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)

Human monocytes use the products of phosphoinositide hydrolysis (1,2-diacylglycerol and inositol 1,4,5-triphosphate) as second messengers to trigger rapid cellular activation during the occupancy of chemoattractant receptors. The effect of chemoattractants on modulation of gene expression in monocytes was examined in this study. The chemoattractants FMLP and platelet-activating factor induced the progressive increase of c-fos RNA to 6-15-fold over those of control within 30 min after treatment. Similar kinetics of c-fos gene activation was also observed when cells were treated with PMA or sn-1,2-dioctanoylglycerol, but not with the calcium mobilizer ionomycin, suggesting a role for protein kinase C in gene regulation by chemoattractant receptors. Activation of c-fos gene expression by FMLP is mediated through a pertussis toxin-sensitive G protein, since pertussis toxin treatment of the cells blocked the induction of the c-fos gene by FMLP but not PMA. The level of c-myc RNA was slightly decreased after 1 h of treatment with chemoattractants, but not with PMA or diacylglycerol. This implies that chemoattractant receptor occupancy generates signals beyond protein kinase C activation that are capable of selectively downregulating monocyte gene expression. The effect of FMLP and PMA on the accumulation of c-fos RNA appears to result from altering both the rate of transcription and message stability. These observations indicate that signals generated through chemoattractant receptor occupancy may regulate monocyte function at the genetic level.
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PMID:Chemoattractant-induced activation of c-fos gene expression in human monocytes. 310 44

Addition of fluoroaluminate to human platelet suspension stimulated thromboxane synthesis and inositol-1,4,5-triphosphate formation in a time and dose dependent manner. Neomycin inhibited markedly fluoroaluminate induced inositol-1,4,5-triphosphate formation without significantly affecting thromboxane synthesis. Preincubation of platelets with PGE1, also inhibited significantly inositol-1,4,5-triphosphate formation with modest reduction of thromboxane synthesis. On the contrary, pretreatment of platelets with pertussis toxin inhibited fluoroaluminate stimulated thromboxane synthesis without affecting inositol-1,4,5-triphosphate formation. Similarly, preincubation of platelets with phorbol ester, PMA, inhibited markedly thromboxane synthesis with modest reduction of inositol-1,4,5-triphosphate formation. These results indicate that inositol-1,4,5-triphosphate formation and arachidonate release and thromboxane synthesis are controlled separately and are mediated by different G-proteins which are coupled to phospholipase C and phospholipase A2 respectively in platelets.
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PMID:Stimulations of arachidonate release and inositol-1,4,5-triphosphate formation are mediated by distinct G-proteins in human platelets. 311 25

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

The insulin secreting rat Rinm5F cells are often used to study the cytotoxic actions of interleukin-1 (IL-1) on pancreatic beta-cells. We demonstrate here that Rinm5F insulinoma cells express both type I and type II interleukin-1 receptor (IL-1R) mRNAs and gene products. IL-1R agonists, recombinant murine IL-1 alpha (rmIL-1 alpha, 10 ng/ml) and recombinant rat IL-1 beta (rrIL-1 beta, 100 pg/ml or 10 ng/ml) induce the upregulation of mRNA expression for both types of IL-1 receptors (IL-1Rs). This effect of rrIL-1 beta is antagonised by preincubation with recombinant human interleukin 1 receptor antagonist protein (rhIL-1ra, 5 micrograms/ml). Furthermore, this rrIL-1 beta induced upregulation of IL-1R mRNAs is blocked by actinomycin D (7.5 micrograms/ml), whereas cycloheximide (20 micrograms/ml) has no effect. The phorbol ester PMA (20 nM) upregulates the expression of mRNAs both IL-1 receptors, whereas glucose (50 mM) upregulates the expression of the type I IL-1R mRNA only. Pretreatment of cells with pertussis toxin (100 ng/ml) partially blocks the rrIL-1 beta induced expression of mRNA for the type I and, to a lesser extent, the type II IL-1R. Incubation of the cells with rrIL-1 beta also induces a time-dependent expression of c-fos, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) mRNAs. Binding studies with 125I-recombinant human IL-1 beta (125I-rhIL-1 beta) indicate that IL-1R gene products, with the ligand binding characteristics of the type I IL-1R, are constitutively present on Rinm5F cells. Treatment with rrIL-1 beta (6h) increases the number of 125I-rhIL-1 beta binding sites on Rinm5F cells. We have also demonstrated that the number of type II IL-1R binding sites increases after induction with rrIL-1 beta (6h), by indirect immunofluorescence using a monoclonal antibody (ALVA 42) raised against the human type II IL-1R. Furthermore, we have sequenced the type II IL-1R cDNA in the rat insulinoma Rinm5F cells. The comparison of the amino acid sequence of the rat type II IL-1R with that of the mouse and human type II IL-1Rs shows 90% and 62% amino acid identity, respectively. The most important difference between the human and murine type II IL-1Rs, and this rat type II IL-1R cDNA, is an open reading frame coding for a six amino acid longer, strongly charged (QIKEMK), cytosolic domain.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Interleukin-1 stimulates the expression of type I and type II interleukin-1 receptors in the rat insulinoma cell line Rinm5F; sequencing a rat type II interleukin-1 receptor cDNA. 752 17

alpha-Adrenergic stimulation is known to play a role in cardiac arrhythmogenesis and to modulate a variety of cardiac K+ currents. The effects of alpha-adrenergic stimulation on Cl- currents are largely unknown. Many cardiac cell types show a volume-sensitive Cl- current induced by cell swelling (ICl.swell). The present experiments were designed to assess the potential alpha-adrenergic modulation of ICl.swell in rabbit atrial myocytes. ICl.swell was induced with the use of a hypotonic superfusate, under conditions designed to prevent currents carried by K+, Na+, and Ca2+ ions. A basal Cl- current (ICl.b) was observed under isotonic conditions in 128 of 150 cells (85%), had the same dependency on [Cl-]o as ICl.swell, and was reduced by cell shrinkage induced by hypertonic superfusion, suggesting that ICl.b is carried by the same volume-sensitive Cl- conductance as ICl.swell. Phenylephrine produced a concentration-dependent and near-complete inhibition of ICl.b and ICl.swell, with EC50 values of 86 +/- 5 and 72 +/- 7 (mean +/- SEM) mumol/L, respectively, at +20 mV. Norepinephrine (administered in the presence of 1 mumol/L propranolol) also inhibited ICl.b and ICl.swell, with EC50 values of 2.6 +/- 0.1 and 2.8 +/- 0.4 mumol/L, respectively. The concentration-response curve for phenylephrine was shifted significantly (P < .001) to the right by the alpha 1-adrenoceptor antagonist prazosin and by the alpha 1A-receptor antagonists (+)-niguldipine and 5-methylurapidil but was unaltered by the alpha 1B-receptor antagonist chloroethylclonidine (100 mumol/L). Inhibition of protein kinase C (PKC) with staurosporine, H-7, or 18-hour preincubation with the phorbol ester 4 beta-phorbol 12-myristate 13-acetate (PMA, 500 nmol/L) blocked the effects of phenylephrine on ICl.swell, and the highly selective PKC inhibitor bisindolylmaleimide blocked the effects of norepinephrine on ICl.swell and ICl.b. Both PMA and 1-oleoyl-2-acetylglycerol inhibited ICl.swell in a concentration-dependent fashion. In blinded studies, the phorbol ester phorbol 12,13-didecanoate (PDD) reduced ICl.swell by 91 +/- 3%; its inactive analogue 4 alpha-PDD had no effect (mean change, 3 +/- 1%). Preincubation with pertussis toxin (PTX) prevented the actions of phenylephrine on ICl.swell, indicating a role for a PTX-sensitive guanine nucleotide-binding (G) protein. We conclude that alpha-adrenergic agonists inhibit volume-sensitive Cl- currents in rabbit atrial cells by interacting with an alpha 1A-adrenoceptor mechanism that is coupled to PKC via a PTX-sensitive G protein.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alpha-adrenergic control of volume-regulated Cl- currents in rabbit atrial myocytes. Characterization of a novel ionic regulatory mechanism. 754 83

We reassessed the involvement of Bordetella pertussis toxin (PTX)-sensitive proteins in the IL-1 signaling pathway on the responses induced by IL-1 on the murine thymoma cell line EL4 6.1. We demonstrate that the ADP-ribosyltransferase activity of PTX, and not its cell-anchoring B oligomer part, is responsible for the inhibition of IL-1-induced IL-2 release, since 1) the concentration of PTX (< or = 1 ng/ml) required to block the secretion is 100 to 1000 times lower than the concentration needed with the B oligomer; and 2) the mutated PT-9K/129G, devoid of ADP-ribosyltransferase activity, was inactive at 100 ng/ml. We found that partial ADP-ribosylation of the Gi2/Gi3 proteins before stimulation with IL-1 was sufficient to obtain full inhibition of IL-2 release. PTX did not however inhibit the appearance on the cell surface of the high affinity IL-2 receptors or the IL-2 release induced by PMA. In addition, we show that PTX prevented the expression of the IL-2 mRNA induced by IL-1, without affecting the binding of IL-2 specific nuclear factors to the T cell distal element of the IL-2 promoter. Furthermore, PTX also inhibited IL-1-induced proliferation of non-transformed thymocytes. In conclusion, our results demonstrate that IL-1-induced IL-2 release is sensitive to PTX-catalyzed ADP-ribosylation and that IL-1 activates a diverging pathway on EL4 6.1 cells.
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PMID:IL-1 stimulates a diverging signaling pathway in EL4 6.1 thymoma cells. IL-2 release, but not IL-2 receptor expression, is sensitive to pertussis toxin. 760 94

Degranulation of eosinophils and release of toxic granule proteins play key roles in allergic diseases such as bronchial asthma. However, the intracellular signaling mechanisms that trigger eosinophil degranulation remain unclear. In this study, we investigated protein tyrosine kinase (PTK) involvement in the degranulation of human blood eosinophils induced by immobilized Ig. Eosinophils stimulated with Sepharose beads coated with secretory IgA (slgA) or IgG showed rapid increases in the tyrosine phosphorylation of intracellular proteins with molecular masses of 50 to 56, 73, 78, 100, and 105 kDa. The Ig-induced phosphorylation response was not affected by pertussis toxin, a known inhibitor of Ig-dependent eosinophil activation. The tyrosine kinase inhibitors genistein and herbimycin A inhibited both the tyrosine phosphorylation and degranulation responses of eosinophils induced by sIgA- or IgG-coated beads. In contrast, eosinophil degranulation induced by PMA was not affected by genistein. Treatment of eosinophils with the protein phosphatase inhibitor pervanadate induced the phosphorylation of a similar set of intracellular proteins as well as cellular degranulation. Pervanadate also stimulated an increase in phosphoinositide hydrolysis, which was consistent with the activation of a phospholipase C-gamma isoform by this stimulus. Genistein pretreatment blocked the Ig-induced phospholipase C activation, providing evidence for PTK involvement in this reaction. These findings indicate that a PTK-dependent signaling pathway plays an important role in triggering the degranulation responses of human eosinophils to immobilized sIgA and IgG.
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PMID:Tyrosine phosphorylation is required for eosinophil degranulation induced by immobilized immunoglobulins. 760 11

We have recently identified a novel human B cell differentiation factor, 446-BCDF, derived from anti-CD3-stimulated peripheral blood (PB) T cells. This novel cytokine, which may act through a pertussis toxin-sensitive Gi-linked receptor, induces a 5- to 100-fold increase in immunoglobulin (Ig) secretion by SAC (0.001%, v/v)-activated PB B cells. Coculture of B cells with 446-BCDF induces a decrease in intracellular cAMP which is necessary but not sufficient to drive terminal B cell differentiation. A second signal appears to be required. We therefore measured Ca2+ flux in indo-1 AM-loaded PB B cells. Stimulation with 446-BCDF resulted in an immediate rise in intracellular Ca2+ comparable to that seen with the anti-IgM mAb HB57. Ca2+ appeared to be mobilized from internal stores as pretreatment with BAPTA but not EGTA inhibited the response. Ca2+ mobilization was critical for the induction of differentiation as BAPTA pretreatment of PB B cells completely inhibited Ig secretion without affecting cell viability. In contrast, neither SAC, rIL6, IL2, IFN-gamma, nor IL4 could mobilize Ca2+. Pertussis toxin, a Gi and G0 protein inhibitor, was able to inhibit 446-BCDF-induced Ca2+ flux as well as Ig secretion. To determine whether the Ca2+ flux was generated in the course of inositol phosphate turnover, we measured IP3 turnover and the translocation of PKC from cytosol to membrane. An increase in IP3 comparable to that seen with a monoclonal anti-human IgM antibody was noted and was specifically inhibited by the 446-BCDF-specific mAb 929. Interestingly, no membrane PKC was demonstrable in either SAC- or BCDF-stimulated B cells, although PMA (50 ng/ml) could directly activate PKC. To confirm these findings functionally, B cells were stimulated with SAC and 446-BCDF in the presence of two known PKC inhibitors, staurosporin and calphostin. No inhibition of Ig secretion was detected at any concentration tested (0.39-100 nM staurosporin and 0.0625-1 microM calphostin C). These data suggest that induction of B cell differentiation is a Ca(2+)-dependent and PTX-sensitive event.
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PMID:B cell differentiation factor-induced human B cell maturation: stimulation of intracellular calcium release. 765 31

In the endothelial cell line EAhy 926, 1-oleoyl-lysophosphatidic acid (LPA) stimulated the tyrosine phosphorylation of the pp42 isoform of mitogen-activated protein (MAP) kinase. Maximum phosphorylation was observed within 5 min of LPA addition, but the response was sustained for up to 120 min. Re-addition of LPA after 60 min stimulated a further sustained increase in the tyrosine phosphorylation of MAP kinase. In cells pretreated with phorbol 12-myristate 13-acetate (PMA; 24 h) or preincubated with the protein kinase C inhibitor Ro-318220, LPA-induced tyrosine phosphorylation of pp42 MAP kinase was substantially reduced at 2 min but potentiated at 60 min. Ro-318220 in combination with either PMA or pertussis toxin pretreatment abolished the LPA response at all time points, suggesting an involvement of protein kinase C in the pertussis toxin-sensitive part of the pathway. Agents which raised intracellular cyclic AMP levels did not affect the initial phase of LPA-stimulated MAP kinase activation, but abolished the late phase. However, this effect was prevented by Ro-318220, implicating a greater role for protein kinase C than protein kinase A in the regulation of sustained MAP kinase responses. LPA stimulated an increase in the tyrosine phosphorylation of focal adhesion kinase pp125 (pp125FAK) in EAhy 926 cells which was both protein kinase C- and pertussis toxin-independent. These results are discussed in terms of the pathways regulating both MAP kinase and pp125FAK in response to LPA in the EAhy 926 endothelial cells line.
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PMID:Regulation of lysophosphatidic acid-stimulated tyrosine phosphorylation of mitogen-activated protein kinase by protein kinase C- and pertussis toxin-dependent pathways in the endothelial cell line EAhy 926. 774 5

The hypothesis that carboxylmethylation of gamma subunits plays a role in G protein activation was tested by examining the ability of N-acetyl-S-farnesyl-L-cysteine (AFC) and its methyl ester (AFC-ME) to inhibit G protein-mediated signalling in intact HL-60 granulocytes and isolated HL-60 plasma membranes. Incubation of HL-60 granulocytes with AFC or AFC-ME inhibited superoxide release stimulated by fMet-Leu-Phe, but not by opsonized bacteria. AFC-ME, but not AFC, inhibited NaF- and PMA-stimulated superoxide release. Addition of AFC to HL-60 membranes inhibited fMet-Leu-Phe-, leukotriene B4- (LTB4) and C5a-stimulated GTP gamma S binding and GTP hydrolysis more potently than it inhibited basal guanine nucleotide exchange. AFC-ME inhibited basal- and ligand-stimulated G protein activation with equal potency, but less potently than AFC. AFC also inhibited mastoparan-stimulated GTP gamma S binding. Binding of fMet-Leu-Phe and LTB4 to HL-60 membranes was completely inhibited by AFC, while AFC-ME inhibited ligand binding by less than 50%. Neither AFC nor AFC-ME inhibited pertussis toxin or cholera toxin-catalysed ADP-ribosylation of alpha i. It was concluded that AFC interrupts signal propagation in G protein-dependent pathways by multiple mechanisms, including inhibition of ligand-receptor interactions, of receptor-G protein coupling and of guanine nucleotide binding to G proteins. Carboxylmethylation alters the specificity of AFC interruption of signal propagation in intact cells and isolated membranes.
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PMID:Effect of prenylcysteine analogues on chemoattractant receptor-mediated G protein activation. 781 93


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