UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pertussis toxin inhibits chemotaxis of neutrophils by preventing chemoattractant receptors from activating trimeric G proteins in the Gi subfamily. In HEK293 cells expressing recombinant receptors, directional migration toward appropriate agonist ligands requires release of free G protein betagamma subunits and can be triggered by agonists for receptors coupled to Gi but not by agonists for receptors coupled to two other G proteins, Gs and Gq. Because activation of any G protein presumably releases free Gbetagamma, we tested the hypothesis that chemotaxis also requires activated alpha subunits (Galphai) of Gi proteins. HEK293 cells were stably cotransfected with the Gi-coupled receptor for interleukin-8, CXCR1, and with a chimeric Galpha, Galphaqz5, which resembles Galphai in susceptibility to activation by Gi-coupled receptors but cannot regulate the Galphai effector, adenylyl cyclase. These cells, unlike cells expressing CXCR1 alone, migrated toward interleukin-8 even after treatment with pertussis toxin, which prevents activation of endogenous Galphai but not that of Galphaqz5. We infer that chemotaxis does not require activation of Galphai. Because chemotaxis is mediated by Gbetagamma subunits released when Gi-coupled receptors activate Galphaqz5, but not when Gq- or Gs-coupled receptors activate their respective G proteins, we propose that Gi-coupled receptors transmit a necessary chemotactic signal that is independent of Galphai.
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PMID:Galphai is not required for chemotaxis mediated by Gi-coupled receptors. 991 16

Interleukin-8 (IL-8), a pro-inflammatory chemokine, induces trafficking of neutrophils across the vascular wall. The release of IL-8 is triggered by inflammatory signals from a large variety of cells. The diversity in the cellular source indicates pleiotropy of its functions. IL-8 plays a key role in host defense mechanism through its effects on neutrophil activation, but a continued presence of IL-8 in circulation in response to inflammatory conditions may lead to a variable degree of tissue damage. Like most of the peptide hormones or mediators, IL-8 transmits its signals through distinct cell surface receptors. The membrane spanning heptahelical IL-8 receptor is coupled with the effector enzyme(s) through the intermediacy of heterotrimeric GTP-binding regulatory proteins. A growing number of studies demonstrated regulation of IL-8 activity by pertussis toxin treatment, implying a role of pertussis toxin sensitive G proteins (Gi), in IL-8 induced effects. IL-8 induced activation of G-protein results in activation of phospholipase C b2 (PLCb2). This enzyme catalyzes the hydrolysis of membrane phosphoinositides to yield diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (IP3), which in turn activates protein kinase C (PKC) and mobilizes the intracellular Ca2+, respectively. Neutrophils activation of phospholipase D (PLD) and superoxide generation in response to IL-8 have also been demonstrated. Furthermore, IL-8-mediated activation of mitogen activating protein kinase (MAPK) and tyrosine phosphorylation of cellular proteins have been observed. It appears that the signalling pathways induced by IL-8 are subject to fine modulations by the demand and presence of IL-8. The presence of IL-8 in various pathophysiological condition implies that blockade of its actions could be exploited for therapeutic purposes.
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PMID:Interleukin-8: An autocrine inflammatory mediator. 1010 Dec 23

The effect of interleukin-8 (IL-8) and growth-related oncogene alpha (GROalpha) on [35S]-guanosine 5'-O-(3-thiotriphosphate) ([35S]GTPgammaS) binding, forskolin-stimulated cyclic AMP accumulation and cytosolic calcium concentration were determined in recombinant CHO cells expressing HA-tagged CXC-chemokine receptors 1 and 2 (CXCR1 and CXCR2). Radioligand binding assays confirmed that the binding profiles of the recombinant receptors were similar to those of the native proteins. IL-8 displaced [125I]-IL-8 binding to CXCR1 and CXCR2 with pKi values of 8.89+/-0.05 and 9.27+/-0.03, respectively. GROalpha, a selective CXCR2 ligand, had a pKi value of 9.66+/-0.39 at CXCR2 but a pKi>8 at CXCR1. Calcium mobilization experiments were also consistent with previous reports on native receptors. Activation of both receptors resulted in stimulation of [35S]GTPgammaS binding and inhibition of adenylyl cyclase. A comparison of the functional data at CXCRI showed that a similar potency order (IL-8> >GROalpha) was obtained in all three assays. However, at CXCR2 whilst the potency orders for calcium mobilization and inhibition of adenylyl cyclase were similar (IL-8 > or = GROalpha), the order was reversed for stimulation of [35S]GTPgammaS binding (GROalpha > IL-8). All of the functional responses at both receptors were inhibited by pertussis toxin (PTX), suggesting coupling to a Gi/Go protein. However, the calcium mobilization induced by IL-8 at CXCR1 was not fully inhibited by PTX, suggesting an interaction with a G-protein of the Gq family. Our results with pertussis toxin also suggested that, in the [35S]GTPgammaS binding assay, CXCR1 displays some constitutive activity. Thus, we have characterized the binding and several functional responses at HA-tagged CXCRs 1 and 2 and have shown that their pharmacology agrees well with that of the native receptors. We also have preliminary evidence that CXCR1 displays constitutive activity in our cell line and that CXCR2 may traffic between different PTX sensitive G-proteins.
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PMID:Signalling by CXC-chemokine receptors 1 and 2 expressed in CHO cells: a comparison of calcium mobilization, inhibition of adenylyl cyclase and stimulation of GTPgammaS binding induced by IL-8 and GROalpha. 1018 95

The chemotactic potencies of ELR(+)-CXC chemokines during acute inflammation are regulated by their binding affinities and by their ability to activate, desensitize, and internalize their specific receptors, CXCR1 and CXCR2. To gain insight into the fine mechanisms that control acute inflammatory processes, we have focused in this study on the highly potent ELR(+)-CXC chemokine Granulocyte Chemotactic Protein 2 (GCP-2), and on its ability to control the cell surface expression of CXCR1 and CXCR2. Although GCP-2 has been considered an effective ligand for both CXCR1 and CXCR2, our findings demonstrated that it was a potent inducer of CXCR2 internalization only. A functional hierarchy was shown to exist between GCP-2 and 2 other ELR(+)-CXC chemokines, IL-8 and NAP-2, in their abilities to induce CXCR1 and CXCR2 internalization, according to the following: IL-8 > GCP-2 > NAP-2. By the use of pertussis toxin (PTx), it was demonstrated that the actual events of G(alphai)-coupling to CXCR2 do not have a major role in the regulation of its internalization. Rather, CXCR2 internalization was shown to be negatively controlled by induction of signaling events, as indicated by the promotion of CXCR2 internalization following exposure to wortmannin, a potent inhibitor of phosphatidylinositol (PI) 3 kinases and PI4 kinases. Furthermore, our results suggest that rab11(+)-endosomes participate in the trafficking of CXCR2 through the endocytic pathway, to eventually allow its recycling back to the plasma membrane. To conclude, our findings shed light on the interrelationships between GCP-2 and other ELR(+)-CXC chemokines, and determine the mechanisms involved in the regulation of GCP-2-induced internalization and recycling of CXCR2. (Blood. 2000;95:1551-1559)
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PMID:GCP-2-induced internalization of IL-8 receptors: hierarchical relationships between GCP-2 and other ELR(+)-CXC chemokines and mechanisms regulating CXCR2 internalization and recycling. 1068 7

Infection with tissue-migrating helminths is frequently associated with intense granulocyte infiltrations. Several host-derived factors are known to mediate granulocyte recruitment to the tissues, but less attention has been paid to how parasite-derived products trigger this process. Parasite-derived chemotactic factors which selectively recruit granulocytes have been described, but nothing is known about which cellular receptors respond to these agents. The effect of products from the nematodes Ascaris suum, Toxocara canis, and Anisakis simplex on human neutrophils were studied. We monitored four parameters of activation: chemotaxis, cell polarization, intracellular Ca(2+) transients, and priming of superoxide anion production. Body fluids of A. suum (ABF) and T. canis (TcBF) induced strong directional migration, shape change, and intracellular Ca(2+) transients. ABF also primed neutrophils for production of superoxide anions. Calcium mobilization in response to A. suum-derived products was completely abrogated by pretreatment with pertussis toxin, implicating a classical G protein-coupled receptor mechanism in the response to ABF. Moreover, pretreatment with interleukin-8 (IL-8) completely abrogated the response to ABF, demonstrating desensitization of a common pathway. However, ABF was unable to fully desensitize the response to IL-8, and binding to CXCR1 or CXCR2 was excluded in experiments using RBL-2H3 cells transfected with the two human IL-8 receptors. Our results provide the first evidence for a direct interaction between a parasite-derived chemotactic factor and the host's chemotactic network, via a novel G protein-coupled receptor which interacts with the IL-8 receptor pathway.
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PMID:Ascaris suum-derived products induce human neutrophil activation via a G protein-coupled receptor that interacts with the interleukin-8 receptor pathway. 1134 70

Stimulation of microvascular endothelial cells with interleukin (IL)-8 leads to cytoskeletal reorganization, which is mediated by combined activation of the CXCR1 and the CXCR2. In the early phase actin stress fibers appear, followed by cortical actin accumulation and cell retraction leading to gap formation between cells. The early response (between 1 and 5 min) is inhibited by an antibody that blocks the CXCR1. The later phase (from about 5 to 60 min), which is associated with cell retraction, is prevented by anti-CXCR2 antibody. Furthermore, anti-CXCR2, but not anti-CXCR1, antibody blocked IL-8-mediated haptotaxis of endothelial cells on collagen. The later phase of the IL-8-mediated actin response is inhibited by pertussis toxin, indicating that the CXCR2 couples to G(i). In contrast, the early phase is blocked by C3 botulinum toxin, which inactivates Rho, and by Y-27632, which inhibits Rho kinase, but not by pertussis toxin. Furthermore, the early CXCR1-mediated formation of stress fibers was prevented by dominant negative Rho. Dominant negative Rac on the other hand initially translocated to actin-rich filopodia after stimulation with IL-8 and later prevented cell retraction by blocking the CXCR2-mediated cytoskeletal response. These results indicate that IL-8 activates both the CXCR1 and the CXCR2 on microvascular endothelial cells, using different signal transduction cascades. The retraction of endothelial cells due to activation of the CXCR2 may contribute to the increased vascular permeability observed in acute inflammation and during the angiogenic response.
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PMID:IL-8 activates endothelial cell CXCR1 and CXCR2 through Rho and Rac signaling pathways. 1135 Jul 88

Agonist activity at G protein-coupled receptors (GPCRs) that regulate heterotrimeric G proteins of the Galpha(i/o) or Galpha(q) families has been shown to result in activation of the mitogen-activated protein (MAP) kinase cascade. To facilitate compound screening for these classes of GPCR, we have developed a reporter gene that detects the activation of the ternary complex transcription factor Sap1a following MAP kinase activation. In contrast to other reporter gene assays for Galpha(i/o)-coupled GPCRs, the MAP kinase reporter generates an increase in signal in the presence of agonist. The reporter gene has been transfected into Chinese hamster ovary cells to generate a "host" reporter gene-containing cell line. The Galpha(i)-coupled human CXCR1 chemokine receptor was subsequently transfected into this cell line in order to develop a 384-well format screen for both agonists and antagonists of this receptor. Agonists activated the reporter gene with the expected rank order of potency and with similar concentration dependence as seen with the regulation of other signal transduction cascades in mammalian cells: interleukin-8 (IL-8) (pEC(50) = 7.0 +/- 0.1) > GCP-2 (pEC(50) = 6.3 +/- 0.1) > NAP-2 (pEC(50) < 6). CXCR1-mediated activation of MAP kinase was inhibited by pertussis toxin and the MEK inhibitor PD98059, demonstrating that receptor activation of MAP kinase is due to pertussis toxin-sensitive Galpha(i/o)-family G proteins to cause the activation of MEK kinase. Using the 384-well format, assay performance was unaffected by solvent concentrations of 0.5% ethanol, 0.15% glycerol, or 1% DMSO. Signal crosstalk between adjacent wells was less than 1%. The assay exhibited a Z factor of 0.53 and a coefficient of variation of response to repeated application of IL-8 (100 nM) of 15.9%.
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PMID:Development of a homogeneous MAP kinase reporter gene screen for the identification of agonists and antagonists at the CXCR1 chemokine receptor. 1167 62

The human chemokine receptors CXCR5 and CXCR1 activate signaling pathways via pertussis toxin-sensitive as well as insensitive G proteins. CXCR5 induces Ca2+ signaling and chemotaxis independently of inhibitory G proteins, whereas the same signaling pathways are entirely dependent on inhibitory G proteins for CXCR1. In contrast, activation of the MAP kinase cascade via ERK1/2 is a pertussis toxin-sensitive signaling event for both receptors. Using chimeric CXCR1/CXCR5 receptors we investigated structural requirements for the activation of signal transduction pathways by CXCR5. Individual or multiple intracellular domains of CXCR1 were exchanged for the corresponding sequences of CXCR5, leading to receptors resembling CXCR5 at the cytoplasmic surface to a varying extent. Replacing the second intracellular domain of CXCR1 had a major influence on signaling mediated by inhibitory G proteins, whereas the exchange of the third or carboxy-terminal intracellular domain had only minor effects on signal transduction. Activation of the MAP kinase cascade via ERK1/2 and chemotaxis are largely reduced in chimeras comprising the second intracellular domain of CXCR5, although coupling to inhibitory G proteins is retained in all chimeric receptors. In summary, these data characterize the contribution of the intracellular domains of CXCR5 to receptor signaling, thereby disclosing unique structural requirements that modulate G protein coupling by the receptor.
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PMID:Signal transduction by the chemokine receptor CXCR5: structural requirements for G protein activation analyzed by chimeric CXCR1/CXCR5 molecules. 1168 22

There is increasing evidence that both cell adhesion molecules and soluble factors are involved in tumor metastasis. We have found that endothelial cells secrete chemoattractants that can induce melanoma cell chemotaxis. Protein separation on an ion-exchange column shows the association of IL-8 with fractions that contain the chemoattractant activity. This activity is completely lost from the conditioned medium after immunoprecipitation with anti-IL-8 antibodies, indicating that IL-8 is the major melanoma chemoattractant secreted by endothelial cells. IL-877, the predominant endothelial IL-8 isoform that contains 77 amino acids, is found to be twice as potent as the more common 72-amino acid isoform IL-872. Antibody inhibition studies indicate that the chemotactic response of melanoma cells is mediated by the CXC-chemokine receptor CXCR1 and not by the more promiscuous CXCR2. When stimulated by tumor necrosis factor alpha, the nonresponsive WM35 melanoma cells synthesize a higher level of CXCR1 and become chemotactic toward interleukin (IL)-8. Pretreatment of cells with pertussis toxin nullifies their chemotactic response, suggesting the involvement of G proteins. Antibodies against either IL-8 or CXCR1 inhibit melanoma transendothelial migration in a coculture assay by 30%. These results are consistent with a role for IL-8-induced chemotaxis in the transendothelial migration of melanoma cells.
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PMID:Interleukin-8 secreted by endothelial cells induces chemotaxis of melanoma cells through the chemokine receptor CXCR1. 1273 12

Platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycerolphosphocholine; PAF) induces leukocyte accumulation and activation at sites of inflammation via the activation of a specific cell surface receptor (PAFR). PAFR couples to both pertussis toxin-sensitive and pertussis toxin-insensitive G proteins to activate leukocytes. To define the role(s) of G(i) and G(q) in PAF-induced leukocyte responses, two G-protein-linked receptors were generated by fusing G alpha(i3) (PAFR-G alpha(i3)) or G alpha(q) (PAFR-G alpha(q)) at the C terminus of PAFR. Rat basophilic leukemia cell line (RBL-2H3) stably expressing wild-type PAFR, PAFR-G alpha(i3), or PAFR-G alpha(q) was generated and characterized. All receptor variants bound PAF with similar affinities to mediate G-protein activation, intracellular Ca2+ mobilization, phosphoinositide (PI) hydrolysis, and secretion of beta-hexosaminidase. PAFR-G alpha(i3) and PAFR-G alpha(q) mediated greater GTPase activity in isolated membranes than PAFR but lower PI hydrolysis and secretion in whole cells. PAFR and PAFR-G alpha(i3), but not PAFR-G alpha(q), mediated chemotaxis to PAF. All three receptors underwent phosphorylation and desensitization upon exposure to PAF but only PAFR translocated beta arrestin to the cell membrane and internalized. In RBL-2H3 cells coexpressing the PAFRs along with CXCR1, IL-8 (CXCL8) cross-desensitized Ca2+ mobilization to PAF by all the receptors but only PAFR-G alpha(i3) activation cross-inhibited the response of CXCR1 to CXCL8. Altogether, the data indicate that G(i) exclusively mediates chemotactic and cross-regulatory signals of the PAFR, but both G(i) and G(q) activate PI hydrolysis and exocytosis by this receptor. Because chemotaxis and cross-desensitization are exclusively mediated by G(i), the data suggest that differential activation of both G(i) and G(q) by PAFR likely mediate specific as well as redundant signaling pathways.
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PMID:Activation and regulation of platelet-activating factor receptor: role of G(i) and G(q) in receptor-mediated chemotactic, cytotoxic, and cross-regulatory signals. 1692 Sep 64

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