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)

Chemokine-induced eosinophil chemotaxis is mediated primarily through the C-C chemokine receptor, CCR3. We have now detected CCR3 immunoreactivity on epithelial cells in biopsies of patients with asthma and other respiratory diseases. CCR3 mRNA was detected by Northern blot analysis after TNF-alpha stimulation of the human primary bronchial epithelial cells as well as the epithelial cell line, BEAS-2B; IFN-gamma potentiated the TNF-alpha-induced expression. Western blots and flow cytometry confirmed the expression of CCR3 protein. This receptor is functional based on studies demonstrating eotaxin-induced intracellular Ca(2+) flux and tyrosine phosphorylation of cellular proteins. The specificity of this functional response was confirmed by blocking these signaling events with anti-CCR3 mAb (7B11) or pertussis toxin. Furthermore, (125)I-eotaxin binding assay confirmed that CCR3 expressed on epithelial cells have the expected ligand specificity. These studies indicate that airway epithelial cells express CCR3 and suggest that CCR3 ligands may influence epithelial cell functions.
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PMID:Expression of the C-C chemokine receptor CCR3 in human airway epithelial cells. 1116 Jan 84

Eosinophils are predominant effector cells in allergic diseases attracted by several CC chemokines into the inflammatory tissue. According to their important role in attracting leukocytes, several kinds of chemokine receptor antagonists have been developed. Therefore, the aim of this study was to investigate the effect of aminooxypentane (AOP)-RANTES on the activation of the CC chemokine receptor 3, CCR3, exemplary on human eosinophils, because they represent the dominant CCR3+ cell type. AOP-RANTES dose-dependently induced an increase of intracellular calcium concentration ([Ca(2+)](i)) and a release of reactive oxygen species, which could be inhibited by pertussis toxin, in human eosinophils from normal nonatopic donors. AOP-RANTES was as effective as RANTES but less effective than eotaxin and eotaxin-2 in the activation of the respiratory burst. Flow-cytometric analyses revealed that eosinophils constitutively expressed the CC chemokine receptors CCR1 and CCR3, whereas CCR5 was not expressed. AOP-RANTES, RANTES, eotaxin and eotaxin-2, but not Met-RANTES, induced a downregulation of CCR3 at 37 degrees C. Reexpression of CCR3 on eosinophils was observed within 120 min. Whereas no differences of CCR3 downregulation and recycling after stimulation with AOP-RANTES, RANTES, eotaxin and eotaxin-2 were found there exists a distinct profile of activity with respect to the activation of the respiratory burst in human eosinophils.
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PMID:Aminooxypentane-RANTES induces CCR3 activation and internalization of CCR3 from the surface of human eosinophils. 1130 77

Mounting evidence suggests that lipopolysaccharide (LPS) modulates bronchoconstriction and eosinophil function in asthma. We have investigated the role of different chemokines in the eosinophil influx to the pleural cavity after LPS stimulation. Expression of mRNA for eotaxin, regulated on activation, normal T cells expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, MIP-2, and monocyte chemotactic protein (MCP)-1 was increased in cells recovered from the mouse pleural cavity 6 h after LPS administration. Eotaxin and RANTES, but not MIP-1alpha, protein levels were also increased in cell-free pleural washes recovered 6 h after LPS stimulation (LPW). Antimurine eotaxin and antimurine RANTES antibodies (Abs) failed to inhibit LPS-induced eosinophil influx into mouse pleural cavity in vivo. Pertussis toxin inhibited LPW-induced eosinophil shape change in vitro, suggesting the involvement of G protein-coupled receptors in LPW signaling. Blockade of CCR3 receptors diminished eosinophil shape change induced by LPW fractions in vitro and LPS-induced eosinophil accumulation in vivo. To investigate further contribution of CC chemokines, we administered a 35-kD CC chemokine neutralizing protein (vCKBP) in vivo. vCKBP inhibited the eosinophil accumulation induced by eotaxin and ovalbumin, but did not block that induced by LPS or LPW. Our data suggest that LPS-induced eosinophil accumulation depends on G protein-coupled CCR3 receptor activation, through a mechanism independent of eotaxin, RANTES, or other vCKBP-inhibitable CC chemokines.
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PMID:LPS induces eosinophil migration via CCR3 signaling through a mechanism independent of RANTES and Eotaxin. 1172 91

Leukocyte infiltration into inflammatory sites is regulated by the expression of adhesion and activation proteins, yet the role of these proteins in shear-dependent transmigration is poorly understood. We examined eosinophil recruitment on cytokine-stimulated human umbilical vein endothelial cells (HUVECs) under laminar flow conditions. Eosinophils rapidly transmigrated on interleukin (IL)-4-, but not TNF-stimulated HUVECs. Transmigration was shear dependent, with up to 90% of eosinophils transmigrating in the presence of shear and less than 25% of cells transmigrating under static conditions. Eosinophils express CC chemokine receptor CCR3 and are responsive to various CC chemokines. The effects of chemokines are mediated primarily through G(alpha)i, which is pertussis toxin sensitive. Greater than 65% of shear-dependent eosinophil transmigration on IL-4-stimulated HUVECs was blocked by either pertussis toxin or by an anti-CCR3 monoclonal antibody. Using reverse transcription polymerase chain reaction (RT-PCR) and Western blots, we found that IL-4-stimulated HUVECs produce both mRNA and protein for eotaxin-3. Eotaxin-3 was both released by HUVECs and expressed on the endothelial cell surface. Pretreatment of HUVECs with an anti-eotaxin-3 antibody blocked eosinophil transmigration to the same extent as an anti-CCR3 antibody. These results indicate that IL-4-stimulated HUVECs support shear-dependent eosinophil transmigration by upregulating eotaxin-3, and that surface association is critical for the role of eotaxin-3 in transmigration.
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PMID:Shear-dependent eosinophil transmigration on interleukin 4-stimulated endothelial cells: a role for endothelium-associated eotaxin-3. 1174 72

The CC chemokine eotaxin/CCL11 is known to bind to the receptor CCR3 on eosinophils and Th2-type lymphocytes. In this study, we demonstrate that CCR3 is expressed on a subpopulation of primary human dermal microvascular endothelial cells and is up-regulated by TNF-alpha. We found that incubation of human dermal microvascular endothelial cells with recombinant eotaxin/CCL11 suppresses TNF-alpha-induced production of the neutrophil-specific chemokine IL-8/CXCL8. The eotaxin/CCL11-suppressive effect on endothelial cells was not seen on IL-1beta-induced IL-8/CXCL8 release. Eotaxin/CCL11 showed no effect on TNF-alpha-induced up-regulation of growth-related oncogene-alpha or IFN-gamma-inducible protein-10, two other CXC chemokines tested, and did not affect production of the CC chemokines monocyte chemoattractant protein-1/CCL2 and RANTES/CCL5, or the adhesion molecules ICAM-1 and E-selectin. These results suggest that eotaxin/CXCL11 is not effecting a general suppression of TNF-alphaR levels or signal transduction. Suppression of IL-8/CXCL8 was abrogated in the presence of anti-CCR3 mAb, pertussis toxin, and wortmannin, indicating it was mediated by the CCR3 receptor, G(i) proteins, and phosphatidylinositol 3-kinase signaling. Eotaxin/CCL11 decreased steady state levels of IL-8/CXCL8 mRNA in TNF-alpha-stimulated cells, an effect mediated in part by an acceleration of IL-8 mRNA decay. Eotaxin/CCL11 may down-regulate production of the neutrophil chemoattractant IL-8/CXCL8 by endothelial cells in vivo, acting as a negative regulator of neutrophil recruitment. This may play an important biological role in the prevention of overzealous inflammatory responses, aiding in the resolution of acute inflammation or transition from neutrophilic to mononuclear/eosinophilic inflammation.
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PMID:Eotaxin/CCL11 suppresses IL-8/CXCL8 secretion from human dermal microvascular endothelial cells. 1188 59

Human eosinophils are potential sources of inflammatory and immunomodulatory mediators, including cysteinyl leukotrienes, chemokines, and cytokines, which are pertinent to allergic inflammation. We evaluated the means by which IL-16, a recognized eosinophil chemoattractant, might act on eosinophils to affect their capacity to release leukotriene C(4) (LTC(4)) or their preformed stores of chemokines (eotaxin, RANTES) or Th1 (IL-12) or Th2 (IL-4) cytokines. IL-16 dose dependently (0.01-100 nM) elicited new lipid body formation, intracellular LTC(4) formation at lipid bodies, and priming for enhanced calcium ionophore-activated LTC(4) release. IL-16 also elicited brefeldin A-inhibitable, vesicular transport-mediated release of preformed IL-4, but not IL-12, from eosinophils. CD4 is a recognized IL-16R, and accordingly anti-CD4 Fab, soluble CD4, and a CD4 domain 4-based IL-16 blocking peptide inhibited the actions of IL-16 on eosinophils. Although CD4 is not G-protein coupled, pertussis toxin inhibited IL-16-induced eosinophil activation. IL-16 actions were found to be mediated by the autocrine activity, not of platelet-activating factor, but rather of endogenous CCR3-acting chemokines. IL-16 induced the rapid vesicular transport-mediated release of RANTES. The effects of IL-16 were blocked by CCR3 inhibitors (met-RANTES, anti-CCR3 mAb) and by neutralizing anti-eotaxin and anti-RANTES mAbs, but not by platelet-activating factor receptor antagonists (CV6209, BN52021). RANTES and eotaxin each enhanced LTC(4) and IL-4 (but not IL-12) release. Therefore, IL-16 activation of eosinophils is CD4-mediated to elicit the extracellular release of preformed RANTES and eotaxin, which then in an autocrine fashion act on plasma membrane CCR3 receptors to stimulate both enhanced LTC(4) production and the preferential release of IL-4, but not IL-12, from within eosinophils.
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PMID:IL-16 promotes leukotriene C(4) and IL-4 release from human eosinophils via CD4- and autocrine CCR3-chemokine-mediated signaling. 1197 Oct 26

We investigated the actions of a panel of nonsteroidal anti-inflammatory drugs on eosinophils, basophils, neutrophils, and monocytes. Indomethacin alone was a potent and selective inducer of eosinophil and basophil shape change. In eosinophils, indomethacin induced chemotaxis, CD11b up-regulation, respiratory burst, and L-selectin shedding but did not cause up-regulation of CD63 expression. Pretreatment of eosinophils with indomethacin also enhanced subsequent eosinophil shape change induced by eotaxin, although treatment with higher concentrations of indomethacin resulted in a decrease in the expression of the major eosinophil chemokine receptor, CCR3. Indomethacin activities and cell selectivity closely resembled those of prostaglandin D(2) (PGD(2)). Eosinophil shape change in response to eotaxin was inhibited by pertussis toxin, but indomethacin- and PGD(2)-induced shape change responses were not. Treatment of eosinophils with specific inhibitors of phospholipase C (U-73122), phosphatidylinositol 3-kinase (LY-294002), and p38 mitogen-activated protein kinase (SB-202190) revealed roles for these pathways in indomethacin signaling. Indomethacin and its analogues may therefore provide a structural basis from which selective PGD(2) receptor small molecule antagonists may be designed and which may have utility in the treatment of allergic inflammatory disease.
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PMID:Indomethacin causes prostaglandin D(2)-like and eotaxin-like selective responses in eosinophils and basophils. 1198 Sep 3

Eotaxin is a critical chemokine eliciting migration of eosinophils and basophils in the pathogenesis of bronchial asthma. Recent studies have shown that the specific receptor for eotaxin, CCR3, is expressed in bronchial epithelial cells. Although mitogen-activated protein (MAP) kinases are involved in diverse cell functions of bronchial epithelial cells, their role in eotaxin signaling is unknown. In this study, we studied the activation and functional relevance of MAP kinases in bronchial epithelial cells stimulated with eotaxin. Eotaxin (1-100 nM) induced tyrosine/threonine phosphorylation and activation of extracellular regulated kinase (ERK) 1/2 and p38 in NCI-H(292) cells and normal human bronchial epithelial cells. The phosphorylation of these MAP kinases was detectable after 30 s, and peaked at 5 min. Eotaxin stimulated production of interleukin-8 and granulocyte macrophage colony-stimulating factor. Pretreatment of Compound X (a specific CCR3 antagonist), pertussis toxin, genistein, and wortmannin reduced the MAP kinase phosphorylation and cytokine production. The eotaxin-induced cytokine production was inhibited by specific inhibitors for MAP/ERK kinase (PD98059) and p38 MAP kinase (SB202190). These results suggest that both ERK1/2 and p38 MAP kinase activated by eotaxin have a critical role in the pathogenesis of asthma.
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PMID:The role of mitogen-activated protein kinases in eotaxin-induced cytokine production from bronchial epithelial cells. 1220 95

Naive Th cells, bearing receptors for cutaneous antigens, become activated in skin-draining lymph nodes and express cutaneous lymphocyte antigen (CLA), which confers to these cells the capacity to migrate into the skin to exert their normal effector functions. In the case of atopic dermatitis (AD), allergen-specific Th2 cells generate exacerbated responses and induce skin inflammation. In such a situation, interfering with the specific mechanism of skin homing would provide a therapeutic benefit. Here we report that CLA+ Th2 memory cells, derived from skin lesions of AD patients, selectively migrate to human skin grafts transplanted onto SCID mice in response to CCR4 but not CCR3, CCR8 or CXCR3 ligands. Skin homing of human CCR4+ Th2 memory cells was Pertussis toxin sensitive and restricted to the CLA+ subset. Furthermore, treatment of these mice with anti-E-selectin monoclonal antibody was sufficient to prevent CCL22-mediated Th2 cell migration to human skin, which both, validates the model and highlights the importance of CLA/E-selectin interactions in the homing process of Th2 cells to the skin. Using this mechanistic model we demonstrate that skin homing of human Th2 memory cells can be efficiently suppressed using a low molecular weight E-selectin antagonist, which is of clinical relevance for the treatment of inflammatory skin diseases, including AD.
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PMID:Targeting CLA/E-selectin interactions prevents CCR4-mediated recruitment of human Th2 memory cells to human skin in vivo. 1255 62

Eotaxin-3 (CCL26) belongs to the group of CC chemokines that attract eosinophils, basophils, and Th2 lymphocytes. Like eotaxin (CCL11) and eotaxin-2 (CCL24), eotaxin-3 mediates its activity through CCR3. Here we show that eotaxin-3 also binds to CCR2 on monocytes and CCR2-transfected cells. In contrast to monocyte chemotactic protein 1 (MCP-1; CCL2), eotaxin-3 does not trigger intracellular calcium mobilization, enzyme release, or phosphorylation of the mitogen-activated protein (MAP) kinase ERK and induces a weak chemotaxis in monocytes. Instead, eotaxin-3 inhibits MCP-1-mediated responses, thus acting as a natural antagonist for CCR2. This study also demonstrates that eotaxin-3 promotes active movement of monocytes away from a gradient of eotaxin-3 in vitro. This repellent effect is amplified when an additional gradient of MCP-1 is applied, demonstrating that the 2 mechanisms are synergistic. Eotaxin-3 effects on monocytes are largely abolished when cells are pretreated with MCP-1 or CCR2 antagonists. Like MCP-1-mediated migration, repulsion is sensitive to Bordetella pertussis toxin, indicating the involvement of Gi protein-coupled receptors. However, using transfected cells expressing CCR2 we could not detect F-actin formation or an active movement away induced by eotaxin-3, suggesting that either expression of a single receptor type is not sufficient to mediate cell repulsion or that the used transfected cell lines lack additional interaction molecules that are required for reverse migration. Eotaxin-3 was expressed by vascular endothelial cells and was essential for endothelial transmigration of eosinophils. Our data provide a mechanism by which 2 chemokine gradients that are oriented in opposite directions could cooperate in efficiently driving out monocytes from blood vessels into tissue.
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PMID:Eotaxin-3 is a natural antagonist for CCR2 and exerts a repulsive effect on human monocytes. 1268 46


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