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)

The signal transduction mechanisms involved in the regulation of phagocytosis are largely unknown. We have recently shown that in neutrophils, when IgG-mediated phagocytosis is stimulated by formyl-methionyl-leucyl-phenyl-alanine (fMLP), the enhanced ingestion is dependent on the increase in [Ca2+]i which results from ligation of Fc receptors by the IgG-coated target (Rosales, C., and Brown, E. (1991) J. Immunol. 146, 3937-3944). Now, we have studied the mechanism by which this rise in [Ca2+]i occurs. Aggregated IgG, the monoclonal antibody 3G8 (which recognizes Fc receptor type III), and insoluble immune complexes caused an increase in [Ca2+]i. The rise in [Ca2+]i induced by Fc receptor ligation was resistant to pertussis toxin. In contrast, fMLP induced a rise in [Ca2+]i which was inhibited by pertussis toxin. fMLP-induced [Ca2+]i was accompanied by an accumulation of inositol 1,4,5-trisphosphate (IP3) which peaked by 15 s, and which was also abolished by pertussis toxin. IP3 accumulation after aggregated IgG, 3G8, or insoluble immune complexes was much less than after fMLP. Unlike [Ca2+]i rise induced by Fc receptor ligation, this small increase in IP3 was inhibited by pertussis toxin. These data demonstrated that the [Ca2+]i increase induced by Fc receptor ligation is not mediated by IP3. Immediate pretreatment of human polymorphonuclear neutrophils with optimal doses of fMLP also reduced subsequent increase in [Ca2+]i rise from thapsigargin, a sesquiterpene lactone tumor promoter that releases intracellular Ca2+ from IP3-sensitive stores without IP3 turnover. Similarly, to its effects on thapsigargin, fMLP inhibited the [Ca2+]i rise upon subsequent immune complex binding. Pretreatment of cells with immune complexes also prevented subsequent [Ca2+]i rise from thapsigargin and fMLP. These data demonstrate that IgG Fc receptor ligation and fMLP activation of human polymorphonuclear neutrophils use distinct signal transduction mechanisms to release Ca2+ from the same thapsigargin-sensitive intracellular pool. In contrast to fMLP, signal transduction for increased [Ca2+]i after Fc receptor stimulation does not involve a pertussis toxin-sensitive G protein, and is independent of IP3.
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PMID:Signal transduction by neutrophil immunoglobulin G Fc receptors. Dissociation of intracytoplasmic calcium concentration rise from inositol 1,4,5-trisphosphate. 153 82

Immune complexes (ICs) induce an initial transient increase in cytosolic intracellular calcium [( Ca2+]in) levels in human neutrophils (PMN). Changes in PMN [Ca2+]in were measured with the fluorescent calcium indicator Indo-1 ( [1-[2-amino-5-(6-carboxylindol-2-yl]-phenoxyl]-2-(2'-amino-5 '- methylphenoxy]ethane-N,N,N'N'-tetraacetic acid), at the level of individual cells by flow cytometry. Two kinds of immune complexes (ICs) were used in this study: an insoluble (IIC) and a more soluble less valent immune complex (SIC) with fewer available Fc receptor binding ends per molecule of SIC than IIC. Simultaneous binding and activation studies performed on the flow cytometer with fluoresceinated IIC or SIC demonstrated that a majority of the cells bound each stimulus uniformly. However, only an IC dose-dependent proportion of those IC-bound cells responded with an increase in [Ca2+]in. Analysis of Indo-1 fluorescence signals from neutrophils exposed to IIC, corrected for the contribution of the nonresponding population, indicated that every dose of IIC elicited a similar maximum [Ca+2]in within the responding population. In contrast, the magnitude of the increase in [Ca2+]in elicited by low doses of SIC did become dependent on dose. Cells treated with pertussis toxin and exposed to IIC exhibited a normal [Ca2+]in response both in magnitude and expression. Therefore, [Ca2+]in responses induced by immune complexes are expressed by subpopulations of PMN, in a response which is dependent on the valency of the stimulus. In addition, pertussis toxin sensitive G protein(s) appear not to have a major role in IIC-induced [Ca2+]in changes, membrane potential changes, production of superoxide anions, and elastase release.
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PMID:Calcium changes in immune complex-stimulated human neutrophils. Simultaneous measurement of receptor occupancy and activation reveals full population stimulus binding but subpopulation activation. 207 90

Data presented in this paper indicate that polymorphonuclear leukocyte (PMN) Fc receptor-mediated phagocytosis can be markedly augmented and that this augmentation is under regulatory control. Stimulation of PMN with either a low m.w., heat-labile cytokine(s) (the culture supernatant effluent from a YM-10 Centricon unit, YM-10E), phorbol esters (phorbol dibutyrate), or the polyene antibiotic, amphotericin B, enhances Fc-mediated ingestion in a dose-dependent manner. YM-10 effluent- and amphotericin B-stimulated ingestion is completely abrogated by treating the PMN with either pertussis toxin (PT), cholera toxin (CT), or a monoclonal antibody (mAb), 1C2. However, neither toxin nor mAb 1C2 affects nonstimulated ingestion or phagocytosis stimulated by phorbol esters or synthetic diacylglycerol. Increasing intracellular cyclic adenosine monophosphate levels by stimulation with prostaglandin E1 and the phosphodiesterase inhibitor, isobutylmethylxanthine, does not mimic the effect of either toxin or mAb 1C2. In addition, toxin-mediated inhibition is not due to loss of either the Fc receptor recognized by mAb 3G8 or the antigen recognized by mAb 1C2. These data indicate that both CT and PT regulate the phagocytic response of PMN, in a manner like mAb 1C2, probably by affecting a guanosine 5'-triphosphate-binding protein distinct from those that regulate adenylate cyclase. Since phorbol ester-stimulated ingestion is not inhibited by either PT, CT, or mAb 1C2 and phorbol esters activate protein kinase C directly, phagocytosis amplification regulated by PT, CT, and mAb 1C2 may involve protein kinase C activation.
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PMID:Cholera toxin and pertussis toxin regulate the Fc receptor-mediated phagocytic response of human neutrophils in a manner analogous to regulation by monoclonal antibody 1C2. 244 62

The correlation between the increase of [Ca2+]i and the activation of hydrolysis of phosphoinositide-4,5-bisphosphate and formation of inositol(1,4,5)trisphosphate in neutrophils treated with Fc receptor-binding agonists is still under discussion. In this communication evidence is presented supporting the conclusion that, as it is widely accepted for the activation of other receptors, also upon the activation of Fc receptors the stimulation of the production of inositol(1,4,5) trisphosphate is involved in the increase in [Ca2+]i. In fact: i) treatment of neutrophils with immune complexes induced a very rapid phosphoinositide hydrolysis measured as [3H]inositol phosphates production from [3H]phosphoinositides and as inositol(1,4,5) trisphosphate formation measured with radioreceptor assay, ii) immune complexes caused a dose-dependent increase of [Ca2+]i; iii) the increase of [Ca2+]i correlated with the production of inositol(1,4,5) trisphosphate with respect to time course, dose dependence and pertussis toxin insensitivity.
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PMID:Formation of inositol (1,4,5) trisphosphate and increase of cytosolic Ca2+ mediated by Fc receptors in human neutrophils. 825 Aug 80

The interaction between human neutrophils and wild-type Bordetella pertussis or mutants expressing altered lipopolysaccharide or lacking virulence factors-pertussis toxin, adenylate cyclase toxin, dermonecrotic toxin, filamentous hemagglutinin (FHA), pertactin, or BrkA-was examined. In the absence of antibodies, the wild-type strain and the mutants, with the exception of mutants lacking FHA, attached efficiently to neutrophils. The addition of opsonizing antibodies caused a significant reduction (approximately 50%) in attachment of the wild-type strain and most of the mutants expressing FHA, suggesting that bacterium-mediated attachment is more efficient than Fc-mediated attachment. Phagocytosis was also examined. In the absence of antibodies, about 12% of the wild-type bacteria were phagocytosed. Opsonization caused a statistically significant reduction in phagocytosis (to 3%), possibly a consequence of reduced attachment. Phagocytosis of most of the mutants was similar to that of the wild type, with the exception of the mutants lacking adenylate cyclase toxin. About 70% of the adenylate cyclase toxin mutants were phagocytosed, but only in the presence of opsonizing antibody, suggesting that Fc receptor-mediated signaling may be needed for phagocytosis. These studies indicate that FHA mediates attachment of B. pertussis to neutrophils, but adenylate cyclase toxin blocks phagocytosis.
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PMID:Bordetella pertussis virulence factors affect phagocytosis by human neutrophils. 1067

The human opioid receptor-like (ORL(1)) receptor was tagged with the immunoglobulin G1 Fc fragment at the carboxy-terminus and expressed in human embryonic kidney 293 cells. Expression of the ORL(1)-Fc receptor was confirmed by immunohistochemical staining. The fusion protein was enriched by affinity chromatography and then verified by immunodetection. The function of the ORL(1)-Fc receptor was determined by examining nociceptin/OFQ-induced inhibition of cAMP accumulation. The ORL(1)-Fc receptor inhibited the forskolin-stimulated cAMP accumulation. The inhibitory response was selectively induced by nociceptin/OFQ in a dose-dependent and pertussis toxin-sensitive manner. Our results indicate that the carboxy-terminal Fc-tagged ORL(1) receptor retained the ability to interact with G(i) proteins to inhibit adenylyl cyclase.
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PMID:Immunoglobulin G1 Fc fragment-tagged human opioid receptor-like receptor retains the ability to inhibit cAMP accumulation. 1096 58

A previous study showed that opsonization with human immune serum could either promote or antagonize phagocytosis of Bordetella pertussis by human neutrophils depending on whether the bacteria expressed adenylate cyclase toxin. Opsonization of the wild-type strain inhibited phagocytosis relative to unopsonized controls. In contrast, mutants lacking adenylate cyclase toxin were efficiently phagocytosed when opsonized with human immune serum. In this study, we examined opsonization in the presence or absence of monoclonal antibodies to adenylate cyclase toxin. Addition of neutralizing monoclonal antibodies to adenylate cyclase toxin converted a serum that previously inhibited both attachment and phagocytosis of the wild-type strain to one that increased both attachment and phagocytosis compared to the no-serum control. Monoclonal antibodies that recognize the adenylate cyclase toxin but fail to neutralize activity were without effect. These results suggest that adenylate cyclase toxin inhibits both Fc receptor-mediated attachment and phagocytosis of B. pertussis by neutrophils.
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PMID:Neutralizing antibodies to adenylate cyclase toxin promote phagocytosis of Bordetella pertussis by human neutrophils. 1108 45

In the present studies, we initiated experiments to identify the signal transduction factors involved in activating phagocytosis, oxidative burst, and degranulation following the binding of IgG-opsonized SE to Fc receptors on the surface of avian heterophils. Peripheral blood heterophils were isolated and exposed to known inhibitors of signal transduction pathways for either 20min (chelerythine, genistein, or verapamil) or 120min (pertussis toxin) at 39 degrees C. The cells were then stimulated for 30min at 39 degrees C with SE opsonized with IgG purified from SE-immune chickens. Phagocytosis, luminol-dependent chemiluminescence (LDCL), and beta-D-glucuronidase release were then evaluated in vitro. The G-protein inhibitor, pertussis toxin, the protein kinase C inhibitor, chelerythine, and the Ca(++) channel blocker, verapamil, markedly reduced phagocytosis in a dose responsive manner. Genistein, a tyrosine kinase inhibitor, had no effect on the phagocytosis of the opsonized SE. Both pertussis toxin (66-98%) and verapamil (47-76%) had marked inhibitory effect on LDCL. Chelerythine (13-25%) and genistein (5-25%) had far less biologically significant effects on LDCL. Neither chelerythine nor genistein had a significant effect on degranulation. Verapamil (2-28%) and pertussis toxin (25-29%) had a moderate inhibitory effect on degranulation stimulated by IgG-opsonized SE. As was found with complement receptor mediated activation of heterophils, the binding of Fc receptors by the IgG-SE complex activated distinct signaling pathways that regulate the functional activities of avian heterophils. Pertussis toxin-sensitive, Ca(++)-dependent, G-proteins and protein kinase C-dependent protein phosphorylation play a major role in the phagocytosis of IgG-opsonized SE. Pertussis toxin-sensitive, Ca(++)-dependent, G-proteins appear to regulate LDCL following Fc receptor binding. The signal transduction inhibitors used in these studies did not affect Fc receptor mediated degranulation by avian heterophils.
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PMID:Signal transduction pathways activated by engaging immunoglobulin Fc receptors on chicken heterophils. 1147 85

Fc receptors of avian heterophils play a primary role in the elimination of bacterial pathogens in poultry. The cross-linking of Fc receptors with IgG-bacteria complexes results in the secretion of toxic oxygen metabolites and anti-bacterial granules. We have been investigating the upstream signaling events that precede degranulation following crosslinkage of Fc receptors on heterophils. Previously when using the non-selective pharmacological inhibitors genistein, chelerythrine, verapamil, and pertussis toxin, we found no significant inhibitory effects on Fc-mediated heterophil degranulation. In the present studies, we used more selective pharmacological inhibitors to investigate the roles of protein tyrosine kinases, phospholipase C (PLC), phosphatidylinositol 3'-kinase, and the family of mitogen-activated protein kinases (MAPK) on Fc-mediated heterophil degranulation. Inhibitors of the receptor-linked tyrosine kinases (the tryphostins AG 1478 and AG 1296) had no attenuating effects on the Fc receptor-mediated degranulation of chicken heterophils. Likewise, PP2, a selective inhibitor of the Src family of protein tyrosine kinases, had no inhibitory effects on degranulation. However, piceatannol, a selective inhibitor of Syk tyrosine kinase, significantly attenuated the effect of Fc receptor-mediated degranulation. Additionally, Fc-mediated degranulation was significantly attenuated by SB 203580, an inhibitor of p38 MAPK, but not by PD98059, an inhibitor of the extracellular signal-regulated kinase (ERK). An inhibitor of phospholipase C, U73122 and LY294002, an inhibitor of phosphoinositol-3 kinase significantly decreased heterophil degranulation. These results suggest that the Fc receptors on chicken heterophils, like their counterparts on mammalian neutrophils, have no intrinsic tyrosine kinase activity, but probably mediate downstream events through activation of tyrosine-based activation motifs (ITAM). Activation of the Syk tyrosine kinase stimulates downstream phosphorylation of p38 MAPK, phospholipase C, and phosphatidylinositol-3 kinase as signaling pathways that regulate Fc-receptor-mediated degranulation of chicken heterophils. Engaging Fc receptors on chicken heterophils activates a Syk-->PLC-->PI3-K-->p38 MAPK signal transduction pathway that induces degranulation.
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PMID:Selective pharmacological inhibitors reveal the role of Syk tyrosine kinase, phospholipase C, phosphatidylinositol-3'-kinase, and p38 mitogen-activated protein kinase in Fc receptor-mediated signaling of chicken heterophil degranulation. 1218 37

We provide evidence that platelet factor 4 (PF4), but not the related chemokine neutrophil-activating polypeptide-2, induced highly purified human natural killer (NK) cells to produce interleukin (IL)-8 in a time- and dosage-dependent manner. This ability was retained even while PF4 was bound to heparin. PF4 increased the steady state level of IL-8 mRNA, likely implying a transcriptional effect of PF4. Stimulation of NK cells through the Fc receptor for immunoglobulin G-IIIA was found to synergistically increase the effect of PF4 on IL-8 production but did not affect IL-2-related activities such as cytotoxic activity and proliferation. Pertussis toxin did not block the PF4-derived IL-8 production in NK cells, but this response was sensitive to wortmannin, implicating a role of phosphatidylinositol 3-kinase in the intracellular signaling pathway triggered by PF4. Our results characterize a new capacity for PF4 and provide further evidence for the pivotal role of NK cells in the environment of inflammation.
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PMID:Platelet factor 4 induces human natural killer cells to synthesize and release interleukin-8. 1222 28


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