Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Leukocyte adhesion and trafficking at the endothelium requires both cellular adhesion molecules and chemotactic factors. A newly identified CX3C chemokine, fractalkine, expressed on activated endothelial cells, plays an important role in leukocyte adhesion and migration. We examined the functional effects of fractalkine on beta1 and beta2 integrin-mediated adhesion using a macrophage-like cell line, THP-1 cells. In this study, we report that THP-1 cells express mRNA encoding a receptor for fractalkine, CX3CR1, determined by Northern blotting. Scatchard analysis using fractalkine-SEAP (secreted form of placental alkaline phosphatase) chimeric proteins revealed that THP-1 cells express a single class of CX3CR1 with a dissociation constant of 30 pM and a mean expression of 440 sites per cell. THP-1 cells efficiently adhered, in a fractalkine-dependent manner, to full-length of fractalkine immobilized onto plastic and to the membrane-bound form of fractalkine expressed on ECV304 cells or TNF-alpha-activated HUVECs. Moreover, soluble-fractalkine enhanced adhesion of THP-1 cells to fibronectin and ICAM-1 in a dose-dependent manner. Pertussis toxin, an inhibitor of Gi, inhibited the fractalkine-mediated enhancement of THP-1 cell adhesion to fibronectin and ICAM-1. Finally, we found that soluble-fractalkine also enhanced adhesion of freshly separated monocytes to fibronectin and ICAM-1. These results indicate that fractalkine may induce firm adhesion between monocytes and endothelial cells not only through an intrinsic adhesion function itself, but also through activation of integrin avidity for their ligands.
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PMID:CX3C-chemokine, fractalkine-enhanced adhesion of THP-1 cells to endothelial cells through integrin-dependent and -independent mechanisms. 1075 31

Immobilized stromal cell-derived factor-1 alpha (SDF-1 alpha) has been shown to induce tight adhesion of T cells to purified ICAM-1 in assays done under flow conditions. In this study, we show that soluble SDF-1 alpha induced a rapid (within 20 s) cessation of rolling and tight adhesion of >90% of the rolling T cells on monolayers of activated endothelial cells under similar flow. Within 4 min, the T cells had either started to migrate between the endothelial cells or re-entered the rolling and circulating lymphocyte pool. This deadherence of the firmly bound cells, with either ensuing transmigration or continued rolling, was most likely due to desensitization of lymphocytes to the continuously present SDF-1 alpha. The released rolling lymphocytes could still respond to other activating signals by a second round of tight adhesion. Pretreating the lymphocytes with pertussis toxin almost completely blocked the effect of the chemokine, confirming that the induction of firm adhesion was due to the function of the chemokine on the lymphocytes and not the endothelial cells. Pretreating the endothelium with SDF-1 alpha did not lead to firm adhesion of subsequently added lymphocytes, also indicating that the effect was due to soluble, not endothelially bound, chemokine. Blocking experiments showed that the same molecules mediated rolling before and after SDF-1 alpha-induced tight adhesion. This is the first study to demonstrate the effect of soluble SDF-1 alpha on T cell rolling on an endothelial cell monolayer. The data broaden our understanding of the stimulatory factors directing the firm adhesion and ensuing transmigration of leukocytes into tissues through activated endothelium.
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PMID:Effects of continuous exposure to stromal cell-derived factor-1 alpha on T cell rolling and tight adhesion to monolayers of activated endothelial cells. 1079 58

Movement towards or away from a given stimulus guides the directional migration of prokaryotes, simple eukaryotes and neurons. As bi-directional cues may influence entry and exit of immune effector cells from tissue sites, we evaluated the migratory responses of T-cell subsets to varying concentrations of the chemokine stromal cell derived factor-1 (SDF-1). There was selective repulsion of subpopulations of T cells at high concentrations of recombinant SDF-1 or naturally occurring bone marrow-derived SDF-1, which could be inhibited by pertussis toxin and antibody against the chemokine receptor CXCR4. Distinct sensitivity profiles to genistein, herbimycin and 8-Br-cAMP biochemically distinguished movement of cells towards or away from an SDF-1 gradient. In vivo, antigen-induced T-cell recruitment into the peritoneal cavity was reversed by high but not low concentrations of SDF-1. The phenomenon of movement away from a chemokine represents a previously unknown mechanism regulating the localization of mature T cells. It adds to the functional repertoire of chemokines that may participate in immune physiology and may be applied therapeutically to alter the immune response.
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PMID:Active movement of T cells away from a chemokine. 1080 10

We investigated whether pertussis toxin (PT)-sensitive heterotrimeric Gi proteins (Gi1, Gi2, Gi3) are involved in the regulation of TCR-induced activation of human T cells. First, Gi proteins were inactivated by PT: pretreatment with PT of purified blood T lymphocytes before CD3 cross-linking inhibited cell proliferation (-71.1 +/- 22.0%, P < 0.001), production of interleukin-2 (IL-2; -47.3 +/- 12.6%, P = 0.008), and expression of CD25 (-24.6 +/- 11.7%, P < 0.001) and CD69 (-25.7 +/- 9.0%, P < 0.001). Then, to identify which of the three Gi was involved, Gi1, Gi2, and Gi3 proteins were specifically inactivated by stably transfecting dominant-negative mutated forms of their alpha subunit in Jurkat cells. After activation, IL-2 production and CD69 expression were inhibited only in cells expressing inactive Gi2. We then studied the effects of interleukin-8 (IL-8), a CXC-chemokine with receptors coupled to Gi2 and produced in an autocrine fashion by activated T cells. Although its effects varied among donors, exogenous IL-8 stimulated proliferation and CD25 expression (up to, respectively, 200 and 77%) of PB T lymphocytes in response to CD3 activation, in a PT-sensitive manner. IL-8 also stimulated IL-2 production (by up to 42%) and CD69 expression, although weakly (+27%). Anti-human IL-8 antibody inhibited proliferation (-43%) and CD25 up-regulation (-45%) of activated T lymphocytes. In summary, several major responses of human T lymphocytes to TCR-mediated activation are regulated by Gi2 proteins, which for this function can be activated by IL-8 in an autocrine manner.
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PMID:Positive regulation of human T cell activation by Gi2 proteins and interleukin-8. 1081 Oct 16

Human T lymphocyte transendothelial migration (TEM) was examined in response to chemokines across cytokine-activated endothelium. Monocyte chemotactic protein-1 (MCP-1), RANTES, and macrophage inflammatory protein-1alpha (MIP-1alpha) induced TEM by memory T cells, while stromal cell-derived factor-1 (SDF-1) induced TEM by both naive and memory T cells. Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) increased endothelial adhesion molecule (CAM) expression, whereas interferon-gamma (IFN-gamma) induced little up-regulation of CAM. However, both TNF-alpha and IFN-gamma strongly facilitated T cell migration, which was completely inhibited by pertussis toxin and both greatly increased TEM to RANTES, MIP-1alpha, and SDF-1 selectively of memory but not naive T cells. Thus, the dual selective effect on memory T cells of endothelial activation and these chemokines promotes the preferential recruitment of memory T cells to inflammatory sites. However, the enhanced chemokine-induced migration by memory T cells across activated endothelium appears to be independent of the increase in endothelial CAM expression. G-protein-linked stimuli may play an important part in T cell TEM across cytokine-activated endothelium.
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PMID:Regulation of chemokine-induced transendothelial migration of T lymphocytes by endothelial activation: differential effects on naive and memory T cells. 1085 55

Human immunodeficiency virus type 1 (HIV-1) envelope protein gp41 mediates viral fusion with human host cells. In this study we show that N36, a synthetic peptide derived from the N-terminus of gp41, induced directional migration and calcium mobilization in human monocytes and neutrophils. The activity of N36 on phagocytes was pertussis toxin sensitive, suggesting involvement of a Gi-coupled seven-transmembrane receptor(s). Since high concentrations of the bacterial chemotactic peptide fMet-Leu-Phe (fMLF) partially desensitized the calcium mobilizing activity of N36 in phagocytes, we postulated that N36 might use a low-affinity fMLF receptor. By using cells stably expressing fMLF receptor FPR or FPRL1, we demonstrate that N36 uses FPRL1 as a functional receptor. Our results suggest that HIV-1 gp41 may contain a fragment(s) that activates the innate host immune cells through FPRL1. Since the activation of FPRL1 in monocytes has been shown to heterologously desensitize chemokine receptors, the reduced phagocyte response to chemoattractants seen in AIDS patients may be attributed, at least in part, to heterologous desensitization.
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PMID:N36, a synthetic N-terminal heptad repeat domain of the HIV-1 envelope protein gp41, is an activator of human phagocytes. 1096 42

Microglia are the resident immune cells of the CNS. Upon brain damage, these cells are rapidly activated and function as tissue macrophages. The first steps in this activation still remain unclear, but it is widely believed that substances released from damaged brain tissue trigger this process. In this article, we describe the effects of the blood coagulation factor thrombin on cultured rodent microglial cells. Thrombin induced a transient Ca(2+) increase in microglial cells, which persisted in Ca(2+)-free media. It was blocked by thapsigargin, indicating that thrombin caused a Ca(2+) release from internal stores. Preincubation with pertussis toxin did not alter the thrombin-induced [Ca(2+)](i) signal, whereas it was blocked by hirudin, a blocker of thrombin's proteolytic activity. Incubation with thrombin led to the production of nitric oxide and the release of the cytokines tumor necrosis factor-alpha, interleukin-6, interleukin-12, the chemokine KC, and the soluble tumor necrosis factor-alpha receptor II and had a significant proliferative effect. Our findings indicate that thrombin, a molecule that enters the brain at sites of injury, rapidly triggered microglial activation.
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PMID:Thrombin-induced activation of cultured rodent microglia. 1098 34

Chemokine receptors are not only able to bind chemokines but, together with CD4, they serve as an entry door for the human immunodeficiency virus type 1 (HIV-1). The signalling capacity of chemokine receptors, which is of fundamental importance for chemokine-induced chemotaxis, is not used by HIV-1 to enter a target cell, nor by chemokines or chemokine-derived ligands to inhibit viral entry. In addition, an ill-defined signal triggered by chemokines can, under some circumstances, lead to an increase in HIV-1 expression. We show here that, in infected cells, exposure to SDF-1 leads to an increased expression of a X4 strain of HIV-1. A similar increase can be induced by an N-terminal peptide of SDF-1 which had previously been shown to elicit an intracellular calcium response and to inhibit the entry of X4 strains of HIV-1. We demonstrate the involvement of extracellular signal-regulated kinases (ERK) in this phenomenon. SDF-1 activates ERK-1 and ERK-2 in Jurkat cells. In HeLa cells, ERK-2 only is activated by SDF-1 or by a SDF-derived peptide. This ERK activation can be blocked by pertussis toxin and by the MEK inhibitor U0126. Most importantly, SDF-1-dependent HIV-1 expression is abolished by pretreating the cells with pertussis toxin or with U0126. The consequences of this SDF-1-induced, ERK-dependent modulation of HIV-1 expression in infected cells may have a clinical relevance for eradicating latent viruses.
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PMID:SDF-1-induced activation of ERK enhances HIV-1 expression. 1102 34

The alpha chemokine receptor CXCR4 and its only characterized chemokine ligand, stromal cell-derived factor-1 (SDF-1), are postulated to be important in the development of the B-cell arm of the immune system. In addition, CXCR4 is a critical coreceptor in support of viral entry by T-cell line tropic strains (X4) of the Human Immunodeficiency Virus Type 1 (HIV-1), viral variants which predominate in some infected individuals in end stage disease. SDF-1 can block X4-tropic HIV-1 infection of CD4+ target cells in vitro, and allelic variants of the human gene encoding SDF-1 in vivo correlate with delayed disease progression. Therefore, CXCR4 may be an appropriate target for therapeutic intervention in acquired immunodeficiency syndrome (AIDS), and knowledge of the pharmacology of SDF-1 binding to its cognate receptor will be important in the interpretation of these experiments. We report here a Kd derived using a competition binding assay of 4.5 nM for CXCR4 endogenously expressed on peripheral blood monocytes and T-cells. This affinity is similar to that which SDF-1 exhibits when binding to endogenous CXCR4 on an established immortal Jurkat T-cell line as well as recombinant CXCR4 transfected into Chinese Hamster Ovary (CHO) cells. We also demonstrate that the determined affinity of SDF-1 for CXCR4 is reflective of its ability to induce a CXCR4-mediated signal transduction in these different cell types. Furthermore, using Bordetella pertussis toxin, we observe that high affinity binding of SDF-1 to CXCR4 is independent of the G-protein coupled state of the receptor, as uncoupling of G-protein did not lead to the appearance of measurable low affinity SDF-1 binding sites. Moreover, binding affinity and receptor number were unaffected by uncoupling for both recombinant and endogenously expressed CXCR4. Thus, SDF-1 is novel among agonist ligands of G protein-coupled receptors in that it appears to have equal affinity for both the G protein-coupled and uncoupled states of CXCR4.
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PMID:The CXCR4 agonist ligand stromal derived factor-1 maintains high affinity for receptors in both Galpha(i)-coupled and uncoupled states. 1110 27

Memory T cells (mTC) express multiple chemokine receptors (including CCR4 and CCR6) that may potentially be involved in their arrest on inflamed endothelia. Herein, we specifically addressed whether CCR6 is required for mTC to arrest on TNF-alpha-activated human dermal microvascular endothelial cells (HDMEC) in vitro under shear stress conditions. Recombinant liver and activation-regulated chemokine (LARC)/CCL20 (a CCR6 ligand) induced firm arrest of cutaneous lymphocyte Ag(+) mTC in a flow chamber system using purified substrates. Strikingly, desensitization of CCR6 with LARC, but not thymus and activation-regulated chemokine/CCL17 or secondary lymphoid tissue chemokine/CCL21, caused a 50-75% decrease (p < 0. 001) in arrest of mTC on HDMEC, which was indistinguishable from the reduction observed when total mTC were treated with pertussis toxin (p > 0.5). CCR6-depleted mTC also had a markedly reduced ability to arrest on HDMEC. Our results suggest that LARC production by activated endothelial cells and CCR6 expression by mTC may be critical components in the pertussis toxin-sensitive arrest of mTC on activated HDMEC.
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PMID:Cutting edge: C-C chemokine receptor 6 is essential for arrest of a subset of memory T cells on activated dermal microvascular endothelial cells under physiologic flow conditions in vitro. 1112 Jul 83


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