory pathogen which colonizes ciliated epithelium, causing whooping cough. We have investigated the effects of the peptidoglycan fragment tracheal cytotoxin (TCT) of B. pertussis on human neutrophil function in vitro. TCT (10(-6) to 10(-8) M) was toxic for human neutrophils, as measured by lactate dehydrogenase release and levels of intracellular ATP. TCT (10(-9) to 10(-15) M) did not stimulate neutrophil migration or chemiluminescence and did not affect neutrophil phagocytosis. Incubation of neutrophils for 20 min with TCT (10(-9) to 10(-11) M) significantly inhibited (P < 0.05) their subsequent migration toward the chemotactic factor N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP; 10(-9) M). Incubation of neutrophils for 20 min with TCT (10(-9) to 10(-15) M) significantly inhibited (P < 0.05) chemiluminescence stimulated by FMLP (10(-5) M). TCT (10(-6) to 10(-12) M) did not stimulate interleukin-1 alpha production by neutrophils or serum complement activation by the alternate pathway. We conclude that TCT at concentrations of < 10(-8) M affects important neutrophil functions and at higher concentrations is toxic. TCT may therefore contribute to the survival of B. pertussis within the airways in vivo.
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PMID:Effect of tracheal cytotoxin from Bordetella pertussis on human neutrophil function in vitro. 830 Feb 20

Studies of human peripheral blood neutrophils (PMNs) demonstrated that botulinum neurotoxin D (BT-D) ADP-ribosylates a 22-kDa PMN G protein (G22k) and inhibits the exocytosis of both specific and azurophilic granules stimulated by FMLP. Furthermore, this inhibition of PMN exocytosis by BT-D was found to be correlated with the degree of irreversible ADP-ribosylation of G22k by BT-D and to require modification of at least 85% of PMN G22k before significant inhibition of secretion is observed. Although both pertussis toxin and BT-D inhibited exocytosis in FMLP-stimulated PMNs, the inhibitory effects of the two toxins were found to be additive. Pertussis toxin and BT-D also inhibited Ca2+/GTP/GTP gamma S-induced secretion in digitonin-permeabilized PMNs, but there were distinct differences between the inhibitory effects of the two toxins. In contrast to BT-D, the exotoxin botulinum C3 was found to ADP-ribosylate primarily a 24- to 25-kDa PMN protein, and it was not found to inhibit Ca(2+)- and GTP-induced secretion in permeabilized PMNs. Ultrastructural studies of BT-D-treated PMNs showed an accumulation of distinct membrane-bound organelles in the periphery of the cells after FMLP stimulation, suggestive of a toxin-induced block in organelle-plasma membrane fusion. Taken together, these findings indicate that BT-D-sensitive G22k has a functional role in stimulated exocytosis of PMNs.
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PMID:Involvement of a botulinum toxin-sensitive 22-kDa G protein in stimulated exocytosis of human neutrophils. 830 Nov 38


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