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)

Transmembrane signalling mechanisms of tumor necrosis factor alpha (TNF alpha) were examined with special reference to the involvement of G-protein, in intact and permeabilized murine osteoblast-like cells. TNF alpha stimulated the release of 3H radioactivity from intact cells labeled with [3H]arachidonic acid within 10 min in a dose dependent manner and the production of lyso forms of phospholipids, an event presumably mediated through the activation of phospholipase A2. Production of cAMP and inositol 1,4,5-trisphosphate was not affected by TNF alpha. Pretreatment of the cells with pertussis toxin inhibited the liberation of [3H]arachidonate. GTP gamma S (guanosine 5'-3-O-(thio)triphosphate) reduced the binding affinity of [125I]TNF alpha to beta-escin-permeabilized cells. The addition of TNF alpha together with an unhydrolyzable analog of GTP, GTP gamma S, to the beta-escin-permeabilized cells prelabeled with [3H]arachidonic acid led to a release of the 3H radioactivity. The production of prostaglandin E2 (PGE2) was markedly stimulated by TNF alpha in a dose over 100 ng/ml, with a latent time of about 3 h, and the stimulation was abolished by pretreatment with pertussis toxin. The time and dose requirements for this process differed from those for the possible activation of phospholipase A2, thereby indicating that other process(es) in addition to the activation of phospholipase A2 may be responsible for the enhanced production of PGE2. The activity of cyclooxygenase (i.e. the combined activities of prostaglandin endoperoxide syntase and PGH2-PGE2 isomerase) was stimulated by TNF alpha with much the same time and dose requirements as for the production of PGE2, and the activation was found to be due to the increased amount of the enzyme, as assessed by a Western blot analysis with anti-cyclooxygenase antibody. This process was also sensitive to pertussis toxin. Therefore, receptors for TNF alpha in MC3T3-E1 cells apparently couple to G-protein sensitive to pertussis toxin and the coupling regulates the activations of phospholipase A2 and the de novo synthesis of cyclooxygenase.
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PMID:Signal transduction by tumor necrosis factor alpha is mediated through a guanine nucleotide-binding protein in osteoblast-like cell line, MC3T3-E1. 137 94

Thromboxane (Tx) A2 is a product of cyclooxygenase catalyzed metabolism of arachidonic acid. It is formed via prostaglandin (PG) endoperoxide intermediates (PGG2 and PGH2) by a specific synthase. PGH2 appears to exert the same biologic effects as TxA2. The cDNA for a TxA2 receptor has been cloned from a human placental library. Although pharmacologic and biochemical studies suggest the presence of multiple isoforms, this remains to be confirmed at the molecular level. A hydropathy plot of the deduced amino acid sequence of the available clone suggests that it has 7 transmembrane spanning domains, typical of a G protein linked receptor. Pharmacologic studies imply that Tx receptors in platelets are linked to phospholipase C activation via pertussis toxin insensitive G proteins. Candidates include the 42 kD Gq and the 60 kD Ge. TxA2 acts as an amplifying signal for platelet agonists and the response to this eicosanoid is tightly regulated. Mechanisms include rapid hydrolysis of the agonist to the inactive TxB2, autoinactivation of Tx synthase, rapid homologous TxA2 receptor desensitization due to receptor-G protein uncoupling, coincidental sensitization to counterregulatory Gs linked receptor systems and stimulation of prostacyclin formation by TxA2. Due to its role as an amplification signal in platelet activation, inhibition of Tx synthesis and action is an effective mechanism for preventing platelet-dependent vascular occlusion. Aspirin is of proven efficacy in this regard. Tx synthase inhibitors and antagonists are under clinical investigation.
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PMID:Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists. 189 57

The present study and the previous report (6) show that the cyclooxygenase path is a primary route of metabolism of arachidonic acid in FRTL-5 rat thyroid cells. The production of PGD2 and PGE2 is an active process in intact cells treated with complete medium including TSH, insulin and 5% calf serum. In contrast, PGF2 alpha and HHT are probably nonenzymatic degradation products of an unstable intermediate, PGH2, since the two compounds are produced and occupy a significant proportion of the cyclooxygenase metabolites only in the homogenate system; this is true in other cells. Although the production of prostaglandins involves three steps, i.e. the release of free arachidonic acid, the production of PGH2 by PGH synthase (cyclooxygenase) and the conversion of PGH2 to various prostaglandins by specific isomerases or synthetases, the first step, the release of free arachidonic acid, has been, until recently, believed to be the sole step important for the regulation of prostaglandin synthesis. This presumption rested on the following observations. Only the free form of arachidonic acid is converted to prostaglandins and the intracellular free arachidonic acid pool is very small compared to the esterified form in phospholipids. The size of the free arachidonic acid pool is regulated by the balance between release from phospholipids by phospholipases and reacylation into phospholipids. When resting cells are stimulated, the release of arachidonic acid and the production of prostaglandins increase concomitantly. The present study shows, however, that all three steps of prostaglandin synthesis are under regulatory control in FRTL-5 rat thyroid cells and that the control is a complex process involving TSH, insulin/IGF-I, and serum. The first step is primarily under the control of TSH. TSH increases the synthesis of arachidonic acid and also, like norepinephrine (5, 6) induces the release of arachidonic acid from the cell by a mechanism involving a pertussis toxin-sensitive G protein. Regulation of the second step can be estimated by measuring cyclooxygenase activity. The present report shows that TSH increases cyclooxygenase activity, presumably by increasing gene expression, but that the TSH effect on cyclooxygenase activity requires insulin/IGF-I or serum. This result is similar to studies showing the effect of TSH and insulin/IGF-I on glycosaminoglycan synthesis, thyroglobulin synthesis, and growth in FRTL-5 thyroid cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The arachidonic acid signal system in the thyroid: regulation by thyrotropin and insulin/IGF-I. 251 71

Thromboxane A2 (TXA2), the major cyclooxygenase (COX) product of arachidonic acid (AA), activates platelets and is a potent vasoconstrictor. The functional importance of this eicosanoid has been demonstrated in syndromes of acute coronary ischaemia. The cellular response to this agonist is tightly regulated. The liberation of AA from membrane phospholipids is conventionally thought to be the rate limiting step in TXA2 biosynthesis. However, the discovery of a second, highly regulated COX gene (COX-2) and the demonstration of product-based inactivation of COX and thromboxane synthase suggest a more complex regulation of TXA2 formation. TXA2 signalling is mediated by a G-protein linked receptor (PGH2/TXA2 receptor) which activates phospholipase C (PLC). Pharmacological studies suggest two distinct binding sites on platelets, but receptor heterogeneity has yet to be documented at a molecular level. The PGH2/TXA2 receptors are linked via a pertussis and cholera toxin-insensitive G-protein which has not been fully characterized, but is thought to belong to the Gq class of G-proteins. The diversity of G-protein alpha subunits, and growing evidence suggesting functional roles for the beta-gamma subunit, support a possible dual signalling mechanism of cellular activation. This may be of particular importance in regulating the response to eicosanoids with contrasting actions. A receptor for prostacyclin (PGI2) has not yet been cloned but biochemical studies suggest that it is linked to the activation of adenylate cyclase via Gs. At least three distinct prostaglandin E receptors have been identified. Desensitization of the cellular responses to the activation of TXA2, PGI2 and PGE receptors have been demonstrated and potential phosphorylation sites in their COOH terminal ends may be important in mediating this effect.
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PMID:Cellular activation by thromboxane A2 and other eicosanoids. 813 96

Treatment of cells with LPS-free oxLDL significantly enhanced protein kinase C (PKC) activity in cell extracts from P388D1 macrophage-like cells as determined by phosphorylation of histone H1 or Ac-MBP[4-14] substrate peptide. This effect was abolished by the PKC inhibitors H-7 and bisindolylmaleimide I while pertussis toxin failed to block stimulation. The phosphotransferase activity was also increased by acetylated LDL (acLDL) and maleylated albumin (malBSA), the oxLDL effect was inhibited by chloroquine which also blocked oxLDL-induced stimulation of tyrosine kinase activity. Marginal stimulation of PKC activity was observed when lipid extracts from oxLDL were used, indicating that uptake via scavenger receptors (SR) is mandatory. Polyinosinic acid (poly I) exhibited a concentration-dependent inhibition of the oxLDL-induced effect suggesting that SR II/I but not CD36 interactions are critical to PKC activation. Modified (lipo)proteins increased the concentration of diacylglycerol and differentially affected the levels of individual PKC isoenzymes predominantly in the cytosolic fraction. Changes of activity induced by oxLDL could be primarily assigned to alterations of the activities and levels of the isoenzymes beta and delta. Treatment with oxLDL, acLDL, and malBSA was also accompanied by increased production of prostaglandins as well as by an enhanced level of cyclooxygenase 2 (COX 2) as determined by Western blot analysis. Effects (correction) of oxLDL on PKC activity/expression was suppressed by the cyclooxygenase, 2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,2-dihydro-1H-pyrrolizine-5- ylacetic acid (ML 3000), and by treatment with the specific COX 2-inhibitor N-(2-cyclohexyloxy-4-nitrophenyl) methane-sulfonamide (NS-398). These results indicate that oxLDL, acLDL, and malBSA exhibit a COX 2-dependent and isotype specific effect on PKC in P388D1 cells following uptake via SR II/I and subsequent lysosomal degradation.
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PMID:Oxidized low-density lipoprotein stimulates protein kinase C (PKC) and induces expression of PKC-isotypes via prostaglandin-H-synthase in P388D1 macrophage-like cells. 866 83

5-Hydroxytryptamine (5-HT, 'serotonin') is a potent inducer of the early response gene cyclo-oxygenase 2 (Cox-2; prostaglandin G/H synthase) in mesangial cells. Protein kinase C (PKC), Ca2+-dependent enzymes and mitogen-activated protein kinase (p42/44 MAPK) have previously been shown to be essential modules of the signalling pathway leading from the pertussis-insensitive 5-HT2A receptor to the induction of Cox-2 mRNA expression. In the present study, PKC activation was linked to the 5-HT-mediated phosphorylation and thus the activation of p42/44 MAPK: the inhibition of PKC by the specific inhibitor GF109203x prevented p42/44 MAPK activation. Ca2+/calmodulin-dependent (CaM) kinase II delta2 was detected in mesangial cells by Western blot analysis. The inhibition of CaM kinase by the inhibitors KN62 or KN93 led to a partial inhibition of 5-HT-induced Cox-2 mRNA expression and decreased basal, but not PMA-mediated, Cox-2 expression. The 5-HT-mediated activation of MAPK was not decreased by KN62 or KN93, excluding CaM kinase as a signalling module upstream of p42/44 MAPK. Taken together, these results indicate a modulatory involvement of CaM kinase in the regulation of 5-HT-mediated Cox-2 mRNA expression in addition to the main pathway that consists of the activation of PKC and p42/44 MAPK.
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PMID:Independent regulation of cyclo-oxygenase 2 expression by p42/44 mitogen-activated protein kinases and Ca2+/calmodulin-dependent kinase. 1019 Dec 63

Transforming growth factor beta 1 (TGF-beta1) affects growth plate chondrocytes through Smad-mediated mechanisms and has been shown to increase protein kinase C (PKC). This study determined if PKC mediates the physiological response of rat costochondral growth zone (GC) chondrocytes to TGF-beta1; if the physiological response occurs via type II or type III TGF-beta receptors, and, if so, which receptor mediates the increase in PKC; and the signal transduction pathways involved. Treatment of confluent GC cells with TGF-beta1 stimulated [(3)H]thymidine and [(35)S]sulfate incorporation as well as alkaline phosphatase (ALPase) and PKC specific activities. Inhibition of PKC with chelerythrine, staurosporine, or H-7 caused a dose-dependent decrease in these parameters, indicating that PKC signaling was involved. TGF-beta1-dependent PKC and the physiological response of GC cells to TGF-beta1 was reversed by anti-type II TGF-beta receptor antibody and soluble type II TGF-beta receptor, showing that TGF-beta1 mediates these effects through the type II receptor. The increase in [3H]thymidine incorporation and ALPase specific activity were also regulated by protein kinase A (PKA) signaling, since the effects of TGF-beta1 were partially blocked by the PKA inhibitor H-8. The mechanism of TGF-beta1 activation of PKC is through phospholipase A(2) (PLA(2)) and not through phospholipase C (PLC). Arachidonic acid increased PKC in control cultures and was additive with TGF-beta1. Prostanoids are required, as indomethacin blocked the effect of TGF-beta1, and Cox-1, but not Cox-2, is involved. TGF-beta1 stimulates prostaglandin E(2) (PGE(2)) production and exogenous PGE(2) stimulates PKC, but not as much as TGF-beta1, suggesting that PGE(2) is not sufficient for all of the prostaglandin effect. In contrast, TGF-beta1 was not regulated by diacylglycerol; neither dioctanoylglycerol (DOG) nor inhibition of diacylglycerol kinase with R59022 had an effect. G-proteins mediate TGF-beta1 signaling at different levels in the cascade. TGF-beta1-dependent increases in PGE(2) levels and PKC were augmented by the G protein activator GTP gamma S, whereas inhibition of G-protein activity via GDP beta S, pertussis toxin, or cholera toxin blocked stimulation of PKC by TGF-beta1, indicating that both G(i) and G(s) are involved. Inhibition of PKA with H-8 partially blocked TGF-beta1-dependent PKC, suggesting that PKA inhibition on the physiological response was via PKA regulation of PKC signaling. This indicates that multiple interacting signaling pathways are involved: TGF-beta1 stimulates PLA(2) and prostaglandin release via the action of Cox-1 on arachidonic acid. PGE(2) activates the EP2 receptor, leading to G-protein-dependent activation of PKA. PKA signaling results in increased PKC activity and PKC signaling regulates proliferation, differentiation, and matrix synthesis.
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PMID:Transforming growth factor-beta1 regulation of growth zone chondrocytes is mediated by multiple interacting pathways. 1206 64

Postoperative ileus, a major cause of morbidity after abdominal surgery, is characterized by intestinal dysmotility and inflammation. The aim was to investigate the involvement of sphingolipids in postoperative intestinal inflammation using a standardized rat model of intestinal surgical manipulation. Sphingolipid analysis (ESI-MS) of intestinal muscularis after manipulation revealed a time-dependent increase of sphingosine 1-phosphate (S1P) and of ceramide 1-phosphate (C1P). We therefore established a culture system of primary rat intestinal smooth muscle cells and examined the potential role of these sphingolipids in intestinal inflammation. Incubation of cells with either of the two sphingolipid-phosphates resulted in an elevated production of PGE(2). Further analysis revealed that S1P enhances cyclooxygenase 2 (COX-2) expression whereas C1P increases release of arachidonic acid, indicating an enhanced phospholipase A(2) activity. S1P-induced COX-2 expression was pertussis toxin sensitive, suggesting the involvement of Gi/o protein-coupled S1P receptors. Further downstream mediators of S1P induced COX-2 expression appear to be extracellular regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). Collectively, our results demonstrate that intestinal smooth muscle cells represent a major target for both C1P and S1P activity. Thus, the sustained elevated concentration of the two bioactive sphingolipids in this tissue could at least in part explain postoperative intestinal dysmotility.
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PMID:Effects of sphingosine-1-phosphate and ceramide-1-phosphate on rat intestinal smooth muscle cells: implications for postoperative ileus. 1687 27

Adrenomedullin (ADM) is upregulated in cardiac tissue under various pathophysiological conditions, particularly in septic shock. The intracellular mechanisms involved in the effect of ADM on adult rat ventricular myocytes are still to be elucidated. Ventricular myocytes were isolated from adult rats 4 h after an intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Membrane potential and L-type calcium current (I(Ca,L)) were determined using whole cell patch-clamp methods. APD in LPS group was significantly shorter than control values (time to 50% repolarization: LPS, 169 +/- 2 ms; control, 257 +/- 2 ms, P < 0.05; time to 90% repolarization: LPS, 220 +/- 2 ms; control, 305 +/- 2 ms, P < 0.05). I(Ca,L) density was significantly reduced in myocytes from the LPS group (-3.2 +/- 0.8 pA/pF) compared with that of control myocytes (-6.7 +/- 0.3 pA/pF, P < 0.05). The ADM antagonist ADM-(22-52) reversed the shortened APD and abolished the reduction of I(Ca,L) in shock myocytes. In myocytes from control rats, incubating with ADM for 1 h induced a marked decrease in peak I(Ca,L) density. This effect was reversed by ADM-(22-52). The G(i) protein inhibitor, pertussis toxin (PTX), the protein kinase A (PKA) inhibitor, KT-5720, and the specific cyclooxygenase 2 (COX-2) inhibitor, nimesulide, reversed the LPS-induced reduction in peak I(Ca,L). The results suggest a COX-2-involved PKA-dependent switch from G(s) coupled to PTX-sensitive G(i) coupling by ADM in adult rat ventricular myocytes. The present study delineates the intracellular pathways involved in ADM-mediated effects on I(Ca,L) in adult rat ventricular myocytes and also suggests a role of ADM in sepsis.
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PMID:The effect of adrenomedullin on the L-type calcium current in myocytes from septic shock rats: signaling pathway. 1776 82

Bordetella pertussis causes a profound inflammatory response in lungs of infected individuals. The adenylate cyclase toxin (ACT) of B. pertussis is a potent enzyme that converts cytosolic ATP into cAMP, and is required for virulence in vivo. During infection, secreted ACT binds to macrophages utilizing the beta2 integrin, Mac-1 (CR3, CD11b/CD18), and subsequent intoxication by ACT inhibits essential antibacterial activities of macrophages. Additionally, Mac-1 has been reported to be a co-receptor for TLR4 required for the full induction of some LPS-responsive genes, including pro-inflammatory cyclooxygenase 2 (COX-2). We have examined the effect of ACT on COX-2 expression in HEK293T cells expressing Mac-1 and in murine macrophages. We report that ACT induces COX-2 in a manner that absolutely requires the catalytic activity of this enzyme and Mac-1 expression dramatically enhanced the sensitivity of cells to ACT-dependent COX-2 induction. The mechanism of COX-2 induction by ACT utilizes the cAMP-PKA-CREB-dependent pathway. Finally, ACT and TLR2 or TLR4 act synergistically to increase COX-2 expression. These data suggest that ACT contributes significantly to the inflammatory response induced by B. pertussis infection by augmenting COX-2 expression and provides evidence against the concept that ACT functions exclusively via its inhibitory effects on phagocytic leucocytes.
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PMID:Bordetella pertussis adenylate cyclase toxin (ACT) induces cyclooxygenase-2 (COX-2) in murine macrophages and is facilitated by ACT interaction with CD11b/CD18 (Mac-1). 1792 97


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