Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Cytokines belonging to the RANTES/SIS family are highly induced in a number of pathophysiological processes such as autoimmune disorders, cancers, atherosclerosis, and chronic inflammation. However, apart from their chemotactic activity on monocytes and particular lymphocyte types, the biological activities in the human system of this recently discovered cytokine family are largely unknown. Here we report that one family member, described as monocyte chemotactic protein 1 (MCP-1), strongly activates mature human basophils in a pertussis toxin-sensitive manner. MCP-1 causes a rise in the cytosolic free calcium level in basophils and monocytes, but not in other blood leukocyte types, and triggers basophil degranulation at low concentrations (ED50 = 3-10 nM). Thus, MCP-1 is a cytokine capable of directly inducing histamine release by basophils. Furthermore, MCP-1 promotes the formation of leukotriene C4 by basophils pretreated with interleukin 3 (IL-3), IL-5, or granulocyte/macrophage colony-stimulating factor. MCP-1-induced basophil mediator release may play an important role in allergic inflammation and other pathologies expressing MCP-1.
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PMID:Monocyte chemotactic protein 1 is a potent activator of human basophils. 156 97

Activation of the formyl peptide chemoattractant receptor (FPCR) of phagocytic cells mobilizes intracellular calcium stores and affects the plasma membrane potential. Affinity crosslinking of FPCR has demonstrated a 60-80 kDa glycoprotein, with core peptide of 32 kDa. It is not known whether functional FPCR is this single peptide or requires multiple subunits. We used Xenopus oocyte expression system to determine the size of mRNA required for synthesis of functional FPCR. Injection of oocytes with poly(A)+ RNA from HL60 cells differentiated to the granulocyte phenotype resulted in acquisition of formyl peptide-specific responses (inward transmembrane current with a reversal potential consistent with a chloride conductance, and calcium efflux). FPCR activity expressed in oocytes had a ligand concentration dependence, ligand structure dependence and pertussis toxin sensitivity similar to those reported in phagocytic cells. When RNA was size fractionated, a single peak of FPCR activity at 2 kilobases was observed after injection of mRNA into oocytes. Our data strongly suggest that FPCR is composed of a single-sized polypeptide.
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PMID:The formyl peptide chemoattractant receptor is encoded by a 2 kilobase messenger RNA. Expression in Xenopus oocytes. 169 Jan 50

We investigated functional interactions between granulocyte-monocyte-colony-stimulating factor (GM-CSF) and the insulin family hormones using the GM-CSF- and insulin-dependent human acute myeloid leukemia cell line AML-193. Recombinant human GM-CSF and insulin enhanced AML-193 cell proliferation 3- and 5-fold, respectively, and showed a synergistic 10-fold increase when added in combination. Insulin-like growth factors I and II (IGFI and IGFII) increased AML-193 cell proliferation 4-fold and 2-fold, respectively, and also demonstrated synergy when combined with GM-CSF. Blocking experiments with monoclonal antibodies against the insulin and IGFI receptors indicated that the proliferative effects of insulin and IGFI were mediated through both their homologous and heterologous receptors. Pertussis toxin and cholera toxin, which ADP ribosylate GTP-binding proteins (G proteins), and the cyclic AMP analogue, dibutyryl cyclic AMP, decreased the proliferation induced by GM-CSF or insulin. Specific receptor binding of 125I-insulin, -IGFI, and -GM-CSF to AML-193 cells was demonstrated and not affected by preincubation with pertussis toxin or cholera toxin. Radiolabeled GM-CSF, insulin, and IGFI did not cross-compete with the heterologous ligands for receptor binding. These studies demonstrate (a) association between receptor binding and proliferative effects of GM-CSF and the insulin family hormones, (b) involvement of the G proteins in signal transduction provoked by these hormones which occurs at a postreceptor-binding level, and (c) synergistic mitogenic interactions between GM-CSF and the insulin family hormones, suggesting that their receptors are linked to divergent signaling mechanisms in addition to sharing G protein-coupled pathways.
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PMID:Functional interactions between colony-stimulating factors and the insulin family hormones for human myeloid leukemic cells. 169 37

Recombinant human granulocyte-colony stimulating factor (G-CSF) and recombinant human granulocyte/macrophage-colony stimulating factor (GM-CSF) stimulate neutrophil production from precursors in the marrow and enhance granulocyte functions in vitro. We studied the effects of G-CSF and GM-CSF on neutrophil superoxide production and secretion. G-CSF and GM-CSF alone stimulated neither superoxide production nor secretion, but both agents primed neutrophils for superoxide production stimulated by either N-formylmethionyl-leucyl-phenylalanine (FMLP) or ionomycin. Optimal priming occurred with G-CSF at 5.3 ng/ml for 20 minutes and for GM-CSF at 1 ng/ml for 60 minutes. Priming by GM-CSF was more readily inhibited by the tyrosine kinase inhibitor ST638 but was unaffected by staurosporine. Conversely, G-CSF priming was inhibited by staurosporine but not by ST638. Neither protein kinase C translocation nor increased protein kinase C activity, however, were observed after G-CSF/GM-CSF treatment. Priming by G-CSF and GM-CSF was sensitive to pertussis toxin, suggesting the involvement of guanine nucleotide-binding proteins (G-proteins). Neutrophils from three siblings with cyclic neutropenia were studied to observe the effects of G-CSF treatment on neutrophil function in vivo; sibling 1 and sibling 2 were treated with G-CSF for 6 months, but sibling 3 was not in the treatment group. Compared with neutrophils from normal donors, neutrophils from sibling 1 and sibling 2 were primed in vivo for superoxide release stimulated by either ionomycin or FMLP. Superoxide released by neutrophils from sibling 3 was similar to control cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Recombinant human G-CSF and GM-CSF prime human neutrophils for superoxide production through different signal transduction mechanisms. 172 Aug 2

We examined the role of augmented formation of intracellular cyclic AMP (cAMP) in the mediation of stromal cell growth factor production that occurs constitutively or upon cytokine stimulation. Clonal murine marrow adherent cell lines were stimulated under serum-free conditions by interleukin-1 (IL-1) or lipopolysaccharide (LPS) and one (+/+ -1.LDA11) was found to produce low quantities of granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF identity was confirmed by the ability of supernatants from stromal cells to promote proliferation of the factor-dependent cell line FDC-P1, neutralization of this activity by antiserum to GM-CSF, and by Northern blot analysis. However, optimal concentrations of IL-1 and tumor necrosis factor-alpha (TNF-alpha), in combination, led to synergistic (greater than 5-fold higher quantity) GM-CSF production compared with either stimulus alone in the +/+ -1. LDA11 cell line, capable of GM-CSF production after only single stimulation with IL-1 or LPS. In addition, synergistic stimulation by IL-1 and TNF-alpha led to equivalent high amounts of GM-CSF in another cell line incapable of GM-CSF production after induction with only IL-1 or LPS. Any of several means to raise intracellular cAMP levels, including addition of 8-bromo-cyclic AMP (8Br cAMP) (0.25-1mM), pertussis toxin (20-100 ng/ml), or addition of prostaglandin E1 (PGE1) (1 microM), failed to stimulate GM-CSF production alone and strongly inhibited GM-CSF production in stromal cells stimulated by IL-1, LPS, or the synergistic combination of IL-1 and TNF-alpha. In addition, PGE1 and pertussis intoxication were agonists of adenylate cyclase in membranes of marrow adherent cells, whereas IL-1 and LPS were not. The role for regulators of intracellular cAMP was specific because any of the cAMP agonists alone, or in the presence of cytokine stimulators of stromal cells, strongly enhanced IL-6 production, an event known to be cAMP-responsive. Thus, acute formation of intracellular cAMP is a negative regulator of stromal cell GM-CSF production mediated by cytokines, but positively regulates IL-6 production and may be an important determinant of cytokine-directed marrow microenvironmental function. These findings on the requirement for augmentation versus inhibition of cytokine-mediated production of hemopoietic growth factors might be applied to an analysis of marrow stromal cell heterogeneity.
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PMID:Role for cyclic AMP in the postreceptor control of cytokine-stimulated stromal cell growth factor production. 216 2

Human recombinant granulocyte-macrophage CSF (GM-CSF) "primes" neutrophils for enhanced biologic responses to a number of secondary stimuli. Here, we examined the properties of neutrophil priming by GM-CSF and other growth factors such as human rTNF and granulocyte CSF. Although GM-CSF has a negligible direct effect on [3H]arachidonic acid release, it enhances or "primes" neutrophils for three- to fivefold increased release of [3H]arachidonic acid, induced by 1.0 microM A23187 and the chemotactants FMLP, platelet-activating factor, and leukotriene B4 (LTB4) (all 0.1 microM). The priming effects of GM-CSF were concentration- and time-dependent (maximum 100 pM, 1 h at 23 degrees C), and consistent with the determined dissociation constant of the human GM-CSF receptor. Indomethacin (10(-8) M), cycloheximide (100 micrograms/ml), and pertussis toxin (200 ng/ml, 2 h at 37 degrees C) had no effect on GM-CSF-, A23187, or platelet-activating factor-induced [3H]arachidonic acid release. The lipoxygenase inhibitor, nordihydroguaiaretic acid, however, totally abolished A23187-induced [3H]arachidonic acid release from both diluent- and GM-CSF-treated neutrophils. Consistent with this observation, we found that GM-CSF-pretreated neutrophils synthesize increased levels of LTB4 after stimulation with A23187 and chemotactic factors. GM-CSF enhances neutrophil arachidonic acid release and LTB4 synthesis, and thereby may amplify the inflammatory response to chemotactic factors and other physiologically relevant stimuli.
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PMID:Human granulocyte-macrophage colony-stimulating factor and other cytokines prime human neutrophils for enhanced arachidonic acid release and leukotriene B4 synthesis. 245 77

HL-60 is induced to differentiate by retinoic acid (RA) to mature granulocyte-like cells. We found that pretreatment of HL-60 with pertussis toxin (PT) inhibited differentiation induced by various concentrations of RA. This inhibition was observed when PT was prior to the addition of RA. PT ADP-ribosylated a 39,000 Da protein of membrane fraction of HL-60 and did not increase an intracellular cyclic adenosine-3':5'-monophosphate level, indicating that Go, a guanine nucleotide-binding protein, involves signal transduction for RA-induced differentiation. However, Go does not appear to be obligatory for the common pathway of induction of HL-60 differentiation, because PT showed a little or no effect on differentiation induced by other inducers such as 1 alpha,25-dihydroxyvitamin D3, tumor necrosis factor, interferon-gamma, lymphotoxin, prostaglandin E2, cholera toxin, and dimethylsulfoxide.
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PMID:Pertussis toxin inhibits differentiation induced by retinoic acid in a human promyelocytic leukemia cell line HL-60. 250 57

Both TNF and and granulocyte/macrophage CSF (GM-CSF) can activate neutrophils. The aim of this work was to determine the effect of these cytokines on neutrophil degranulation. The secretion of lactoferrin of secondary granules and myeloperoxidase (MPO) of primary granules from single adherent human neutrophils was assayed by use of a reverse hemolytic plaque assay. Both rTNF and rGM-CSF caused secretion of lactoferrin in a dose-dependent manner. Both agents also caused secretion of MPO, but only in the presence of cytochalasin B. Preincubation with pertussis toxin inhibited rGM-CSF-induced secretion of both lactoferrin and MPO. rTNF-induced MPO secretion was also blocked by pertussis toxin, whereas lactoferrin secretion was only slightly affected. Neither rTNF nor rGM-CSF caused any detectable changes in the concentration of cytoplasmic free Ca2+ in fura-2-loaded cells. However, when neutrophils were loaded with increasing concentrations of quin-2 to buffer any local, not detectable, changes in the concentration of cytoplasmic Ca2+, both rTNF- and rGM-CSF-induced secretion of lactoferrin and MPO were almost totally abolished at a relatively low quin-2 concentration. These results suggest a role of a regulatory G-protein and minute local changes in the concentration of cytoplasmic Ca2+ in TNF- and GM-CSF-induced neutrophil degranulation.
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PMID:Effect of tumor necrosis factor and granulocyte/macrophage colony-stimulating factor on neutrophil degranulation. 265 22

We have presented evidence indicating that P2-purinergic receptors may activate the polyphosphoinositide-phospholipase C in HL60 cells via the mediation of a pertussis-toxin-sensitive GTP-binding protein, which also mediates the actions of chemotactic peptide receptors in these and other phagocytic white blood cells. However, our data also suggest that these same receptors can be coupled to the phospholipase via an additional pertussis-toxin-insensitive mechanism. This latter finding raises the possibility that undifferentiated HL60 cells express two distinct GTP-binding proteins coupled to phospholipase C; one of these is very likely to be the GHL/GC protein recently isolated from this cell line. Significantly, the data of Oinuma et al. and Falloon et al. indicate that expression of the 40-kDa alpha-subunit/toxin substrate increases upon differentiation of HL60 cells along the granulocyte pathway. It would be interesting to determine whether expression of the putative pertussis-toxin-insensitive G-protein decreases with differentiation of these and other myelomonocytic progenitor cells. Such studies, which are now in progress, should be facilitated by the fact that the P2-purinergic receptors appear to be expressed in myelopoietic cells from the promyelocytic/promonocytic stages through the terminally differentiated stages represented by circulating neutrophils and monocytes.
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PMID:Activation of the inositol phospholipid signaling system by receptors for extracellular ATP in human neutrophils, monocytes, and neutrophil/monocyte progenitor cells. 285 20

The tyrosine phosphorylation responses initiated in human neutrophils by soluble and particulate agonists were characterized. Chemotactic factors, hematopoietic growth factors, and inflammatory microcrystals stimulated in a time- and concentration-dependent manner the tyrosine phosphorylation of distinct patterns of substrates: pp120, pp85, pp70, and pp60 in the case of chemotactic factors; pp155, pp130, pp120, pp85, pp60, and pp40 in the case of granulocyte macrophage-CSF; and pp130, pp120, pp70, and pp60 in the case of monosodium urate (MSU) crystals. Several of the single bands on one-dimensional blots (including pp40, pp70, and pp120) could be resolved into multiple spots on two-dimensional gels. The responses of several other chemotactic factors resembled those of FMLP. Cytokineplasts retained the capacity to respond to FMLP, granulocyte-macrophage-CSF, or MSU crystals with a stimulation of tyrosine phosphorylation, and contained the major substrates detected in intact neutrophils. Several unrelated tyrosine kinase inhibitors (herbimycin A, genistein, and erbstatin) strongly diminished the tyrosine phosphorylation response to chemotactic factors. Pertussis toxin abrogated the tyrosine phosphorylation response to FMLP, whereas protein kinase C (Ro 21-8220, chelerithryn) inhibitors were without effect. Chelation of intracellular calcium attenuated the tyrosine phosphorylation response to FMLP. These results indicate that G proteins play a crucial role in the coupling of chemotactic factor receptors to tyrosine phosphorylation and that this coupling occurs in parallel to that of phospholipase C. These results also underline the complexity of the transduction pathways implicated in the initiation of tyrosine phosphorylation.
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PMID:Tyrosine phosphorylation in activated human neutrophils. Comparison of the effects of different classes of agonists and identification of the signaling pathways involved. 751 26


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