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)

Cultured mouse astrocytes respond to the CC chemokine RANTES by production of chemokine and cytokine transcripts. Stimulation of astrocytes with 1 nM RANTES or 3-10 nM of the structurally related chemokines (eotaxin, macrophage inflammatory protein-1alpha and -beta [MIP-1alpha, MIP-1beta]) induced transcripts for KC, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), MIP-1alpha, MIP-2, and RANTES in a chemokine and cell-specific fashion. Synthesis of chemokine (KC and MCP-1) and cytokine (TNF-alpha) proteins was also demonstrated. RANTES-mediated chemokine synthesis was specifically inhibited by pertussis toxin, indicating that G-protein-coupled chemokine receptors participated in astrocyte signaling. Astrocytes expressed CCR1 and CCR5 (the redundant RANTES receptors). Astrocytes derived from mice with targeted mutations of either CCR1 or CCR5 respond after RANTES stimulation, suggesting multiple chemokine receptors may separately mediate RANTES responsiveness in astrocytes. Preliminary data suggest activation of the MAP kinase pathway is also critical for RANTES-mediated signaling in astrocytes. Treatment with RANTES specifically modulated astrocyte receptors upregulating intercellular adhesion molecule 1 (ICAM-1) and downregulating CX3CR1 expression. Thus, after chemokine treatment, astrocytes release proinflammatory mediators and reprogram their surface molecules. The combined effects of RANTES may serve to amplify inflammatory responses within the central nervous system.
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PMID:RANTES stimulates inflammatory cascades and receptor modulation in murine astrocytes. 1211 72

The binding subunit of pertussis toxin (PTX-B) has been shown recently to inhibit the entry and postentry events in HIV-1 replication in primary T lymphocytes and monocyte-derived macrophages. While the effect of PTX-B on HIV-1 entry was shown to involve CCR5 desensitization, the mechanism of postentry inhibition remained unclear. In T lymphocytes, PTX-B affected transcription or stability of Tat-stimulated HIV-1 mRNAs. In this study, we sought to identify the mechanism of postentry inhibition of HIV-1 replication by PTX-B in U-937 promonocytic cells. We demonstrate that in these cells PTX-B inhibits expression of luciferase reporter gene controlled by the HIV-1 LTR promoter. This effect is Tat-independent and is not restricted to the HIV-1 LTR promoter. Instead, PTX-B activity is mediated through suppression of the cellular transcription factor, NF-kappaB. PTX-B inhibits phosphorylation and nuclear translocation of the p65 subunit of NF-kappaB. This effect is independent of the cytoplasmic NF-kappaB inhibitor, IkappaBalpha, as PTX-B stimulates phosphorylation and subsequent degradation of this protein. The suppressive activity of PTX-B on NF-kappaB p65 phosphorylation and nuclear translocation is delayed, suggesting that PTX-B signaling might initiate synthesis and cytoplasmic accumulation of a p65 phosphorylation inhibitor.
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PMID:B-oligomer of pertussis toxin inhibits HIV-1 LTR-driven transcription through suppression of NF-kappaB p65 subunit activity. 1242 28

We have recently reported that the mean number of CCR5 coreceptors at the surface of CD4(+) T cells (CCR5 density) correlates with viral load and disease progression in HIV-1-infected persons. Here, we definitively establish that CCR5 density determines the level of virus production and identify the stages of HIV-1 replicative cycle modulated by this effect. We show, by transducing the CCR5 gene into CCR5(+) cells, that CCR5 overexpression resulted in an HIV-1 overinfectability. We sorted HOS-CD4(+)-CCR5(+) cells into two subpopulations, HOS(high) and HOS(low), the former expressing seven times more cell surface CCR5 molecules than the latter. Virus production was 30-80 times higher in HOS(high) cells than in HOS(low) cells after a single round of infection. In contrast, only twice as many viral particles entered the cytosol of HOS(high) cells as compared with the cytosol of HOS(low) cells. Yet, seven times as many early, and 24 times as many late, reverse transcription products were found in HOS(high) cells as compared with HOS(low) cells. Moreover, a 24- to 30-fold difference in the number of copies of integrated HIV-1 DNA was observed. No difference in HIV-1 LTR activation between the two cell lines was evident. Finally, we show that the higher virus production observed in HOS(high) cells is inhibited by pertussis toxin, a Galphai protein inhibitor. Thus, CCR5 density mainly modulates postentry steps of the virus life cycle, particularly the reverse transcription. These data explain why CCR5 density influences HIV-1 disease progression and underline the therapeutic interest of lowering CCR5 expression.
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PMID:Cell surface CCR5 density determines the postentry efficiency of R5 HIV-1 infection. 1243 15

Human immunodeficiency virus (HIV) gp120 induces multiple cellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3-kinase) pathway. The role of the PI3-kinase pathway in HIV-1 replication is not understood. Here we examined whether HIV-1 gp120 upregulates the PI3-kinase pathway and whether PI3-kinase activity plays a role in virus replication in primary human CD4(+) T cells and macrophages. Soluble and virion-associated HIV-1 gp120 induced calcium mobilization and phosphorylation of the PI3-kinase downstream effectors PKB/Akt and p70 S6 kinase. gp120-induced PI3-kinase activity and calcium mobilization were inhibited by pertussis toxin and blocking antibodies directed against CCR5 and CXCR4, suggesting that the signaling is mediated through the chemokine receptor. The PI3-kinase inhibitor LY294002 inhibited infection of CD4(+) T cells and macrophages with X4 and R5 HIV-1-pseudotyped viruses at concentrations that did not induce cell toxicity or downregulate HIV-1 coreceptor expression. When gp120-induced signaling was bypassed with the vesicular stomatitis virus G envelope protein, infection was still sensitive to PI3-kinase inhibition, suggesting that basal PI3-kinase activity is required for infection. LY294002 inhibited HIV-1 infection when added after viral entry and did not affect formation of the HIV-1 reverse transcriptase products R/U5 and long terminal repeat/Gag in the presence of the inhibitor. However, when the inhibitor was added after viral integration had occurred, no inhibition of HIV infection was observed. Our studies show that inhibition of the PI3-kinase signaling pathway suppresses virus infection post-viral entry and post-reverse transcription but prior to HIV gene expression. This type of host-virus interaction has implications for anti-HIV therapeutics that target cellular signaling machinery.
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PMID:Phosphatidylinositol 3-kinase regulates human immunodeficiency virus type 1 replication following viral entry in primary CD4+ T lymphocytes and macrophages. 1255 92

L-selectin mediates leukocyte tethering and rolling, the first step in a sequential process of leukocyte adhesion and migration. Additionally, L-selectin has important signaling roles perhaps contributing to leukocyte activation and integrin-mediated adhesion. Because chemokines are critically involved in leukocyte activation, we questioned whether L-selectin signaling affects chemokine receptor expression and function. We observed that whereas only 5% to 15% of freshly isolated lymphocytes expressed CXCR4 on the cell surface, intracellular CXCR4 was detectable in all cells. Engagement of L-selectin by antibody cross-linking or the L-selectin ligands fucoidan or sulfatide mobilized intracellular CXCR4 to significantly increase surface CXCR4 expression but did not affect CCR5, CCR7, or beta2-integrin expression. L-selectin stimulation also inhibited stromal-derived factor 1 (SDF-1)-induced CXCR4 internalization. The combined effects of L-selectin on CXCR4 trafficking are likely important in markedly enhancing cell activation by SDF-1. Blockade of SDF-1-induced CXCR4 internalization resulted in enhanced actin polymerization on subsequent exposure to SDF-1. Physiologically more important, L-selectin stimulation increased SDF-1-induced lymphocyte adhesion and transendothelial migration, which were inhibited by anti-leukocyte function-associated antigen 1 antibodies, tyrosine kinase inhibitors, and pertussis toxin. To further corroborate the additive stimulating effects, L-selectin signaling and SDF-1 increased beta2-integrin activation. Taken together, L-selectin-mediated signals specifically enhance CXCR4 expression and function, suggesting a novel mechanism for the modulation of lymphocyte activation during cell adhesion and transmigration.
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PMID:L-selectin stimulation enhances functional expression of surface CXCR4 in lymphocytes: implications for cellular activation during adhesion and migration. 1260 46

We have previously shown that the CC-chemokine 1-309 (CCL1) protects mouse thymic lymphomas against corticoid-induced apoptosis. Here, we analyzed the signal transduction pathways involved in this activity on BW5147 lymphoma. Inhibition of the CCL1 activity by pertussis toxin suggested the involvement of a G protein-coupled chemokine receptor. The role of CCR8 was supported by the observation that vMIP-I, another CCR8-ligand identified from the genome of a T cell transforming herpes virus, shared CCL1 anti-apoptotic activity. In addition to CCR8, BW5147 cells also expressed the CXCR4 receptor but its ligand, SDF-1 (CXCL12) showed only a modest anti-apoptotic activity. Other chemokines acting on CCR2, CCR4 and CCR5 failed to protect against apoptosis and to induce BW5147 chemotaxis, suggesting that these receptors were not functionally expressed. By contrast, both CCL1 and vMIP-I up-regulated ERK1/2 MAPK phosphorylation in BW5147 cells. Further analysis demonstrated that CCL1 activates the MAPK pathway in CCR8-transfected CHO cells. The implication of this pathway was confirmed by the fact that PD98059, an inhibitor of MEK kinases, as well as a dominant negative isoform of the M-RAS protein specifically blocked the anti-apoptotic activity of CCL1.
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PMID:CCR8-dependent activation of the RAS/MAPK pathway mediates anti-apoptotic activity of I-309/ CCL1 and vMIP-I. 1264 48

Chemokines are implicated in tumor pathogenesis, although it is unclear whether they affect human cancer progression positively or negatively. We found that activation of the chemokine receptor CCR5 regulates p53 transcriptional activity in breast cancer cells through pertussis toxin-, JAK2-, and p38 mitogen-activated protein kinase-dependent mechanisms. CCR5 blockade significantly enhanced proliferation of xenografts from tumor cells bearing wild-type p53, but did not affect proliferation of tumor xenografts bearing a p53 mutation. In parallel, data obtained in a primary breast cancer clinical series showed that disease-free survival was shorter in individuals bearing the CCR5Delta32 allele than in CCR5 wild-type patients, but only for those whose tumors expressed wild-type p53. These findings suggest that CCR5 activity influences human breast cancer progression in a p53-dependent manner.
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PMID:CCR5 expression influences the progression of human breast cancer in a p53-dependent manner. 1459 37

Chemokines play pivotal roles in the recruitment of inflammatory cells into the kidney. The chemokine receptors CXCR3 and CCR5 are expressed on activated T lymphocytes, and expression of CXCR3 by mesangial cells has been suggested. Detailed description of CXCR3 expression might form a rational basis for use as a diagnostic marker and for therapeutic CXCR3 targeting in human glomerulonephritis. We studied the expression of CXCR3 in renal biopsies by immunohistochemistry (n = 45), and real time RT-PCR (n = 78). Biopsies were from patients with IgA nephropathy, lupus nephritis, and membranoproliferative glomerulonephritis. Furthermore, cultured human mesangial cells (HMC) were studied for CXCR3 expression, and for functional responses to the ligands CXCL10/IP-10 and CXCL9/Mig. CXCR3-positive cells were rarely found in glomerular tufts, but formed a major part of the tubulointerstitial infiltrates. Consistently, CXCR3 mRNA expression was too low to be quantified in glomerular compartments, and was not detectable in HMC. The published staining for CXCR3 of mesangial cells could be traced to cross-reactivity of an antibody for CXCR3 with a potentially related chemokine receptor as revealed by FACS analysis. Despite an absence of CXCR3 expression, mesangial cells reacted to CXCR3 ligands by proliferation and migration, which was blocked by pertussis toxin but not by an anti-CXCR3 antibody. These results indicate that HMC do not express the classical CXCR3, but may potentially express a related receptor with shared ligand specificity. By immunohistochemistry the number of CXCR3-positive cells, mainly interstitial T cells, correlated with renal function, proteinuria, and percentage of globally sclerosed glomeruli. A significant morphological and numerical correlation between CD3, CXCR3, and CCR5-positive cells indicated a CXCR3/CCR5 double-positive T cell population. No apparent difference in the CXCR3 expression pattern was found between disease entities. CXCR3 expression was localized to interstitial T cells, and these cells correlated strongly with important prognostic markers. Therefore interstitial CXCR3, as well as CCR5-positive T cells might play an important role during progressive loss of renal function, and are potential therapeutic targets in human glomerular diseases.
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PMID:CXCR3 is involved in tubulointerstitial injury in human glomerulonephritis. 1474 68

Spatially restricted activation of signaling molecules governs critical aspects of cell migration; the mechanism by which this is achieved nonetheless remains unknown. Using time-lapse confocal microscopy, we analyzed dynamic redistribution of lipid rafts in chemoattractant-stimulated leukocytes expressing glycosyl phosphatidylinositol-anchored green fluorescent protein (GFP-GPI). Chemoattractants induced persistent GFP-GPI redistribution to the leading edge raft (L raft) and uropod rafts of Jurkat, HL60, and dimethyl sulfoxide-differentiated HL60 cells in a pertussis toxin-sensitive, actin-dependent manner. A transmembrane, nonraft GFP protein was distributed homogeneously in moving cells. A GFP-CCR5 chimera, which partitions in L rafts, accumulated at the leading edge, and CCR5 redistribution coincided with recruitment and activation of phosphatidylinositol-3 kinase gamma in L rafts in polarized, moving cells. Membrane cholesterol depletion impeded raft redistribution and asymmetric recruitment of PI3K to the cell side facing the chemoattractant source. This is the first direct evidence that lipid rafts order spatial signaling in moving mammalian cells, by concentrating the gradient sensing machinery at the leading edge.
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PMID:Dynamic redistribution of raft domains as an organizing platform for signaling during cell chemotaxis. 1498 Oct 96

Liver-expressed chemokine (LEC)/CCL16 is a human CC chemokine that is constitutively expressed by the liver parenchymal cells and present in the normal plasma at high concentrations. Previous studies have shown that CCL16 is a low-affinity ligand for CCR1, CCR2, CCR5, and CCR8 and attracts monocytes and T cells. Recently, a novel histamine receptor termed type 4 (H4) has been identified and shown to be selectively expressed by eosinophils and mast cells. In this study, we demonstrated that CCL16 induced pertussis toxin-sensitive calcium mobilization and chemotaxis in murine L1.2 cells expressing H4 but not those expressing histamine receptor type 1 (H1) or type 2 (H2). CCL16 bound to H4 with a K(d) of 17 nM. By RT-PCR, human and mouse eosinophils express H4 but not H3. Accordingly, CCL16 induced efficient migratory responses in human and mouse eosinophils. Furthermore, the responses of human and mouse eosinophils to CCL16 were effectively suppressed by thioperamide, an antagonist for H3 and H4. Intravenous injection of CCL16 into mice induced a rapid mobilization of eosinophils from bone marrow to peripheral blood, which was also suppressed by thioperamide. Collectively, CCL16 is a novel functional ligand for H4 and may have a role in trafficking of eosinophils.
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PMID:Liver-expressed chemokine/CC chemokine ligand 16 attracts eosinophils by interacting with histamine H4 receptor. 1526 43


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