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)

Endothelin-1 (ET-1) and parathyroid hormone (PTH) increase calcium transients in rodent osteoblastic cells. To investigate the role of phospholipase C (PLC) in these hormone-stimulated calcium signals, the effects of U-73122 (1-[6-[[17 beta-3-methoxyestra-1,3,5(10)- trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione), a reported PLC inhibitor, and its inactive analog, U-73343 (1-[6[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]- 1H-pyrrolidine-2,5-dione), were determined. Intracellular calcium transients were measured in UMR-106 cells with the fluorescent indicator fluo-3. In normal calcium containing medium, prior exposure (3 min) to U-73122 inhibited ET-1 and PTH stimulated calcium transients in a dose-dependent (0.2-10 microM) manner with an IC50 of 1.5-1.8 microM. A concentration of 6-8 microM was required for complete inhibition of responses to 100 nM ET-1 or PTH. U-73343 elicited no effects over this concentration range. In cells in which external calcium was reduced to less than 1 microM by the addition of EGTA, ET-1 signals were completely inhibited by 4-6 microM U-73122 and the IC50 was 0.8 microM. In the low external calcium medium, the PTH response was abolished by 2 microM U-73122 (IC50 = 0.5 microM). U-73122, 8 microM, significantly (P < 0.01) inhibited the effect of ET-1 on inositol trisphosphate production at 3 min whereas U-73343 did not. Pertussis toxin (100 ng/ml) likewise significantly inhibited the effect of ET-1 on phosphoinositol turnover as well as on intracellular calcium concentration. In conclusion, the results support the hypothesis that PLC plays a role in the calcium transients elicited by ET-1 and PTH, and that ET-1 transmits its signal in part via a pertussis toxin sensitive G-protein coupled receptor. Furthermore they suggest that U-73122 is useful for investigating PLC-mediated process in osteoblastic cells.
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PMID:U-73122, a phospholipase C antagonist, inhibits effects of endothelin-1 and parathyroid hormone on signal transduction in UMR-106 osteoblastic cells. 780 18

Activation of the complement system plays an important role in the pathogenesis of atherosclerosis. The proinflammatory cytokine interleukin (IL)-6 is potentially involved in the progression of the disease. We therefore investigated whether the terminal complement complex C5b-9 affects IL-6 production from vascular smooth-muscle cells (VSMC) and set out to determine the underlying signal transduction pathway. Stimulation of human VSMC with C5b-9 resulted in an increase of IL-6 transcript and production of IL-6 protein. Pretreatment with pertussis toxin or pyrrolidine dithiocarbamate inhibited complement-dependent IL-6 mRNA expression and IL-6 release, suggesting the involvement of Gi-proteins and nuclear factor-kB (NF-kB). C5b-9 also induced formation of reactive oxygen species, which, along with IL-6 release, was inhibited by the antioxidant N-acetylcysteine. C5b-9 activated the redox-sensitive transcription factors NF-kB and activator protein-1 (AP-1), which were both involved in the induction of IL-6 by C5b-9, as demonstrated by cis element double-stranded (decoy) oligonucleotides (ODN). The results demonstrate that activation of the complement system induces IL-6 release from human VSMC by a Gi-dependent pathway involving the generation of oxidative stressand the activation of the redox sensitive transcription factors NF-kB and AP-1. Our data support a new mechanism for the proatherogenic effect of the terminal complement complex.
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PMID:The terminal complement complex C5b-9 stimulates interleukin-6 production in human smooth muscle cells through activation of transcription factors NF-kappa B and AP-1. 1102 8

In radioligand binding assays, AH-9700 (1-[2-(3,4-dihydro-6,7-dimethyl-2-naphthalenyl)ethyl]pyrrolidine fumarate) had high affinity for sigma receptors and moderate affinity for muscarinic receptors. The affinity of AH-9700 for sigma(1) receptors was significantly reduced in the presence of 5'-guanylyl-imidodiphosphate (GppNHp). In isolated bladder strips of rats, AH-9700 inhibited carbachol-induced contractions. In anesthetized rats, i.v. administration of AH-9700 and typical sigma receptor ligands, (+)-pentazocine and 1,3-di-o-tolylguanidine (DTG), but not oxybutynin, dose-dependently inhibited rhythmic isovolumetric reflex bladder contractions. AH-9700 and oxybutynin suppressed the amplitude of rhythmic bladder contractions. On the other hand, at doses lower than used i.v., the i.c.v. administration of AH-9700 or the sigma receptor ligands inhibited rhythmic bladder contractions without suppressing the amplitude. This inhibitory effect of AH-9700 was markedly reduced by pretreatment with i.c.v. pertussis toxin. These results suggest that AH-9700 exerts a marked anti-micturition reflex effect through central sigma receptors possibly related to pertussis toxin-sensitive Gi/o-proteins and a moderate spasmolytic effect based on its peripheral anti-muscarinic activity.
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PMID:Pharmacological actions of AH-9700 on micturition reflex in anesthetized rats. 1116 28

We reported upregulation of endothelial nitric oxide synthase (eNOS) by PGE(2) in tissues and presence of perinuclear PGE(2) receptors (EP). We presently studied mechanisms by which PGE(2) induces eNOS expression in cerebral microvessel endothelial cells (ECs). 16,16-Dimethyl PGE(2) and selective EP(3) receptor agonist M&B28767 increased eNOS expression in ECs and the NO-dependent vasorelaxant responses induced by substance P on cerebral microvessels. These effects could be prevented by prostaglandin transporter blocker bromcresol green and actinomycin D. EP(3) immunoreactivity was confirmed on plasma and perinuclear membrane of ECs. M&B28767 increased eNOS RNA expression in EC nuclei, and this effect was augmented by overexpression of EP(3) receptors. M&B28767 also induced increased phosphorylation of Erk-1/2 and Akt, as well as changes in membrane potential revealed by the potentiometric fluorescent dye RH421, which were prevented by iberiotoxin; perinuclear K(Ca) channels were detected, and their functionality corroborated by NS1619-induced Ca(2+) signals and nuclear membrane potential changes. Moreover, pertussis toxin, Ca(2+) chelator, and channel blockers EGTA, BAPTA, and SK&F96365, as well as K(Ca) channel blocker iberiotoxin, protein-kinase inhibitors wortmannin and PD 98059, and NF-kappaB inhibitor pyrrolidine dithiocarbamate prevented M&B28767-induced increase in Ca(2+) transients and/or eNOS expression in EC nuclei. We describe for the first time that PGE(2) through its access into cell by prostaglandin transporters induces eNOS expression by activating perinuclear EP(3) receptors coupled to pertussis toxin-sensitive G proteins, a process that depends on nuclear envelope K(Ca) channels, protein kinases, and NF-kappaB; the roles for nuclear EP(3) receptors seem different from those on plasma membrane.
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PMID:Regulation of eNOS expression in brain endothelial cells by perinuclear EP(3) receptors. 1193 36

Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine synthesized by several cell types, e.g., inflammatory cells, such as monocytes, and resident renal cells, such as human tubular epithelial cells (TECs). Besides induction of monocyte recruitment, MCP-1 has been suggested to induce non-leukocytes to produce cytokines and adhesion molecules. Inflammation of the tubulointerstitium is a hallmark of many renal diseases and contributes to progression of renal failure; the purpose therefore of this study was to investigate the influence of MCP-1 on markers of inflammatory activation in human TECs. MCP-1 stimulated interleukin-6 (IL-6) secretion and intercellular adhesion molecule-1 (ICAM-1) synthesis in a time- and dose-dependent manner. In parallel, MCP-1 increased IL-6 and ICAM-1 mRNA expression in human TECs. Pretreatment with pertussis toxin, GF109203X, BAPTA-AM, and pyrrolidine dithiocarbamate inhibited MCP-1-dependent IL-6 and ICAM-1 synthesis, suggesting the involvement of Gi-proteins, protein kinase C, intracellular Ca(2+), and nuclear factor-kappaB (NF-kappaB) in MCP-1 signaling. Using electrophoretic gel mobility shift assay, we observed that MCP-1 stimulated binding activity of NF-kappaB. Binding activity of the activator protein-1 (AP-1), which has been implicated to regulate induction of the IL-6 gene together with NF-kappaB, was also stimulated by MCP-1. In the present experiments, NF-kappaB and AP-1 were involved in the MCP-1-mediated induction of IL-6, as demonstrated by cis element double-stranded (decoy) oligonucleotides (ODN). In contrast to IL-6 release, MCP-1-induced ICAM-1 expression was predominantly dependent on NF-kappaB activation. These results document for the first time that MCP-1 induces an inflammatory response in human TECs. This may be an important new mechanism in the pathogenesis of tubulointerstitial inflammation.
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PMID:MCP-1 induces inflammatory activation of human tubular epithelial cells: involvement of the transcription factors, nuclear factor-kappaB and activating protein-1. 1203 83

Inflammatory response and chemotaxis of vascular wall cells play an important pathogenic role in the development of atherosclerosis. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant for monocytes. Besides the induction of monocyte recruitment, it has been suggested that MCP-1 may directly activate smooth muscle cells. We investigated whether MCP-1 affects the proliferation and cytokine production of human vascular smooth muscle cells (VSMCs) and determined the underlying signal transduction pathways. Stimulation of VSMCs with MCP-1 induced proliferation and resulted in a concentration- and time-dependent release of the proinflammatory cytokine interleukin-6 (IL-6). Pretreatment with pertussis toxin, GF109203X, and pyrrolidine dithiocarbamate inhibited MCP-1-dependent IL-6 release, suggesting the involvement of G(i) proteins, protein kinase C, and nuclear factor-kappaB (NF-kappaB). MCP-1 also induced extracellular signal-regulated kinase, which, along with IL-6 release, was inhibited by pertussis toxin. PD98059 prevented MCP-1-induced extracellular signal-regulated kinase activation and cell proliferation. MCP-1 stimulated the binding activity of NF-kappaB and of activator protein-1 (AP-1). As demonstrated by cis element double-stranded (decoy) oligodeoxynucleotides, NF-kappaB was involved in IL-6 release by MCP-1, whereas proliferation was dependent on AP-1. The results clearly demonstrate that MCP-1 induces differential activation of NF-kappaB and AP-1 in VSMCs. Thus, our data propose a new mechanism for the proatherogenic effect of MCP-1.
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PMID:Monocyte chemoattractant protein-1 induces proliferation and interleukin-6 production in human smooth muscle cells by differential activation of nuclear factor-kappaB and activator protein-1. 1206 98

Previous work has demonstrated that infection of human bronchial epithelial cells by Bordetella pertussis up-regulates intercellular adhesion molecule-1 (ICAM-1) gene and protein expression. It has also been shown that interaction of the Arg-Gly-Asp (RGD) site of filamentous hemagglutinin (FHA) with host cell very late antigen (VLA)-5 (alpha 5 beta 1 integrin) is required for the up-regulation of epithelial ICAM-1 expression, and that pertussis toxin (PT) impairs this response. We therefore examined the molecular mechanisms leading to B. pertussis-induced ICAM-1 up-regulation in BEAS-2B human bronchial epithelial cells. A colorimetric nuclear factor kappa B (NF-kappa B) activation assay demonstrated that NF-kappa B was activated in response to infection of these cells with B. pertussis. This activation occurred in an FHA(RGD)-dependent manner, and was blocked by an antibody against VLA-5, implying that binding of the RGD to VLA-5 integrin is involved in NF-kappa B activation. Western blot analysis revealed that the activation of NF-kappa B by B. pertussis was preceded by degradation of I kappa B alpha, a major cytoplasmic inhibitor of NF-kappa B. Pretreatment of the BEAS-2B cells with the NF-kappa B inhibitors pyrrolidine dithiocarbamate (PDTC), MG-132, and SN50 resulted in a marked decrease in B. pertussis-induced ICAM-1 expression, implying the involvement of NF-kappa B in ICAM-1 expression. Purified PT abrogated both NF-kappa B activation and I kappa B alpha degradation. These results suggest that ligation of VLA-5 integrin by FHA induces RGD-dependent NF-kappa B activation, thus leading to the up-regulation of epithelial ICAM-1 expression, and that a PT-sensitive G protein may be involved in this signaling pathway.
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PMID:Role of nuclear factor-kappa B in the regulation of intercellular adhesion molecule 1 after infection of human bronchial epithelial cells by Bordetella pertussis. 1294 29

Autotaxin, a lysophospholipase D producing lysophosphatidic acid, augments invasive and metastatic potential of tumor cells. Current investigations have focused on understanding the molecular mechanisms by which autotaxin regulates the expression of a major mediator of tumor invasion and metastasis, urokinase-type plasminogen activator (uPA) in human A2058 melanoma cells. Autotaxin induced uPA expression in a dose-dependent manner that was inhibited by pharmacological inhibitors for Gi (pertussis toxin), phosphoinositide 3-kinase (PI3K, LY294002), Akt inhibitor (AktI), proteosome activity and IkappaB phosphorylation (pyrrolidine dithiocarbamate), and by a dominant negative mutant (DN) of Akt. Autotaxin phosphorylated Akt and induced the translocation of nuclear [corrected] factor-kappaB (NF-kappaB) to the nucleus that were inhibited by AktI or by overexpressing DN-Akt. Consistently, green fluorescence protein-tagged p65 of NF-kappaB accumulated in the nucleus by autotaxin that was abrogated when the cells were transfected with DN-Akt. Moreover, autotaxin increased the DNA binding ability of NF-kappaB and promoter activity of uPA. Collectively, these data strongly suggest autotaxin induces uPA expression via the Gi-PI3K-Akt-NF-kappaB signaling pathway that might be critical for autotaxin-induced tumor cell invasion and metastasis.
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PMID:Autotaxin stimulates urokinase-type plasminogen activator expression through phosphoinositide 3-kinase-Akt-nuclear [corrected] factor kappa B signaling cascade in human melanoma cells. 1701 94

As a transmembrane chemokine, CXCL16 has been detected in various tissues and organs under normal and pathological conditions, it also plays an important role in macrophages/dendritic cells (DC) and T cell interactions and trafficking during inflammation and immune responses. LysoPtdOH, a bioactive lipid mediator has been indicated to regulate DC and epithelial functions during wound healing and inflammation responses. However, the direct link of CXCL16 expression with lysoPtdOH has not been established. Using monocyte-derived macrophages/DC (MoDC), we investigated the roles of lysoPtdOH in CXCL16 production and cell surface presentation. We found that macrophages/MoDC constitutively express and secrete CXCL16, lysoPtdOH significantly enhanced CXCL16 protein production stimulated with lipopolysaccharide (LPS) by more than twofold, which was reflected by increased mRNA transcription by 64-fold. Production of CXCL16 increased by lysoPtdOH and LPS from macrophages was inhibited around 70% by Pertussis toxin (G(i/o) specific inhibitor), exoC3 (Rho specific inhibitor), and pyrrolidine dithiocarbamate (the NF-kappaB-dependent pathway inhibitor) separately. LysoPtdOH treatment increased macrophages' chemotactic activity to activated T cells. The soluble form of CXCL16 produced by macrophages/MoDC was functionally chemoattractive to T cells.
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PMID:LysoPtdOH enhances CXCL16 production stimulated by LPS from macrophages and regulates T cell migration. 1883 Jul 32

Neurodegenerative and neuroinflammatory disorders are commonly associated with local chemokine release. In other way, emerging data indicate that the prostaglandin E2 (PGE(2)), one of the major prostaglandins produced in the brain, play a central role in several pathological diseases. In this study, we investigated the relationship between CXCL12, cyclooxygenase (COX)-2 and PGE(2) in human brain cells. CXCL12 induced COX-2 and secretion of PGE(2) in a dose-dependent manner in human astrocytes. This induction was abolished by treatment with pertussis toxin and AMD3100, confirming the role of CXCR4 signaling. The nuclear factor-kappaB involvement was confirmed by using pyrrolidine dithiocarbamate, and with transient transfection assays. Over-expression of inhibitory proteins of nuclear factor-kappaB abrogated COX-2 induction, and CXCL12 induced p65/relA translocation. Culture supernatants from CXCL12-treated astrocytes reduced viability of neuroblastoma cells, and COX inhibitors abrogated this toxicity. Therefore, the relationship between chemokines and PGs could differentially influence the pathogenic network responsible for neurodegeneration.
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PMID:Nuclear factor-kappaB activation regulates cyclooxygenase-2 induction in human astrocytes in response to CXCL12: role in neuronal toxicity. 2018 Aug 83


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