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)

We have previously shown that the engagement of ICAM-1 on brain endothelial cells (EC) results in the propagation of EC signaling pathways that are necessary for efficient lymphocyte migration across the tight vascular barriers of the brain. Signaling via this receptor alone, however, is unlikely to explain the differential recruitment of leukocytes at different vascular beds. In this study, we investigated the role of EC heterotrimeric G-protein-mediated signaling in supporting transendothelial migration of T lymphocytes. Treatment of brain EC monolayers with pertussis toxin (PTX) resulted in ADP-ribosylation of G-protein alpha subunits and inhibition (>80%) of lymphocyte migration without affecting lymphocyte adhesion. Aortic and high endothelial venule EC treated identically resulted in only partial inhibition of lymphocyte migration (<40%). Expression of ribosylation-resistant (PTX-insensitive) G-protein alpha subunits in brain EC restored their ability to support lymphocyte migration after pretreatment with PTX. Treatment of brain EC with PTX did not inhibit ICAM-1-stimulated tyrosine phosphorylation of focal adhesion kinase, suggesting the effects of PTX in inhibiting EC facilitation of lymphocyte migration are distinct from activation of EC through ICAM-1. We conclude that a heterotrimeric G-protein-mediated signaling pathway in brain EC is essential for efficient transendothelial migration of T lymphocytes into the brain.
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PMID:Lymphocyte trafficking through the blood-brain barrier is dependent on endothelial cell heterotrimeric G-protein signaling. 1215 86

Granulocyte colony stimulating factor (G-CSF) is well known for its ability to drive the maturation and mobilization of neutrophils. G-CSF also appears to have the potential to activate functions of mature neutrophils, influencing recruitment at sites of inflammation and tissue injury. We investigated the ability of G-CSF to stimulate adhesion of isolated blood neutrophils. G-CSF induced significant adherence to intercellular adhesion molecule (ICAM)-1 that was both macrophage antigen-1 (Mac-1) and leukocyte function-associated antigen-1 dependent. The kinetics of G-CSF-stimulated adhesion to ICAM-1 peaked at 11 min without detectable surface upregulation of Mac-1. This was in marked contrast to chemokines, in which peak activation of adhesion is seen within 1 min of stimulation. In contrast to chemokine-induced adhesion, G-CSF stimulation was not inhibited by pertussis toxin. G-CSF also augmented the attachment of neutrophils to activated human umbilical vein endothelial cells (HUVEC) through specific effects on neutrophils, because HUVEC appear to lack functional G-CSF receptors.
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PMID:Granulocyte colony-stimulating factor promotes adhesion of neutrophils. 1238 13

We analyzed differences in the transendothelial migration (TEM) ability of T-helper (Th)-1 and Th2 cells across a murine endothelial cell line (F-2) under static conditions. The TEM abilities of Th1 cells from mice bearing autoimmune diseases and antigen-specific Th1 cell lines were severalfold higher than those of Th2 cells and lines of the same origin. These preferences were observed without exogenous chemoattractant and were insensitive to pertussis toxin, which completely blocks TEM induced by exogenous chemoattractants. Antibodies against LFA-1 and ICAM-1 as well as CD44 markedly blocked the TEM of Th1 cells. TEM ability was also blocked by pharmacological inhibitors of Src family protein-tyrosine kinases (PP2 and herbimycin A), phosphatidylinositol 3-kinase (wortmannin), and phosphatidylinositol-specific phospholipase C (). Cross-linking of CD44 strongly induced highly elongated morphology in Th1 lines, but weakly in Th2 lines. The pharmacological inhibitors that blocked TEM also inhibited this morphological change, whereas pertussis toxin did not. These data indicate that there are signaling pathways for TEM independent of chemokine attraction, but through adhesion molecules including CD44, and that the preferential TEM ability of Th1 over Th2 cells is formed, at least in part, by intrinsic differences in these pathways.
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PMID:Chemokine-independent preference for T-helper-1 cells in transendothelial migration. 1239 98

Adhesion molecules and C-C chemokines play an important role in the accumulation of eosinophils in allergic inflammation. In the present study, the expression and function of adhesion molecules on eosinophils from asthmatic patients and involvement of RANTES and eotaxin were examined. Eosinophils isolated by the CD16 negative selection method were stimulated with or without RANTES or eotaxin. Expression of b integrins on eosinophils and the functional adherence to recombinant soluble intercellular adhesion molecule-1 (r-sICAM-1)-coated plates were examined. Compared with normal subjects, eosinophils from asthmatic patients showed increased expression of b2 integrins and functional adherence to r-sICAM-1-coated plates. RANTES and eotaxin augmented the functional adherence of eosinophils without a significant upregulation of b2 integrins. Anti-b2 integrin antibody inhibited the augmentative effect on eosinophil adherence of RANTES and eotaxin. Pertussis toxin, wortmannin, and genistein inhibited chemokine-induced adherence. RANTES and eotaxin are closely related to eosinophil accumulation not only as chemotactic agents but also as augmentative agents for eosinophil adherence through involvement in functional eosinophil adherence to ICAM-1 by a possible qualitative change of b2 integrins. Pertussis toxin-sensitive G proteins, PI3 kinase, and tyrosine kinase are involved in signal transduction leading to activation of b2 integrins on eosinophil following stimulation with RANTES and eotaxin.
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PMID:Possible involvement of C-C chemokines in functional augmentation of adhesion molecules in asthmatic patients. 1248 19

Protein tyrosine kinase activation is an important requisite for leukocyte migration. Herein we demonstrate that NK cell binding to endothelium activates proline-rich tyrosine kinase 2 (Pyk-2) and the small GTP binding protein Rac that are coupled to integrin and chemokine receptors. Chemokine-mediated, but not integrin-mediated, Pyk-2 and Rac activation was sensitive to pretreatment of NK cells with pertussis toxin, a pharmacological inhibitor of G(i) protein-coupled receptors. Both Pyk-2 and Rac are functionally involved in chemokine-induced NK cell migration through endothelium or ICAM-1 or VCAM-1 adhesive proteins, as shown by the use of recombinant vaccinia viruses encoding dominant negative mutants of Pyk-2 and Rac. Moreover, we found that Pyk-2 is associated with the Rac guanine nucleotide exchange factor Vav, which undergoes tyrosine phosphorylation upon integrin triggering. Finally, we provide direct evidence for the involvement of Pyk-2 in the control of both chemokine- and integrin-mediated Rac activation. Collectively, our results indicate that Pyk-2 acts as a receptor-proximal link between integrin and chemokine receptor signaling, and the Pyk-2/Rac pathway plays a pivotal role in the control of NK cell transendothelial migration.
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PMID:Proline-rich tyrosine kinase 2 and Rac activation by chemokine and integrin receptors controls NK cell transendothelial migration. 1262 62

Central nervous system dysfunction is commonly observed in children with HIV-1 infection, but the mechanisms whereby HIV-1 causes encephalopathy are not completely understood. We have previously shown that human brain microvascular endothelial cells (HBMEC) from children are responsive to gp120 derived from X4 HIV-1 by increasing expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule-1. However, the mechanisms involved in gp120-mediated up-regulation of cell adhesion molecule expression is unclear. In the present study, we found that gp120 derived from both X4 and R5 HIV-1 induced increased expression of ICAM-1 on HBMEC, but the degree of this up-regulation differed among the various HBMEC isolates. The up-regulation of ICAM-1 was inhibited by anti-CD4 antibodies as well as by specific antibodies directed against chemokine receptors and small-molecule coreceptor inhibitors. Anti-CD4 antibodies inhibited the increase in ICAM-1 expression mediated by gp120 derived from X4 and R5 HIV-1, whereas antibodies against chemokine receptors displayed a differential inhibition depending on the source of gp120. Both X4 and R5 gp120-induced ICAM-1 expression was sensitive to pertussis toxin and involved the nuclear factor-kB pathway. These findings indicate a direct involvement of CD4 and a differential involvement of chemokine receptors in the activation of pediatric HBMEC by X4 and R5 gp120. The activation of brain endothelium of children by HIV-1 protein gp120 by way of CD4 and chemokine receptors may have implications for the pathogenesis of HIV-1 encephalopathy in the pediatric population.
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PMID:Induction of intercellular adhesion molecule-1 on human brain endothelial cells by HIV-1 gp120: role of CD4 and chemokine coreceptors. 1469 Dec 97

The mechanism by which osteoblasts (OB) interact and modulate the phenotype and proliferation of T lymphocytes during inflammation is not well known. The effects of two regulatory cytokines, TNFalpha and IFNgamma, on the expression of CD54 (ICAM-1) and CD106 (VCAM-1) adhesion molecules and the CXCR3 ligands (CXCL9, CXCL10, CXCL11), were assessed in a primary culture of human OB by real-time PCR, flow cytometry, and immunohistochemistry. In addition, we functionally evaluated the recruitment and proliferation of T lymphocytes grown with resting or stimulated OB. According to the present data IFNgamma, either alone or in combination with TNFalpha, significantly up-regulates the expression of CD54 and CD106 and induces the expression and release of CXCL9, CXCL10, CXCL11 in OB. The supernatant of TNFalpha- and IFNgamma-activated OB induces the recruitment of T lymphocytes more significantly than stimulation by CXCR3 ligands. T lymphocyte proliferation is significantly enhanced by direct contact with TNFalpha- and IFNgamma-activated OB or by incubation with the supernatant of TNFalpha- and IFNgamma-activated OB. Blocking experiments with anti-CD11a, anti-CD49d, anti-CXCR3, and Bordetella pertussis toxin demonstrate that adhesion molecules and the CXCR3 chemokine receptor play a key role in the proliferation of T lymphocytes. The present study demonstrates the involvement of adhesion molecules (CD11a and CD49d) and chemokine receptor (CXCR3) in the mechanism by which OB recruit, interact, and modulate T lymphocyte proliferation under inflammatory conditions.
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PMID:Recruitment and proliferation of T lymphocytes is supported by IFNgamma- and TNFalpha-activated human osteoblasts: Involvement of CD54 (ICAM-1) and CD106 (VCAM-1) adhesion molecules and CXCR3 chemokine receptor. 1475 44

Inosine is an endogenous purine nucleoside, which is formed by adenosine deaminidase during adenosine breakdown and is released into the extracellular space from the sympathetic nervous system or injured cells. Here, we studied the biological activity of inosine on human dendritic cells (DC), which are specialized antigen presenting cells characterized by their ability to migrate from the blood to peripheral tissues, and then to secondary lymphoid organs where they initiate adaptive immune responses. In immature DC, inosine concentration-dependently stimulated Ca(2+)-transients, actin polymerization, and chemotaxis. Experiments with adenosine receptor antagonists and pertussis toxin (PTX) as well as desensitization studies suggested that the activity of inosine was mediated by a G protein-coupled receptor pathway independent of adenosine receptors. DC, induced to mature by lipopolysaccharide, lost their ability to respond towards inosine with these activities. Moreover, inosine did neither influence membrane expression of CD54, CD80, CD83, CD86, HLA-DR, and MHC class I molecules nor modulated secretion of interleukin (IL)-12, IL-10, and tumor necrosis factor alpha in immature and lipopolysaccharide-matured DC. In aggregate, our study indicates that inosine may be involved in the trafficking control system of immature DC, and mediates its chemotactic activity by a PTX-sensitive mechanism independent of adenosine receptors.
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PMID:Inosine stimulates chemotaxis, Ca2+-transients and actin polymerization in immature human dendritic cells via a pertussis toxin-sensitive mechanism independent of adenosine receptors. 1497 44

Dendritic cells (DCs) possess a number of unique features that distinguish them from other APCs. One such feature is their ability to trigger Ag-independent responses in T cells. Previous studies have focused on mature DCs, but the prevalence of this phenomenon in the resting-state immature DCs has never been considered. In this study, we show that, in the absence of Ag, human immature DCs trigger multiple responses in autologous primary CD4+ T cells, namely, increased motility, small Ca2+ transients, and up-regulation of CD69. These responses are particularly marked in CD4+ memory T cells. By using several experimental approaches, we found that DC-specific ICAM-3-grabbing nonintegrin plays no role in the induction of T cell responses, whereas ICAM-1/LFA-1 interactions are required. In addition, DC-produced chemokines contribute to the Ag-independent T cell stimulatory ability of DCs, because pertussis toxin-treated T cells exhibit diminished responses to immature DCs. More particularly, CCL17 and CCL22, which are constitutively produced by immature DCs, mediate both T cell polarization and attraction. Thus, immature DCs owe part of their outstanding Ag-independent T cell stimulatory ability to chemokines and ICAM-1, but not DC-specific ICAM-3-grabbing nonintegrin.
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PMID:Immature dendritic cells (DCs) use chemokines and intercellular adhesion molecule (ICAM)-1, but not DC-specific ICAM-3-grabbing nonintegrin, to stimulate CD4+ T cells in the absence of exogenous antigen. 1521 Jul 58

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S-1-P) are both low molecular weight lysophospholipid (LPL) ligands that are recognized by the Edg family of G protein-coupled receptors. In endothelial cells, these two ligands activate Edg receptors, resulting in cell proliferation and cell migration. The intercellular adhesion molecule-1 (ICAM-1, CD54) is one of many cell adhesion molecules belonging to the immunoglobulin superfamily. This study showed that LPA and S-1-P enhance ICAM-1 expression at both the mRNA and protein levels in human umbilical cord vein endothelial cells (HUVECs). This enhanced ICAM-1 expression in HUVECs was first observed at 2 h postligand treatment. Maximal expression appeared at 8 h postligand treatment, as detected by flow cytometry and Western blotting. Furthermore, the effects of S-1-P on ICAM-1 expression were shown to be concentration dependent. Prior treatment of HUVECs with pertussis toxin, a specific inhibitor of G(i), ammonium pyrrolidinedithiocarbamate and BAY 11-7082, inhibitors of the nuclear factor (NF)-kappaB pathway, or Clostridium difficile toxin B, an inhibitor of Rac, prevented the enhanced effect of LPL-induced ICAM-1 expression. However, pretreatment of HUVECs with exoC3, an inhibitor of Rho, had no effect on S-1-P-enhanced ICAM-1 expression. In a static cell-cell adhesion assay system, pretreatment of LPL enhanced the adhesion between HUVECs and U-937 cells, a human mononucleated cell line. The enhanced adhesion effect could be prevented by preincubation with a functional blocking antibody against human ICAM-1. These results suggest that LPLs released by activated platelets might enhance interactions of leukocytes with the endothelium through a G(i)-, NF-kappaB-, and possibly Rac-dependent mechanism, thus facilitating wound healing and inflammation processes.
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PMID:Lysophospholipids increase ICAM-1 expression in HUVEC through a Gi- and NF-kappaB-dependent mechanism. 1529 53


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