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

Incubation of the human glioma cell line HS 683 in the presence of IFN-gamma or retinoic acid strongly stimulates the cell-surface expression of the intercellular adhesion molecule ICAM-1. We have investigated the role of the cAMP-mediated signal transduction pathway in this process and report that pharmacological agents which increased the intracellular levels of cAMP exhibited a biphasic action on ICAM-1 expression in human glioma cell line HS 683. Treatment for 1 hr with 25 microM forskolin or 1 mM isobutylmethylxanthine, or for 12 hr with 100 ng/ml pertussis toxin or 50 micrograms/ml cholera toxin transiently stimulated ICAM-1 expression with a maximal level of expression 8 hr post treatment, after which time ICAM-1 expression returned to the basal level. On the other hand, such pretreatments inhibited the inducing effects of either retinoic acid or IFN-gamma. Indeed, 24 hr after treatment with cAMP-elevating agents, both the retinoic-acid- and the IFN-gamma-induced ICAM-1 expression were inhibited by 60 to 80%, with a maximal 90 to 100% inhibition 72 hr post treatment. This inhibition of the cell-surface expression of ICAM-1 was confirmed at the mRNA level. The intracytoplasmic levels of cAMP were also quantified following treatments with forskolin, retinoic acid or IFN-gamma. In response to forskolin, cAMP levels increased 30-fold within 5 min, whereas a 10-fold increase occurred 60 min following treatment with 10 microM retinoic acid. Interferon gamma, in contrast, did not induce cAMP accumulation. These results were also correlated with an in vitro activation of adenylyl cyclase activity by retinoic acid and inhibition of this activity by IFN-gamma, in a dose-dependent and a GTP-dependent manner. Our results suggest that the suppression of IFN-gamma-induced ICAM-1 expression, obtained upon pre-treatment with cAMP-elevating agents, is due to direct antagonism with IFN-gamma action on adenylyl cyclase. However, the inhibition of retinoic-acid-induced ICAM-1 expression cannot be explained by the same mechanisms. The timing of adenylyl cyclase stimulation and cAMP accumulation, as well as the levels of cAMP accumulation, are probably involved in this inhibition. Our results also emphasize the fact that the induction of ICAM-1 expression is a multi-step process implicating different transductional signals among which cAMP might be involved as a second messenger.
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PMID:Biphasic effect of cAMP-elevating agents on ICAM-1 expression stimulated by retinoic acid and interferon gamma. 137 Apr 36

Exposure to IFN-gamma increases the respiratory burst of polymorphonuclear leukocytes stimulated by the chemoattractant FMLP. However, the mechanism by which IFN-gamma alters the response to FMLP is unclear. We addressed the hypothesis that IFN-gamma enhances the response to FMLP by regulating the expression of elements of the formyl peptide receptor transmembrane-signaling pathway. HL-60 granulocytes were used as a model of FMLP transmembrane signaling. Formyl peptide receptor number and affinity were studied in isolated plasma membranes prepared from control HL-60 cells (CM) and cells exposed to IFN-gamma 100 U/ml for 24 h (IFN-M). Formyl peptide receptors were significantly increased on IFN-M compared with CM (1473 +/- 300 vs 3209 +/- 924). FMLP stimulates increased guanine nucleotide-binding protein (G protein) activation in IFN-M as evidenced by enhanced guanosine 5'-[gamma-thio]triphosphate binding and GTPase activity. Gi sub-unit content was increased in IFN-M as measured by pertussis toxin-catalyzed ADP-ribosylation and immunoblotting with antibodies against alpha i2 and alpha i3 G protein subunits. Guanosine 5'-[gamma-thio]triphosphate equilibrium binding demonstrated an increased number of G proteins coupled to formyl peptide receptors on IFN-M. We conclude that IFN-gamma increases expression of both formyl peptide receptors and G proteins coupled to these receptors, thereby enhancing FMLP-stimulated transmembrane signaling. Regulation of transmembrane signaling element expression may be a significant mechanism by which IFN-gamma regulates cellular functions.
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PMID:IFN-gamma enhances expression of formyl peptide receptors and guanine nucleotide-binding proteins by HL-60 granulocytes. 156 Feb 4

Activation of the respiratory burst in the monocytic cell line U937 by cross-linking human 40-kDa FcR for IgG (Fc gamma RII) with the IgG1 mAb, CIKM5, is dependent on the maturation state of the cell. Addition of anti-Fc gamma RII to undifferentiated cells does not activate the respiratory burst but differentiation with human rIFN-gamma (200 U/ml) for 13 to 15 days results in maximal stimulation by this agonist, with half-maximal responses in cells incubated for 10 to 12 days. During maturation the development of responsiveness to cross-linking Fc gamma RII occurs later than the development of responsiveness to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (maximal responses at 7 to 9 days), or the chemotactic peptide FMLP (half-maximal responses at 7 to 9 days). The late development of maximal Fc gamma RII responses is not associated with either increased Fc gamma RII expression, enhanced calcium mobilization induced by anti-Fc gamma RII, changes in protein kinase C activity (PKC) or a switch in PKC isotype expression. Activation of the respiratory burst via Fc gamma RII may not be mediated by activation of PKC as the kinase inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride and N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride inhibited the Fc gamma RII response by less than 20% at concentrations which inhibit the 12-O-tetradecanoylphorbol-13-acetate-induced respiratory burst by more than 80%. IFN-gamma U937 cells did not metabolize incorporated arachidonate into eicosanoids when stimulated with anti-Fc gamma RII, suggesting that eicosanoids do not mediate activation of the respiratory burst, and this was confirmed by the lack of inhibition by the specific 5'-lipoxygenase and glutathione S-transferase inhibitor, piriprost, and the cyclo-oxygenase inhibitor, indomethacin. In addition there was no significant release of radiolabeled arachidonate in response to anti-Fc gamma RII. The response to anti-Fc gamma RII is inhibited by pertussis toxin, suggesting that signal transduction is via a GTP-binding protein. Agents that elevate intracellular cAMP increased the magnitude of the cAMP transients stimulated by anti-Fc gamma RII and also inhibited the respiratory burst. FMLP responses showed a similar pattern of sensitivity to this range of inhibitors, suggesting that both Fc gamma RII and FMLP receptor share common regulatory mechanisms. However, the termination of the respiratory burst activated via Fc gamma RII and FMLP receptor is independently regulated, in that after FMLP-induced activation there is no subsequent inhibition of the Fc gamma RII-mediated response and vice versa.
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PMID:Differentiation-linked activation of the respiratory burst in a monocytic cell line (U937) via Fc gamma RII. A study of activation pathways and their regulation. 165 5

We have administered the cytokines interleukin 2 (IL-2), alpha-interferon (IFN-alpha), and gamma-interferon (IFN-gamma) to mice and measured the alterations in hepatic drug-metabolizing enzyme activities. For comparative purposes and to understand the mechanism of diphtheria and tetanus toxoids and pertussis (DTP) vaccine-induced inhibition of drug metabolism, we also studied the effects of vaccine administration in mice. The administration of IL-2 alone or in combination with IFN-alpha or IFN-gamma causes dose-dependent increases in hexobarbital-induced sleep times. These increases correlate well with the inhibition of specific microsomal mixed-function oxidase activities. Sublethally irradiated mice and athymic nude mice receiving injections of IL-2 or IL-2 plus IFN-alpha do not show the inhibition of drug metabolism seen in normal mice. However, the inhibition of drug metabolism in DTP vaccine-treated mice was similar in all three groups. These observations indicate a possible role for immune cells (probably T-lymphocytes) in the inhibition of drug metabolism caused by administration of these cytokines, which is different from the inhibition of drug metabolism caused by DTP vaccine.
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PMID:The effects of interleukin 2 and alpha-interferon administration on hepatic drug metabolism in mice. 172 99

These studies were designed to investigate the characteristics of the intracellular second messengers induced by interferons (IFN-alpha/beta and IFN-gamma) after receptor binding. Pretreatment of target cells with V. cholerae toxin, which is Known to activate the GTP-binding stimulatory protein (Gs), potentiated the action of IFN-gamma, but not of IFN-alpha/beta. By contrast, B. pertussis toxin, which is known to act on the GTP-binding inhibitory protein (Gi doesn't affect the action of both IFN) (Gi). Besides this forskolin and PGE1, known to increase intracellular cAMP levels, completely prevented antiviral state induction by IFN-gamma, but had no effects on IFN-alpha/beta. Altogether these results demonstrate that IFN-gamma transduction signal is mediated by a G protein with functional characteristics similar to those of the known Gs protein.
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PMID:[Modulation of the action of interferon-gamma by protein G]. 296 44

Acute experimental allergic encephalomyelitis (EAE) was induced in C57BL/6J and SJL/J mice by injection of isologous spinal cord homogenate given in conjunction with Bordetella pertussis and Freund's adjuvant. SJL/J mice showed a highly aggressive and 100% lethal form of the disease; C57BL/6J mice were much less susceptible as they had low morbidity rates (20 to 40%), low disease scores, and mostly no mortality. Treatment of these low susceptibility mice with neutralizing mAb against IFN-gamma caused an increase in morbidity rates as well as significant mortality (up to 80%). Similar antibody treatment did not affect the course of the disease in the high susceptibility SJL/J mice. However, treatment of these mice with IFN-gamma resulted in reduced morbidity and mortality. A similar but less pronounced inhibition of the disease in SJL/J mice could be obtained by administration of IFN-alpha/beta or by acute infection with lactate dehydrogenase virus. The results indicate that endogenous as well as exogenous IFN can exert a down-regulating effect on the development of EAE. They also indicate that endogenous IFN-gamma is produced during the development of EAE and plays a disease-limiting role.
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PMID:Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma. 312 27

Induction of endogenous tumor necrosis factor (TNF) by administration of Bordetella pertussis vaccine (BPV) as a triggering agent and its therapeutic effect against MM46 carcinoma were investigated in C3H/He mice. Test triggering agents were injected intravenously into mice after intravenous injection of 4-fold dilution of macrophage activating factor (MAF) or 10(4) units of murine interferon-gamma (Mu-IFN-gamma). Then sera were obtained from the mice, and their TNF activities were assayed on L-929 cells by the method of Ruff and Gifford. The triggering activity of BPV was the highest among those of conventional triggers, such as lipopolysaccharide (LPS) of Escherichia coli, and OK-432. The levels of serum TNF activity triggered by BPV (4 X 10(9) cells), LPS of E. coli (3 micrograms) and OK-432 (3 KE) were 5350, 85 and 102 units/ml, respectively. Growth of MM46, a spontaneous mammary carcinoma cell line of C3H/He was observed for 35 days after tumor inoculation and was suppressed significantly by intravenous injection of MAF and BPV (4 X 10(9) cells). On local injection of BPV (2 X 10(9) cells) into murine tumors, complete regression was observed in 67% of the mice tested with or without MAF priming on day 25 after tumor inoculation, and intratumoral TNF activity was observed even in the case of the single injection of BPV.
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PMID:Endogenous tumor necrosis factor induction with Bordetella pertussis vaccine as a triggering agent and its therapeutic effect on MM46 carcinoma-bearing mice. 313 Dec 86

These studies were designed to investigate the characteristics of the intracellular messengers induced by interferons (IFN-alpha/beta and IFN-gamma) after receptor binding. Pretreatment of target cells with V. cholerae toxin, which is known to activate a membrane GTP-binding stimulatory protein (Gs), potentiated the action of IFN-gamma, but not of IFN-alpha/beta. By contrast, B. pertussis toxin, which is known to activate the GTP-binding inhibitory protein (Gi), had no effects on the action of both IFN-alpha/beta and IFN-gamma. Further support to the involvement of G proteins in IFN-gamma transduction signal came from the finding that a non-hydrolizable GTP analog, GTP-gamma-S, enhanced in the presence of phorbol esters (PMA) the antiviral and antiproliferative activity of IFN-gamma, but not of IFN-alpha/beta. On the other hand, forskolin or PGE1, known to increase the intracellular cAMP levels by different metabolic pathways, when added together with IFN-gamma, significantly potentiated its antiviral and antiproliferative activity. Pretreatment of the cultures with the above drugs completely prevented IFN-gamma activity. No effects were observed when forskolin or PGE1 were used with IFN-alpha/beta. Finally, the modulation of IFN-gamma activity by the above drugs was not a consequence of changes in the expression of the specific surface receptors, since [125I]IFN-gamma binding by pretreated target cells was comparable to that of untreated cultures. Altogether these results demonstrate that the IFN-gamma, but not the IFN-alpha/beta, transduction signal is mediated after receptor binding by a G protein with functional characteristics similar to those of the known Gs proteins. Activation of the adenylate cyclase system could be one of the subsequent steps involved in IFN-gamma action.
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PMID:Evidence for a GTP-binding protein involved in interferon-gamma transduction signal. 313 84

Effects of pertussis toxin (PT) on sensitized T-cell populations for delayed-type hypersensitivity (DTH) were examined in mice. DTH was induced by sensitizing mice with ovalbumin (OA) and elicited by injecting OA into the footpad. DTH could be conferred on naive recipient mice by injecting sensitized spleen cells either intravenously into mice or locally into the footpad. When the sensitized mice were given PT at the time of DTH-elicitation, they did not express a high DTH reaction, with the maximum reaction 24 hr after elicitation. When the recipient mice were given PT just before intravenous injection of sensitized spleen cells, DTH was not conferred. In addition, when the sensitized spleen cells were treated with PT in vitro and then transferred intravenously, DTH was not conferred in recipient mice. However, DTH was conferred by local transfer of the sensitized spleen cells even after treatment with PT in vitro. Migration experiments using 51Cr-labeled, sensitized splenic T cells demonstrated that PT treatment of the T-cell population inhibited its accumulation in the DTH reaction site 24 hr after intravenous transfer. On the other hand, experiments on in vitro lymphokine production by the sensitized splenic T cells demonstrated that the PT treatment did not inhibit antigen-dependent production of a macrophage activating factor (MAF). These results suggest that PT suppresses the migration of the sensitized T-cell population from the circulation of the DTH reaction site but not their MAF production. Based on these findings, possible mechanisms by which PT affects DTH are discussed.
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PMID:Effects of pertussis toxin (PT) on T-cell populations sensitized for delayed-type hypersensitivity in mice. 660

On human mature monocytes the immunomodulator IFN-gamma has been shown to down-regulate the receptor for the anaphylatoxic peptide C5a (CD88, C5aR). In this study, we show that in immature myelo-/monoblastic U937, HL60, and MonoMac6 cells, IFN-gamma induces C5aR-ligand binding activity. In U937 cells, this induction cannot be blocked by the protein kinase C inhibitor staurosporine. An increase in free cytosolic Ca2+ upon ligand binding indicates functional coupling of this receptor in U937 and HL-60 cells. G-Proteins involved in this C5a responsiveness after IFN-gamma induction are completely pertussis toxin sensitive. Our data suggest that an additional pertussis toxin-resistant pathway exists in U937 cells after induction by dibutyryl cAMP. However, this is not due to changes in the mRNA level of the pertussis toxin-insensitive G-protein subunit G alpha 16. Induction by dibutyryl cAMP, but not that by IFN-gamma, resulted in C5a-dependent release of N-acetyl-beta-D-glucosaminidase, further highlighting functional differences in the effects of the inducers. Our data show an IFN-gamma-dependent increase in C5aR expression and suggest a maturation-related change in signaling of the C5aR, presumably at the level of receptor coupling.
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PMID:IFN-gamma up-regulates the human C5a receptor (CD88) in myeloblastic U937 cells and related cell lines. 759 3


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