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)

The ability of CD8 T cells derived from human immunodeficiency virus (HIV)-infected patients to produce soluble HIV-suppressive factor(s) (HIV-SF) has been suggested as an important mechanism of control of HIV infection in vivo. The C-C chemokines RANTES, MIP-1 alpha and MIP-1 beta were recently identified as the major components of the HIV-SF produced by both immortalized and primary patient CD8 T cells. Whereas they potently inhibit infection by primary and macrophage-tropic HIV-1 isolates, T-cell line-adapted viral strains tend to be insensitive to their suppressive effects. Consistent with this discrepancy, two distinct chemokine receptors, namely, CXCR4 (ref. 7) and CCR5 (ref. 8), were recently identified as potential co-receptors for T-cell line-adapted and macrophage-tropic HIV-1 isolates, respectively. Here, we demonstrate that the third hypervariable domain of the gp 120 envelope glycoprotein is a critical determinant of the susceptibility of HIV-1 to chemokines. Moreover, we show that RANTES, MIP-1 alpha and MIP-1 beta block the entry of HIV-1 into cells and that their antiviral activity is independent of pertussis toxin-sensitive signal transduction pathways mediated by chemokine receptors. The ability of the chemokines to block the early steps of HIV infection could be exploited to develop novel therapeutic approaches for AIDS.
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PMID:The V3 domain of the HIV-1 gp120 envelope glycoprotein is critical for chemokine-mediated blockade of infection. 909 60

Previous results have shown that pertussis toxin-sensitive Gi proteins are likely to be involved in regulating the emigration of mature thymocytes from the thymus. In this study, a low stringency polymerase chain reaction (PCR) approach was used to identify Gi protein-coupled cell surface receptors expressed in mouse thymocytes. Among the ten G protein-coupled receptor cDNA isolated, the most prevalent cDNA encoded a polypeptide highly homologous to the human leukocyte-expressed seven-transmembrane-domain receptor LESTR, also referred to as HIV entry cofactor, fusin, or CXCR4. Isolation of full-length cDNA revealed that alternative RNA splicing produces transcripts encoding two isoforms of the murine LESTR, differing by the presence of two amino acids in the N-terminal portion of the longer protein. Functional reconstitution of recombinant murine LESTR with recombinant heterotrimeric G proteins in baculovirus-infected insect cells showed that both receptor variants mediate stromal cell-derived factor 1alpha activation of the pertussis toxin-sensitive G protein Gi2. Receptor subtype-specific reverse transcriptase-PCR analysis revealed differential expression of the two receptor mRNA in lymphoid tissues and brain, indicating that distinct functions are mediated by the two receptor isoforms in these tissues. The presence of LESTR mRNA in very early thymocytes as well as in immature (CD4+ CD8+) thymocytes suggests that both CD4 and LESTR are co-expressed and render developing human thymocytes susceptible for HIV entry, which may affect generation of both CD4+ CD8- and CD4- CD8+ mature lineages.
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PMID:Two murine homologues of the human chemokine receptor CXCR4 mediating stromal cell-derived factor 1alpha activation of Gi2 are differentially expressed in vivo. 929 51

Although it is well-established that G protein-coupled receptor signaling systems can network with those of tyrosine kinase receptors by several mechanisms, the point(s) of convergence of the two pathways remains largely undelineated, particularly for opioids. Here we demonstrate that opioid agonists modulate the activity of the extracellular signal-regulated protein kinase (ERK) in African green monkey kidney COS-7 cells transiently cotransfected with mu-, delta-, or kappa-opioid receptors and ERK1- or ERK2-containing plasmids. Recombinant proteins in transfected cells were characterized by binding assay or immunoblotting. On treatment with corresponding mu- ([D-Ala2,Me-Phe4,Gly-ol5]enkephalin)-, delta- ([D-Pen2,D-Pen5]enkephalin)-, or kappa- (U69593)-selective opioid agonists, a dose-dependent, rapid stimulation of ERK1 and ERK2 activity was observed. This activation was inhibited by specific antagonists, suggesting the involvement of opioid receptors. Pretreatment of cells with pertussis toxin abolished ERK1 and ERK2 activation by agonists. Cotransfection of cells with dominant negative mutant N17-Ras or with a betagamma scavenger, CD8- beta-adrenergic receptor kinase-C, suppressed opioid stimulation of ERK1 and ERK2. When epidermal growth factor was used to activate ERK1, chronic (>2-h) opioid agonist treatment resulted in attenuation of the stimulation by the growth factor. This inhibition was blocked by the corresponding antagonists and CD8- beta-adrenergic receptor kinase-C cotransfection. These results suggest a mechanism involving Ras and betagamma subunits of Gi/o proteins in opioid agonist activation of ERK1 and ERK2, as well as opioid modulation of epidermal growth factor-induced ERK activity.
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PMID:Opioid modulation of extracellular signal-regulated protein kinase activity is ras-dependent and involves Gbetagamma subunits. 945 57

CD4+ helper T lymphocytes and CD8+ killer T lymphocytes are both generated in the thymus from common precursor cells expressing CD4 and CD8. The development of immature CD4 CD8+ thymocytes into mature 'single-positive' T cells requires T cell antigen-receptor (TCR)-mediated positive selection signals. Although it is known that the recognition specificity of TCR expressed by CD4+ CD8+ thymocytes determines their fate to become either CD4+ or CD8+ T cells, the molecular signals that direct precursor thymocytes to become CD4+ and CD8+ T cells are unclear. By using ZAP-70 mutant thymus organ cultures in which T cell development is arrested at the CD4+ CD8+ thymocyte stage, the present study shows that distinct biochemical treatments can selectively restore the generation of mature CD4+ and CD8+ T cells, bypassing TCR-induced positive selection signals. The combination of phorbol ester and ionomycin selectively restores the generation of CD4+ CD8- TCR(high) cells, consistent with previous results. On the other hand, we find that the generation of CD4- CD8+ TCR(high) cells is selectively induced by pertussis toxin. Interestingly, the signals generated by pertussis toxin, which increase Notch expression, can dominate the signals by phorbol ester and ionomycin, steering thymocyte development to CD8 lineage. These results indicate that distinct biochemical signals replace TCR signals that selectively induce positive selection of CD4+ and CD8+ T cells, and that biochemical treatment can manipulate the development and choice of CD4+ and CD8+ T cells.
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PMID:Pertussis toxin can replace T cell receptor signals that induce positive selection of CD8 T cells. 946 20

CC chemokines produced by CD8(+) T cells are known to act as HIV-suppressive factors. We studied the possible role of these chemokines in HIV-1-specific killing of target cells. We found that the activity of cytotoxic T lymphocytes (CTLs) in CTL lines or freshly isolated peripheral blood mononuclear cells from HIV-1-infected individuals is markedly enhanced by RANTES (regulated on activation, normal T cell expressed and secreted) and virtually abolished by an antibody neutralizing RANTES or the RANTES receptor antagonist RANTES(9-68). Lysis was mediated by CD8(+) major histocompatibility complex class I-restricted T cells and was obtained with target cells expressing epitopes of the HIV-1LAI proteins Gag, Pol, Env, and Nef. The cytolytic activity observed in the presence or absence of added RANTES could be abolished by pretreatment of the CTLs with pertussis toxin, indicating that the effect is mediated by a G protein-coupled receptor. The chemokines monocyte chemotactic protein (MCP)-3, MCP-4, and eotaxin acted like RANTES, whereas macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, MCP-1, and stromal cell-derived factor 1 were inactive, suggesting a role for the eotaxin receptor, CCR3, and ruling out the involvement of CCR1, CCR2, CCR5, and CXCR4. CTL activity was abrogated by an antibody that blocks CCR3, further indicating that specific lysis is triggered via this chemokine receptor. These observations reveal a novel mechanism for the induction of HIV-1-specific cytotoxicity that depends on RANTES acting via CCR3.
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PMID:HIV-specific T cell cytotoxicity mediated by RANTES via the chemokine receptor CCR3. 968 38

Vasopressin is the key regulator of water homeostasis in vertebrates. Central to its antidiuretic action in mammals is the redistribution of the water channel aquaporin 2 (AQP2) from intracellular vesicles to the apical membrane of kidney epithelial cells, an event initiated by an increase in cAMP and activation of protein kinase A. The subsequent steps of the signaling cascade are not known. To identify proteins involved in the AQP2 shuttle we exploited a recently developed cell line (CD8) derived from the rabbit cortical collecting duct and stably transfected with rat AQP2 cDNA. Treatment of CD8 cells with pertussis toxin (PTX) inhibited both the vasopressin-induced increase in water permeability and the redistribution of AQP2 from an intracellular compartment to the apical membrane. ADP-ribosylation studies revealed the presence of at least two major PTX substrates. Correspondingly, two alpha subunits of PTX-sensitive G proteins, Galphai2 and Galphai3, were identified by Western blotting. Introduction of a synthetic peptide corresponding to the C terminus of the Gi3 alpha subunit into permeabilized CD8 cells efficiently inhibited the cAMP-induced AQP2 translocation; a peptide corresponding to the alpha subunits of Gi1/2 was much less potent. Thus a member of the Gi family, most likely Gi3, is involved in the cAMP-triggered targeting of AQP2-bearing vesicles to the apical membrane of kidney epithelial cells.
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PMID:A heterotrimeric G protein of the Gi family is required for cAMP-triggered trafficking of aquaporin 2 in kidney epithelial cells. 971 91

We previously reported that CD8+ T cell-derived factors enhanced HIV long terminal repeat (LTR)-mediated gene expression and replication in monocytic cell lines. We now report that replication of NSI and SI primary isolates of HIV-1 in human macrophages were significantly enhanced by CD8+ T cell supernatants. The CD8-mediated enhancement of HIV replication was abrogated by pertussis toxin in a dose-dependent manner. The sensitivity to pertussis toxin suggests that the CD8+ T cell-derived enhancing factor is acting through a G protein-coupled signalling pathway. Enhanced HIV replication in macrophages was accompanied by increased levels of HIV-1 mRNA, suggesting that CD8 enhancement was mediated at the transcriptional level. Interestingly, the replication of HIV(Bal), which replicates to high levels in macrophages, was not significantly modulated by culture with CD8+ T cell supernatants. Although direct co-culture of activated CD8+ T cells with HIV(Ada)-infected macrophages did not modulate replication, separation of the CD8+ T cells from macrophages in transwell cultures resulted in significant enhancement of replication. The inability to detect a modulatory effect in direct co-cultures appeared to be due to non-specific lysis of infected macrophages. Thus, soluble factors produced by CD8+ T cells exert strong enhancing effects on HIV-1 replication in human macrophages.
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PMID:Enhancement of HIV-1 replication in human macrophages is induced by CD8+ T cell soluble factors. 976 8

Bordetella pertussis secretes a calmodulin-activated adenylate cyclase toxin, CyaA, that is able to deliver its N-terminal catalytic domain (400-aa residues) into the cytosol of eukaryotic target cells, directly through the cytoplasmic membrane. We have previously shown that CyaA can be used as a vehicle to deliver T cell epitopes, inserted within the catalytic domain of the toxin, into antigen-presenting cells and can trigger specific class I-restricted CD8(+) cytotoxic T cell responses in vivo. Here, we constructed a series of recombinant toxins harboring at the same insertion site various peptide sequences of 11-25 amino acids, corresponding to defined CD8(+) T cell epitopes and differing in the charge of the inserted sequence. We show that inserted peptide sequences containing net negative charges (-1 or -2) decreased or completely blocked (charge of -4) the internalization of the toxin into target cells in vitro and abolished the induction of cytotoxic T cell responses in vivo. The blocking of translocation due to the inserted acidic sequences can be relieved by appropriate mutations in the flanking region of CyaA that counterbalance the inserted charges. Our data indicate that (i) the electrostatic charge of the peptides inserted within the catalytic domain of CyaA is critical for its translocation into eukaryotic cells and (ii) the delivery of T cell epitopes into the cytosol of antigen-presenting cells by recombinant CyaA toxins is essential for the in vivo stimulation of specific cytotoxic T cells. These findings will help to engineer improved recombinant CyaA vectors able to stimulate more efficiently cellular immunity.
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PMID:Charge-dependent translocation of Bordetella pertussis adenylate cyclase toxin into eukaryotic cells: implication for the in vivo delivery of CD8(+) T cell epitopes into antigen-presenting cells. 977 May 20

Leukocyte migration into sites of inflammation involves multiple molecular interactions between leukocytes and vascular endothelial cells, mediating sequential leukocyte capture, rolling, and firm adhesion. In this study, we tested the role of molecular interactions between fractalkine (FKN), a transmembrane mucin-chemokine hybrid molecule expressed on activated endothelium, and its receptor (CX3CR1) in leukocyte capture, firm adhesion, and activation under physiologic flow conditions. Immobilized FKN fusion proteins captured resting peripheral blood mononuclear cells at physiologic wall shear stresses and induced firm adhesion of resting monocytes, resting and interleukin (IL)-2-activated CD8(+) T lymphocytes and IL-2-activated NK cells. FKN also induced cell shape change in firmly adherent monocytes and IL-2-activated lymphocytes. CX3CR1-transfected K562 cells, but not control K562 cells, firmly adhered to FKN-expressing ECV-304 cells (ECV-FKN) and tumor necrosis factor alpha-activated human umbilical vein endothelial cells. This firm adhesion was not inhibited by pertussis toxin, EDTA/EGTA, or antiintegrin antibodies, indicating that the firm adhesion was integrin independent. In summary, FKN mediated the rapid capture, integrin-independent firm adhesion, and activation of circulating leukocytes under flow. Thus, FKN and CX3CR1 mediate a novel pathway for leukocyte trafficking.
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PMID:Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow. 978 18

It has previously been demonstrated that T lymphocytes in the conducting airways express a pattern of adhesion molecules that are uniquely different from T lymphocytes found circulating in peripheral blood. To examine the role of airway epithelia in the determination of migratory capacity for human monocyte and lymphocyte populations in vivo, we have developed an in vitro transepithelial migration model using the human transformed bronchial epithelial cell line BEAS-2B S.6. In this study, we have demonstrated the preferential migration of human peripheral blood mononuclear cells (PBMC) across BEAS-2B S.6 cell monolayers in a physiologically appropriate direction (basal to apical epithelial cell surface). Stimulation of BEAS-2B S.6 cells with a combination of interferon-gamma and tumor necrosis factor-alpha upregulated basal-to-apical transepithelial migration by at least twofold. Monocytes migrated most efficiently, but subpopulations of CD19(+) B cells and CD2(+) cells were also recruited across epithelial cell monolayers. In the T lymphocyte subset of PBMC, CD45RO+ "memory" cells migrated preferentially. In addition, CD4(+) cells exhibited a significantly greater capacity to migrate across airway epithelium compared with CD8(+) cells. Migrated CD4(+) cells were predominantly CD29(high)/CD26(high), and within this subset uniformly expressed CD62L (L-selectin) at an intermediate level. PBMC migration across BEAS-2B S.6 cells was significantly inhibited by pertussis toxin; this result implicates a G protein signaling event as an important mediator of lymphocyte/monocyte transepithelial migration. On the basis of these data, we conclude that bronchial epithelium provides a unique microenvironment that supports the selective, G protein-dependent migration of memory T cells.
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PMID:Human airway epithelial monolayers promote selective transmigration of memory T cells: a transepithelial model of lymphocyte migration into the airways. 984 23


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