Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The processes of lymphocyte-endothelial cell interaction and the in vitro assays employed in their study are the subjects of this review. In motility assays in porous filters and gel matrices, it has been shown that lymphocyte migration can be modulated by interleukin-2 (IL-2), IL-3, IL-4, IL-6, and IL-8. Cytokines can also modulate lymphocyte-endothelial adhesion. Endothelial intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are induced or upregulated by IL-1 or tumor necrosis factor. In addition, interferon-gamma upregulates ICAM-1, and IL-4 can induce VCAM-1. The roles of these cytokines and adhesion molecules in transendothelial migration may be studied in assays in which lymphocytes penetrate layers of cultured endothelial cells. These models can distinguish lymphocyte adhesion from subsequent migration. Using such models, we and others have obtained evidence that both lymphocyte function-associated antigen-1 (LFA-1)/ICAM-1 and very late activation antigen 4 (VLA-4)/VCAM-1 interactions mediate lymphocyte adhesion to endothelial cells, but that LFA-1/ICAM-1 interactions play a greater role in transendothelial migration.
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PMID:In vitro models of lymphocyte transendothelial migration. 138 72

Monocytes and polymorphonuclear leukocytes (PMNLs) migrate across cytokine (interleukin-1, tumor necrosis factor) activated endothelium or unstimulated endothelium in response to chemotactic factors in vitro and in vivo utilizing the CD11/CD18 (i.e., beta 2 integrin) adhesion molecule complex. However, in vivo studies have suggested that under some conditions and/or in certain tissues, leukocyte migration can also proceed via CD11/CD18-independent mechanisms. Here we compared adhesion mechanisms involved in the migration of 51Cr-labeled blood monocytes and PMNLs across human umbilical vein endothelium (HUVE) monolayers. We observed that monocyte transendothelial migration was not inhibited by monoclonal antibody (mAb) to CD18, when the HUVE was activated with IL-1 and the chemotactic factor C5a induced the migration. This CD18-independent monocyte migration was blocked by treatment of the monocyte with mAb to beta 1 or alpha 4 integrin, suggesting that very late activation antigen 4 (VLA-4) on the monocyte served as the alternative migration mechanism. In contrast to monocytes, mAb to CD18 inhibited PMNL migration to C5a across IL-1-activated HUVE, but only by 66%, significantly less than with C5a alone (84%) or IL-1-activated HUVE alone (95%). The migration of anti-CD18 mAb-treated PMNLs was not inhibited by function-blocking mAbs to sialyl Lewisx, L-selectin, beta 1 or alpha 4 integrin, the beta 3-related leukocyte response integrin, IL-8, or platelet-activating factor (PAF) antagonists, alone or in combination. Antibody-blocking studies of the ligands on HUVE indicated that E-selectin may be partially involved in this CD18-independent PMNL migration but that ICAM-1, VCAM-1, PECAM-1, and P-selectin are not involved. Of several chemotactic factors tested, C5a and C5adesArg in activated plasma were the most active in inducing CD18-independent migration of PMNLs across IL-1-activated HUVE. These results demonstrate that (1) monocytes can utilize VLA-4 for optimal transendothelial migration and (2) PMNLs may have a novel CD18-independent migration mechanism that is activated by C5a in conjunction with one or more ligands on cytokine-activated endothelium. This may involve, in part, E-selectin interacting with a yet to be identified counterreceptor on PMNLs.
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PMID:CD11/CD18-independent transendothelial migration of human polymorphonuclear leukocytes and monocytes: involvement of distinct and unique mechanisms. 772 14

Optical microscopy and image processing have been employed to study the distribution of several cell surface receptors on living human neutrophils during opsonin-dependent and opsonin-independent phagocytosis. Receptors were labeled using fluorescein-, rhodamine-, or AMCA-conjugated F(ab')2 fragments of anti-Fc gamma RIIIB (CD16), anti-CR3 (CD11b/CD18), and anti-uPAR (urokinase-type plasminogen activator receptor) antibodies, intact phycoerythrin-labeled interleukin 8, and fluorescein- or rhodamine-labeled Con A (concanavalin A), Boc-PLPLP (tert-butyl-oxycarbonyl-Phe(D)-Leu-Phe(D)-Leu-Phe-OH), and N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys. Labeled neutrophils were observed during the phagocytosis of IgG-opsonized erythrocytes and nonopsonized latex beads, Escherichia coli, and Staphylococcus aureus. To quantitate receptor distribution, cells were divided into four quadrants with the first being the point of attachment and the fourth being opposite the point of attachment. Ligated formyl peptide receptors, and to a lesser extent CR3, accumulated at the sites of target internalization for all forms of phagocytosis examined. However, Fc gamma RIIIB, uPAR, IL-8, Con A, and the FPR antagonist FBoc-PLPLP were not polarized on cells during phagocytosis. These data suggest that agonist-labeled formyl peptide receptors may play a broader role in leukocyte function than previously suggested, including possible participation in phagocytosis.
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PMID:Imaging the spatial distribution of membrane receptors during neutrophil phagocytosis. 773 43

Increasing evidence suggests an important role for cytokines in the regulation of eosinophilic inflammation. In the present study we investigated the distribution of leukocytes, lymphocyte subsets, their activation state, and the cytokine profile present in BAL fluid from patients with various lung diseases associated with eosinophilia. For this purpose, we analyzed the levels of IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, GM-CSF, TNF-alpha, and IFN-gamma, as well as soluble IL-2 and TNF receptors, in concentrated bronchoalveolar lavage (BAL) fluid obtained from clearly defined patients with allergic and nonallergic asthma, eosinophilic pneumonia, allergic bronchopulmonary aspergillosis (ABPA), hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis. BAL fluid from normal individuals and sarcoidosis patients was analyzed as noneosinophilic controls. BAL cytokine levels were compared with the cellular infiltrate and the activation state of CD4+ and CD8+ T cells as measured by the expression of IL-2 receptors (CD25), HLA-DR, and the very late activation antigen VLA-1. Beside the characteristic leukocyte infiltrate in the various lung diseases, all patients demonstrated significantly increased numbers of activated CD4 and CD8 T cells compared with normal individuals. The analysis of the cytokine profile present in BAL fluid revealed a T helper type 2 (Th2) cell cytokine pattern, with elevated IL-4 and IL-5 but normal levels of IL-2 or IFN-gamma in allergic asthma. ABPA patients demonstrated significantly increased levels of IL-4 and IL-5, with low but significantly elevated concentrations of IL-2 and IFN-gamma. In contrast, the analysis of the cytokine profile in sarcoidosis patients revealed a Th1 cell cytokine pattern characterized by increased concentrations of IL-2 and IFN-gamma but normal levels of IL-4 or IL-5. All other patient groups showed a cytokine pattern incompatible with a pure Th1 or Th2 cell response, because IL-5, IL-2, and IFN-gamma were found to be significantly increased. The BAL fluid analysis of the other, mainly non-T cell-derived cytokines and soluble receptors showed increased levels in all patients compared with normal individuals and may represent the ongoing inflammatory responses. In conclusion, whereas increased IL-4 levels were found only in diseases characterized by increased IgE production, IL-5 was elevated in all patients with increased numbers of eosinophils. The close correlation between IL-5 levels, number of eosinophils, and activated T cells further supports a role for IL-5 in causing tissue eosinophilia.
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PMID:Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia. 792 34

Cellular and mediator profiles in bronchoalveolar lavage have not been compared systematically between patients with asthma of different severities, mainly because the patients with more severe asthma have an increased need for antiinflammatory medication. Information is limited to comparisons of allergic and intrinsic asthma, which can be distinguished clinically. When patients from these two groups with similar degrees of bronchial hyperresponsiveness were compared, both groups showed increased numbers of activated T-helper lymphocytes; those in the allergic group expressed the IL-2 receptor (CD25+), whereas in patients with intrinsic asthma there was also an increased number of T-suppressor cells with the activation markers CD25, class II histocompatibility antigen, and very late activation antigen-I, as well as T-helper cells class II histocompatibility antigen and very late activation antigen-I. This pattern is compatible with a more chronic T-cell activation in patients with intrinsic asthma. In patients with allergic asthma the cytokine pattern is compatible with a pure TH2 response (elevated IL-4 and IL-5); however, intrinsic asthma is characterized by elevated IL-5 and IL-2 but not IL-4. Our own findings show similar concentrations of IL-1, IL-8, and granulocyte-macrophage colony-stimulating factor in bronchoalveolar lavage fluid of patients with allergic and intrinsic asthma, whereas IL-6 and interferon-gamma tended to be higher in patients with intrinsic asthma. There are probably fundamental differences in the pathogenesis of allergic and intrinsic asthma. These findings suggest that asthma does not depend on the presence of IgE or IL-4, although both may contribute to the pathogenesis of atopic asthma. The only common pathway in the different presentations of asthma that has been related to clinical symptoms appears to be IL-5-mediated activation of eosinophils; therapies aimed at this mechanism may be promising.
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PMID:Inflammatory determinants of asthma severity: mediator and cellular changes in bronchoalveolar lavage fluid of patients with severe asthma. 893 74

Binding of the zymogen serine protease Factor VII (FVII) to its cellular cofactor tissue factor (TF) triggers blood coagulation. Several recent reports have suggested that the formation of this complex may serve additional functions. We have used cDNA arrays to study differential gene expression in response to the interaction of activated FVII (FVIIa) with TF on a human keratinocyte cell line. Of 931 mRNA species observed up to 6 h after FVIIa (10 nM) addition, 24 were significantly up-regulated in what may resemble a wound-type response. Responders included mRNA species coding for transcription regulators (c-fos, egr-1, ETR101, BTEB2, c-myc, fra-1, and tristetraproline), growth factors (amphiregulin, hbEGF, CTGF, and FGF-5), proinflammatory cytokines (IL-1beta, IL-8, LIF, and MIP2alpha), proteins involved in cellular reorganization/migration (RhoE, uPAR, and collagenases 1 and 3), and others (PAI-2, cyclophilin, GADD45, Jagged1, and prostaglandin E(2) receptor). The transcriptional response to FVIIa was abrogated by antibodies to TF and left unaffected by hirudin. The pattern of genes induced suggests that the FVIIa.TF complex may play an active role in early wound repair as well as hemostasis. The former is a novel function ascribed to the complex that may also be contributing to the pathophysiology of unwarranted TF expression.
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PMID:Binding of factor VIIa to tissue factor on keratinocytes induces gene expression. 1069 65

The CD69 glycoprotein is an early activation antigen of T and B lymphocytes but it expression is induced in vitro on cells of most hematopoietic lineages, including neutrophils after stimulation with PMA or fMLP. In this study, we investigated whether CD69 expression on human neutrophils could be modulated by inflammatory or anti-inflammatory cytokines (IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, G-CSF, GM-CSF, TNF-alpha, TGF-beta, IFN-alpha, IFN-gamma). Resting neutrophils from healthy subjects did not express CD69 on the cell surface; moreover, a preformed intracellular pool of CD69 was not evident in these cells. CD69 was barely detectable on these cells after overnight incubation in medium while overnight incubation with GM-CSF, IFN-gamma or IFN-alpha significantly induced CD69 expression on neutrophils with GM-CSF appearing to be the most potent inducer. This induction was dependent on a new protein synthesis as it was significantly inhibited by cycloheximide (about 50% inhibition). CD69 cross-linking on GM-CSF-primed neutrophils sinergized with LPS and increased TNF-alpha production and secretion suggesting a role for CD69-positive neutrophils in the pathogenesis and maintenance of different inflammatory diseases.
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PMID:Induction of CD69 activation molecule on human neutrophils by GM-CSF, IFN-gamma, and IFN-alpha. 1271 36

While cases of silicosis are often complicated by various autoimmune disorders, patients with asbestosis develop malignant tumors such as lung cancer and malignant mesothelioma. These differences may derive from different biological effects, particularly on immunological cells, of silica and asbestos. To find differences between silica and asbestos, the early activation antigen, CD69, on T cells was examined because dysregulated and continuous activation of T cells may promote the survival of self-recognizing T cells. After cultivation of peripheral blood mononuclear cells with or without silica or chrysotile-A, an asbestos, only silica induced CD69 expression on the lymphocytes. This induction of CD69 expression was mediated by protein kinase C activation. In addition, cell-cell contact mediated by HLA-DR was more important than soluble factors secreted from silica-phagocytosed cells such as IL-1beta, IL-6, and IL-8, even though IL-6 and IL-8 were produced during the culture of PBMCs with silica and chrysotile-A. It should be examined how these activated, CD69-expressing lymphocytes affect other immune systems as well as alter themselves in terms of cytokine production and cell-cell interaction, leading to autoimmune disorders in silicosis patients.
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PMID:Induction of CD69 antigen expression in peripheral blood mononuclear cells on exposure to silica, but not by asbestos/chrysotile-A. 1579 May 20

Animal venomous secretions have been explored as source of active substances affecting mammal hemostasis. These active principles impinge on key elements of almost all physiologic pathways and have an enormous potential in the development of new therapeutic drugs. The envenomation caused by the caterpillar Lonomia obliqua (lonomism) is characterized by a hemorrhagic clinical profile. Investigations of caterpillar venom have, in general, involved the isolation and biochemical characterization of active principles related to the pathophysiology of envenomation. In the last few years, these studies focused on the caterpillar's secretions pro-coagulant, fibrin(ogen)olytic, hemolytic, edematogenic and nociceptive activities. Recently, a significant advance was achieved as a result of a transcriptome study, which generated a catalog of putative toxic proteins in the caterpillar venom, giving rise to hypotheses on the molecular basis of pathogenesis which could be experimentally explored. In this investigation, using a microarray methodology, we analyzed the effects of the caterpillar venom on the gene expression profile of cultured human fibroblasts with the aim of gaining insight into genes possibly associated with the clinical manifestations of lonomism. Our hypothesis was that both the direct action L. obliqua venomous proteins on the host as well as an indirect effect caused by alteration in the gene expression pattern in host tissues could function in concert and perhaps synergistically to give rise to the profound symptoms observed during lonomism. Interesting changes in the expression pattern of some genes, such as IL-8, prostaglandin-endoperoxide synthase 2, urokinase-type plasminogen activator receptor and tissue factor, were observed in treated fibroblasts, which could contribute to some of the observed pathological sequela in lonomism. Thus, lonomism appears to be a result of both the previously described direct effects of the venom as well as indirect effects caused by changes in host gene expression profiles. These studies have enhanced our understanding of lonomism and may contribute to insights into more effective treatments.
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PMID:Novel perspectives on the pathogenesis of Lonomia obliqua caterpillar envenomation based on assessment of host response by gene expression analysis. 1836 25

The urokinase-type plasminogen activator receptor (uPAR/CD87) exists both in cell-bound and soluble forms. Neutrophils contain extensive intracellular pools of uPAR that are translocated to the plasma membrane upon activation. In the present study, we investigated the ability of human neutrophils to shed uPAR from cell surface following activation and addressed the possible involvement of the released receptor in the inflammatory response. We first observed that the spontaneous release of suPAR by resting neutrophils was strongly and rapidly (within minutes) enhanced by calcium ionophore ionomycin and to a lesser extent when cells were primed with TNF-alpha and then stimulated with fMLP or IL-8. We demonstrated that suPAR is produced by resting and activated neutrophils predominantly as a truncated form devoid of N-terminal D1 domain (D2D3 form) that lacks GPI anchor. Migration of formyl peptide receptor-like 1 (FPRL1)-transfected human embryonic kidney (HEK) 293 cells toward the supernatants harvested from activated neutrophils was significantly diminished when D2D3 form of suPAR was immunodepleted from the supernatants. We conclude that activated neutrophils release the chemotactically active D2D3 form of suPAR that acts as a ligand of FPRL1. Interestingly, we present evidence that GPI-specific phospholipase D (GPI-PLD) that has previously been shown to shed uPAR in cancer cells is not involved in suPAR release from human neutrophils. We suggest that production of the chemotactically active D2D3 form of suPAR by activated human neutrophils in vivo could contribute to the recruitment of monocytes and other formyl peptide receptors-expressing cells to the sites of acute inflammation where neutrophil accumulation and activation occur.
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PMID:Activated human neutrophils rapidly release the chemotactically active D2D3 form of the urokinase-type plasminogen activator receptor (uPAR/CD87). 1883 May 68


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