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)

Lymphotoxin (LT) can activate human neutrophils. Using a hemolytic plaque assay to detect secretion of lactoferrin and myeloperoxidase (MPO) from single adherent neutrophils, we showed that LT induced secretion from both primary and secondary granules. Incubation of cells with cytochalasin B was required for MPO secretion, and it enhanced lactoferrin secretion. Pertussis toxin, which blocks a G-protein in the plasma membrane, inhibited LT-induced exocytosis of MPO, but not of lactoferrin. Incubation with LT did not induce any detectable changes of the cytoplasmic free [Ca2+] in neutrophils. On the other hand, secretion of granule proteins from adherent neutrophils in response to LT was blocked by loading neutrophils with quin-2 in order to increase the intracellular calcium buffering capacity. This was achieved at a concentration of quin-2, at which the secretion induced by the phorbol ester PMA and the chemotactic peptide FMLP was unaffected. Trifluoroperazine (TFP), a dual protein kinase C and calmodulin inhibitor, significantly inhibited the LT-mediated secretion of lactoferrin from adherent granulocytes. The PMA effect was unaltered by TFP under these conditions, suggesting that the inhibitory effect was on a calcium-calmodulin dependent step. The secretion induced by TNF and GM-CSF was also blocked by buffering changes in the intracellular [Ca2+] and inhibited to a similar extent by TFP. Our results suggest that calmodulin and minute changes in the cytoplasmic free [Ca2+] may be involved in a common signal transduction pathway engaged in activation of adherent neutrophils by several cytokines.
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PMID:Lymphotoxin induces secretion of granule proteins from adherent neutrophils: possible role of intracellular free calcium. 216 92

The killing of L-M cells by murine tumor necrosis factor (mTNF) was investigated by a combination of drug, antiserum neutralization, and kinetic studies. Kinetic studies with 125I-mTNF showed that the bulk of association of ligand with L-M cells peaked within 2 hr and the ligand was not degraded. Cell surface receptors were depleted (down regulated) by 6 hr when death commenced. The off-rates of acid-dissociable (surface bound) and acid-indissociable (internalized) compartments were found to be 9 min and 35 hr, respectively. Nevertheless, complete cell killing required the persistent presence of mTNF for up to 20 hr. This requirement was ablated by the concomitant addition of cycloheximide. Antiserum completely inhibited cytotoxicity when it was applied up to 4 hr after mTNF, but antiserum added 1 hr after mTNF was not neutralizing in the presence of cycloheximide. Thus, the inclusion of cycloheximide temporally dissociated early events (internalization and signal transduction) from lysis. Other drugs with and without cycloheximide were found to preferentially affect either early or later aspects of cell death. Phorbol myristate acetate and the ionophore A23187 were potent inhibitors of cytotoxicity, and staurosporine was a potent enhancer. These agents were more effective when added 1 hr before mTNF and cycloheximide than when added 1 hr after and likely affected early events in the cytolytic program. In contrast, chloroquine and cAMP likely affect more terminal aspects of cytotoxicity. Dibutyrylcyclic AMP, cholera, and pertussis toxins enhanced cytotoxicity. They were equipotent when added either before or after mTNF regardless of the presence of cycloheximide. Likewise, chloroquine was an equipotent inhibitor when added either before or after mTNF regardless of the presence of cycloheximide. Agents that primarily affect association events may be more likely to impinge on other TNF-mediated activities than agents that primarily affect lysis.
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PMID:Drug-induced alterations of tumor necrosis factor-mediated cytotoxicity: discrimination of early versus late stage action. 229 25

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

Preincubation of human neutrophils with recombinant tumor necrosis factor alpha has previously been shown by us to enhance superoxide production of neutrophils in response to the chemotactic peptide formyl-methionyl-leucyl-phenylalanine, and the phorbol ester, phorbol myristate acetate. In this study, we further investigate the biochemical basis for this enhancement. We found that in neutrophils, TNF by itself does not induce: (1) an influx of sodium, (2) an alteration in activity or translocation of the calcium and phospholipid dependent protein kinase (C-kinase), or (3) a release of arachidonic acid from preloaded cells. TNF did, however, induce a time- and concentration-dependent increase in the phosphorylation of several neutrophil proteins, with the most dramatic concentration dependent increase in a 64,000 Da protein. Finally, the enhancement of O2 production by pretreatment of neutrophils with TNF was found to be independent of a pertussis toxin-sensitive guanine nucleotide regulatory protein.
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PMID:Biochemical mechanisms involved in the priming of neutrophils by tumor necrosis factor. 284 26

The capability of platelet-activating factor (PAF) to induce transcription factor activation was examined. In stably transfected Chinese hamster ovary cells expressing the PAF receptor (CHO-PAFR), PAF stimulation resulted in the nuclear expression of a DNA binding activity with specificity to the kappa B sequence. The p50 and p65 proteins, constituents of the prototypic nuclear factor kappa B (NF-kappa B), were identified as components of the DNA protein complexes by antipeptide antibodies in gel supershift as well as UV cross-linking experiments. PAF induced an initial decrease and subsequent increase of cytoplasmic I kappa B alpha levels, accompanied by up-regulation of the I kappa B alpha messenger RNA, a feature of NF-kappa B activation. PAF-induced kappa B binding activity was detected within 15 min after agonist stimulation, peaked at 30-40 min, and remained detectable by 2.5 h. SR 27417, a PAF receptor antagonist, blocked PAF-induced kappa B binding activity but not that induced by tumor necrosis factor-alpha (TNF alpha). Cholera toxin treatment markedly reduced PAF-induced kappa B binding activity, whereas pertussis toxin had no significant inhibitory effect. Neither of the two toxins affected the kappa B binding activity induced by TNF alpha in the same cells. In addition to the CHO-PAFR cells, PAF stimulated kappa B binding activity in the murine P388D1 macrophage and the human ASK.0 B cell lines that express endogenous PAF receptors. These results imply a potential role of PAF in the regulation of gene expression through a G protein-coupled transcription factor activation pathway.
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PMID:Platelet-activating factor induces NF-kappa B activation through a G protein-coupled pathway. 779 72

Immunological properties of a low toxicity lipopolysaccharide (BP-LPS) extracted from Bordetella pertussis (Tohama strain) which was reported to have high antitumor activity against murine tumors were examined and compared with those of LPS extracted from other enterobacteria. The activation or stimulation of murine macrophages and lymphocytes by these LPS, including TNF induction, was found to be similar. However, BP-LPS was clearly less active in its stimulation of murine and human neutrophils as estimated by neutrophil-adherence assay and by their TNF production than E. coli LPS. Furthermore, BP-LPS also suppressed the activation of human neutrophils by Escherichia coli LPS. A comparative study with 7 LPS preparations indicated that their toxicity in terms of animal body weight loss correlated with their ability to induce human neutrophil adherence. The inability of BP-LPS to activate neutrophils may thus have some bearing on its low toxicity.
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PMID:Characterization of immunological activity of a low toxicity antitumor lipopolysaccharide from Bordetella pertussis. 785 14

TNF-alpha enhances the response of polymorphonuclear leukocytes (PMN) to chemoattractants: however, the mechanism by which this occurs is unclear. We addressed the hypothesis that TNF-alpha enhances the PMN response to chemoattractants by increasing chemoattractant receptor transmembrane signaling, using fMLP as the model chemoattractant. fMLP-stimulated guanine nucleotide binding (G) protein activation was significantly increased in plasma membranes isolated from PMNs exposed to TNF-alpha 100 U/ml for 10 minutes (TNF-M), compared to membranes from control cells (CM). Formyl peptide receptor number and affinity were not significantly different in CM and TNF-M. Gi and Gs content were increased in TNF-M as measured by pertussis toxin and cholera toxin (CT) catalyzed ADP-ribosylation, respectively. The increased Gi was coupled to the formyl peptide receptor as shown by receptor-specific CT labeling of Gi. Immunoblot analysis showed that both G alpha i2 and G alpha 3 were increased in TNF-M. The functional activity of the increased G protein content was demonstrated by increased NaF-stimulated phospholipase D activity in TNF-alpha-treated PMNs. We conclude that TNF-alpha rapidly stimulates increased PMN plasma membrane expression of G proteins that couple formyl peptide receptors to effector enzymes. Regulation of G protein expression may be a significant mechanism by which TNF regulates PMN function.
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PMID:TNF-alpha stimulates increased plasma membrane guanine nucleotide binding protein activity in polymorphonuclear leukocytes. 788 23

Human dermal mast cells are capable of releasing cytokines, particularly preformed TNF alpha, upon appropriate stimulation. Mast cell activation in vivo was shown to be associated with an influx and activation of inflammatory cells, initially PMN (polymorphonuclear neutrophilic granulocytes) then eosinophils. In order to learn more about the mechanisms by which TNF alpha is capable of activating eosinophils, in the present study the effect of TNF alpha on morphology and function of highly purified normal eosinophils (> or = 95%) was examined. As estimated by transmission and scanning electron microscopy, TNF alpha-stimulated eosinophils appeared to be strictly adherent and flattened exhibiting a characteristic "hemispheric" shape. TNF alpha induced a dose-dependent, long-lasting production of reactive oxygen species as measured by lucigenin-dependent chemiluminescence (CL), even at a concentration of 0.001 U/ml. The maximal response upon stimulation with TNF alpha, however, was significantly lower than optimal effects induced by IL-5. TNF alpha-induced responses were completely inhibited by cytochalasin B and staurosporin, and partially blocked by pertussis toxin. Separation of eosinophils by discontinuous density gradients revealed the existence of at least two hypodense eosinophil populations with a distinct susceptibility to stimulation with TNF alpha. Based on functional assay systems, in contrast to a significant extracellular, only a small intracellular H2O2 production was detected. Accordingly, H2O2 production, detected by an ultrastructural technique, was observed only on the outer surface of the plasma membrane in the contact zones in between adjacent cells. Extracellular as well as intracellular production of H2O2 was completely inhibited by cytochalasin B. TNF alpha-induced activation of eosinophils is most probably mediated by binding to the 55 kD and the 75 kD TNF-receptor since both receptor molecules could be detected by FACS analysis and immune electron microscopy using receptor-specific antibodies. However, in contrast to its effect on eosinophil oxidative response, TNF alpha did not induce the release of significant concentrations of eosinophil cationic protein or eosinophil peroxidase in supernatants of cytokine-stimulated eosinophils, as detected by functional as well as immunological assay systems. These results clearly indicate that TNF alpha represents a potent eosinophil-activating cytokine which may be of relevance in the allergic inflammatory response.
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PMID:TNF alpha-induced activation of eosinophil oxidative metabolism and morphology--comparison with IL-5. 800 Jul 7

Tumor necrosis factor alpha (TNF-alpha) and 12-0-tetradecanoyl phorbol-13-acetate (TPA) activate human immunodeficiency virus type 1 (HIV-1) in U1 cells that are latently infected with HIV-1 to produce viral particles. Pertussis toxin, which inactivates several members of the G protein family of signaling components, including Gi, Go, and transducin, was found to inhibit either TPA or TNF-alpha induction of HIV-1 in U1 cells at the concentration of 1-10 ng/ml. Chloramphenicol acetyl transferase (CAT) assay revealed that pertussis toxin could inhibit HIV-1 gene expression. B-oligomer, the mitogenic and non-ADP-ribosylating component of pertussis toxin, did not show any effect on HIV-1 replication alone or in combination with TNF in the same concentration range. It was of particular interest to note that a single protein (Gi) with a molecular weight of 40 kDa was dose-dependently ADP-ribosylated after treatment with pertussis toxin in U1 cells. The degree of ADP ribosylation of Gi corresponded well to that of inhibition of HIV-1 upon treatment with pertussis toxin. These results strongly support the contention that TPA and TNF-alpha induction of HIV-1 is mediated by a Gi-like receptor-effector coupling protein in the membrane of U1 cells. On the basis of these findings, we propose a model for signal transduction of HIV-1 expression through c-kinase-dependent (TPA) and c-kinase-independent (TNF-alpha) pathways in the U1 cell to determine the point at which Gi-like protein is involved.
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PMID:Pertussis toxin inhibits induction of human immunodeficiency virus type 1 in infected monocytes. 805 61

Pertussis toxin (PT) has been previously shown to affect a wide variety of immune responses and to cause lymphocyte proliferation. In this study, we examined the effect of PT on cultured human peripheral blood lymphocytes and monocytes with the regard to the capability of this toxin to stimulate the production and release of various cytokines. PT was found to induce the production and release of Tumor Necrosis Factor alfa (TNF-alfa) and Interleukin-6 (IL-6) by both human lymphocytes and monocytes and IL-1 (IL-1B) beta by human monocytes in culture. Most activities of PT in vitro were achieved at the optimal concentration range of 1-0.01 microgram/ml, which is responsible for the adjuvant effect of PT in vivo. Since TNF-alfa, IL-1 beta and IL-6 are potent mediators of inflammation, the production and release of these cytokines by PT and Bordetella pertussis itself may play an important role in antibacterial defenses against such infection.
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PMID:Production and release of tumor necrosis factor alfa, interleukin-1B and interleukin-6 by human mononuclear leukocytes stimulated with pertussis toxin. 826 21


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