Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.59 (MIP)
 4,906 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CC chemokine monocyte chemoattractant protein-3 (MCP-3) activates human monocytes, lymphocytes, basophils, and eosinophils. MCP-3 has been reported to induce [Ca2+]i changes in cells transfected with the monocyte-selective MCP-1 receptor 2B (CC CKR2B) and competes for 125I-MCP-1 binding on CC CKR2B, suggesting that it may mediate monocyte responses to MCP-3. However, we now show that MCP-3 is a ligand and potent agonist for the macrophage inflammatory protein-1 alpha (MIP-1 alpha)/regulated on activation, normal T expressed, and secreted protein (RANTES) receptor CC CKR1 (rank order for [Ca2+]i changes = MIP-1 alpha > MCP-3 > RANTES), which is expressed in monocytes > neutrophils > eosinophils. 125I-MCP-3 bound directly to CC CKR1 and CC CKR2B (Ki = 8 and 7 nM, respectively). Binding to CC CKR1 was competed by all CC chemokines tested except MCP-1. In contrast, binding to CC CKR2B was competed only by MCP-3 and MCP-1. Both MCP-1 and MCP-3 were equipotent agonists (EC50 = 10 nM for [Ca2+]i changes). Thus, MCP-3 is a functional ligand for both CC CKR1 and CC CKR2B, which otherwise have distinct selectivities for CC chemokines. These data suggest that monocyte responses to MCP-3 could be mediated by both CC CKR2B and CC CKR1, whereas eosinophil responses to MCP-3 could be mediated by CC CKR1.
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PMID:Monocyte chemoattractant protein-3 is a functional ligand for CC chemokine receptors 1 and 2B. 853 Mar 54

Herpes simplex virus type 1 (HSV-1) infection on the murine cornea induces an intense inflammatory response which can lead to blindness. This disease, known as herpes stromal keratitis, can be prevented by the timely passive transfer of monoclonal antibody specific for viral glycoprotein D (gD). Precisely how antibody treatment prevents excessive corneal inflammation is not known. In this study we investigated whether chemokine mRNA expression is inhibited by antibody treatment. Total cellular RNAs isolated from normal corneas and at various times after virus infection were analyzed via reverse transcription-PCR for mRNA coding for seven different chemokines. Constitutive levels of IP-10, KC, MIP-2, MCP-1, MIP-1 beta, and RANTES mRNA were detected in uninfected corneas of BALB/c mice. When the cornea was mechanically traumatized, message for all six chemokines was transiently elevated above constitutive levels. In contrast, HSV-1 infection resulted in prolonged enhanced chemokine message expression. The kinetics of mRNA accumulation was distinctive for each chemokine analyzed. MIP-1 alpha message, not detected constitutively, was not evident until day 7 postinfection. Administration of anti-HSV gD monoclonal antibody 1 day after infection was associated with reduced message for MIP-2, MCP-1, MIP-1 alpha, and MIP-1 beta. IP-10, KC, and RANTES messages were not altered. Collectively, our results suggest that anti-gD treatment may protect, at least in part, by inhibiting production of chemokines believed to promote inflammation.
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PMID:Protective antibody therapy is associated with reduced chemokine transcripts in herpes simplex virus type 1 corneal infection. 855 95

We report here the ability of the beta chemokines MIP-1 alpha, MIP-1 beta, RANTES, and MCP-1 to enhance some lymphocyte effector functions. Initial studies focused on the effects of chemokines on human and mouse cytotoxic T lymphocyte (CTL)- and natural killer (NK) cell-specific cytolytic responses. The results demonstrate that beta chemokines are capable of augmenting mouse and human CTL and human NK- but not lymphokine-activated killer cell- or antibody-dependent cell cytotoxicity-specific cytolytic responses. Neutralization analysis utilizing integrin-specific antibodies revealed that CTL/NK tumor cell conjugate formation is required for chemokine-induced killing. In addition, both CTLs and NK cells incubated with various beta chemokines were induced to degranulate and release granule-derived serine esterases, suggesting that chemokines may be important costimulators of CTL and NK cell degranulation and may thus augment local target cell destruction. Chemokines also modulate antigen-driven T cell proliferative responses as well as effects on lymphokine production. Many of the beta chemokines were found to potentiate human and mouse antigen-specific Th1 and Th2 clone activation promoting cellular proliferation and the release of various lymphokines. This chemokine-mediated T cell proliferation was chemokine and antigen dose dependent as well as clone dependent. Chemokine pretreatment analyses with T cells and antigen-presenting cells (APCs) revealed that chemokines up-regulate both T cells and antigen- presenting cells (APCs) revealed that chemokines up-regulate both T cell and APC functions. Costimulation assays using immobilized antiCD3 monoclonal antibody-coated plates and purified human and mouse T cells and T cell clones in the presence of various chemokines also exhibited enhanced proliferation and lymphokine secretion. This costimulation was interleukin-2 dependent and required the presence of free extracellular calcium. Examination of chemokine-treated APCs revealed that the T cell costimulatory molecule B7-1 was induced by various beta chemokines. Neutralization of endogenously produced chemokines, with specific antibodies during an antigen-specific T cell response blocked cellular proliferation, suggesting that the chemokines have an autocrine role in antigen-induced T cell proliferative responses. Together, these results suggest that chemokines play a significant role in the activation of polyclonal as well as antigen-specific helper and cytotoxic T cells during the genesis of an immune response.
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PMID:Beta chemokines costimulate lymphocyte cytolysis, proliferation, and lymphokine production. 855 72

The adherence and transmigration of T cells through microvascular endothelium is an essential step for recruitment into inflammatory lesions, although the factors that stimulate the directional migration of T cells have not been fully characterized. In the present study we investigated the capacity of chemokines to induce migration of T cells across dermal microvascular endothelial cell monolayer. The results showed that recombinant MCP-1 significantly induced transendothelial migration of both resting and activated T cells. Maximal induction of migration was observed at a concentration of 10 ng/ml and a 3- to 4-hr incubation period. In contrast, the chemokines IL-8, RANTES, and MIP-1 alpha failed to stimulate T cell migration at doses as high as 100 ng/ml. In studies designed to investigate the intracellular signaling pathways mediating the MCP-1 effect, the results showed that MCP-1 at doses ranging from 10 to 100 ng/ml did not cause an increase in intracellular calcium ions in T cells, even though this chemokine induced rapid calcium mobilization in monocytes. Furthermore, pretreatment of T cells with either bisindolymaleimide HCl, a specific inhibitor of protein kinase C, or genistein, a protein tyrosine kinase inhibitor, significantly decreased the MCP-1-induced transmigration in a dose-dependent manner. In contrast, T cells pretreated with the protein kinase A-specific inhibitor H89 responded normally to MCP-1 stimulation. Finally, T cell transmigration was inhibited by antibodies against CD11a, thereby confirming the importance of beta 2-integrin in the transmigration process.
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PMID:The intracellular signaling pathways involved in MCP-1-stimulated T cell migration across microvascular endothelium. 860 36

Basophils and eosinophils can be activated in vitro by several chemokines such as RANTES, monocyte chemotactic and activating factor (MCAF/MCP-1), macrophage inflammatory peptide-1 alpha (MIP-1 alpha), and interleukin-8 (IL-8). To explore the clinical relevance of the in vitro observations, we measured here the concentrations of these chemokines in sputa from asthmatic patients during acute attacks. Before the onset of a late-phase exacerbation, sputum MCAF/MCP-1, MIP-1 alpha, and IL-8 levels transiently but markedly increased from the basal levels in all of the patients with exacerbation, whereas the sputum levels of these chemokines remained unchanged during the course in the patients without a late-phase exacerbation. These results suggest the involvement of these chemokines in the late-phase exacerbation of asthma.
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PMID:Increase of chemokine levels in sputum precedes exacerbation of acute asthma attacks. 860 7

We examined the genetic expression of 2 CXC chemokines (IL-8, IP-10), 5 CC chemokines (MCP-1, MIP-lalpha, MIP-1beta, RANTES, 1309) and 1 C chemokine (SCM-1/lymphotactin/ATAC) in various human T-cell lines. By Northern blot analysis, HTLV-1-positive T-cell lines were found to express a number of chemokine genes at variable levels and in different combinations. However, none of the chemokine genes was expressed in HTLV-1-negative T-cell lines. We further confirmed secretion of 3 chemokines (IL-8, MIP-1alpha and RANTES) by some HTLV-1-positive T-cell lines. To examine the role of the HTLV-1-encoded transactivator Tax in the induction of these chemokine genes, we used JPX-9 and JPX-M, which were stably transformed with tax and non-functional tax, respectively, under the control of a metallothionein promoter. Induction of tax in JPX-9 with Cd2+ was accompanied by rapid induction of IL-8, IP-10, MIP-1alpha, MIP-1beta, 1309 and SCM-1 as determined by reverse transcription PCR. No such induction was seen in JPX-M. We thus suggest that Tax is, at least in part, responsible for constitutive expression of certain chemokine genes in HTLV-1-infected T cells. Aberrant production of various chemokines by HTLV-1- infected T cells may impact on the pathophysiology of HTLV-1-associated diseases.
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PMID:Constitutive expression of various chemokine genes in human T-cell lines infected with human T-cell leukemia virus type 1: role of the viral transactivator Tax. 860 55

Chronic inhalation of carbon black can produce carcinomas in rat lungs. At present the mechanisms underlying the rat lung tumor response to carbon black are unknown, although a significant role for inflammation and cell proliferation has been postulated. To investigate the processes which may contribute to development of rat lung tumors after carbon black exposure, we characterized the effects of subchronic inhalation of carbon black by rats on mutagenesis in alveolar epithelial cells, pulmonary inflammation, inflammatory cytokine/growth factor expression, and lung histopathology. Briefly, rats were exposed for 6 hr/day, 5 days/week for up to 13 weeks to 1.1, 7.1, and 52.8 mg/m3 carbon black and the effects on the lung were characterized after 6.5 and 13 weeks of exposure and 3 and 8 months of recovery. Endpoints characterized after carbon black exposure included mutation in the hprt gene of alveolar epithelial cells, changes in bronchoalveolar lavage fluid markers of lung injury and inflammation, expression of mRNA for the chemokines, MIP-2 and MCP-1, and lung histopathology. Lung burdens of carbon black were also determined. After 13 weeks of exposure to 1.1, 7.1, and 52.8 mg/m3 carbon black, lung burdens were 354, 1826, and 7861 micrograms carbon black, respectively. The lung clearance of carbon black appeared impaired after exposure to 7.1 and 52.8 mg/m3 carbon black, with the effects being more pronounced at the higher exposure level. Subchronic inhalation of 1.1 mg/m3 carbon black did not elicit any detectable adverse lung effects. A significant increase in hprt mutation frequency in alveolar epithelial cells was detected immediately after 13 weeks of exposure to 7.1 and 52.8 mg/m3 carbon black as well as after 3- and 8-month recovery periods for the group exposed to 52.8 mg/m3. No increase in hprt mutation frequency was observed for epithelial cells obtained from rats exposed to 1.1 mg/m3 carbon black. The observation that genotoxic effects (i.e., mutations) on alveolar epithelial cells occurred only after carbon black exposures which resulted in significant inflammation and epithelial hyperplasia supports the hypothesis that inflammatory cell-derives oxidants and increased cell proliferation play a role in the pathogenesis of rat lung tumors in response to carbon black.
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PMID:Pulmonary inflammatory, chemokine, and mutagenic responses in rats after subchronic inhalation of carbon black. 861 46

The ability of chemokines, particularly MCP-1, to induce integrin-dependent binding of T lymphocytes to endothelial adhesion molecules or extracellular matrix (ECM) components was examined. MCP-1 induced significant adhesion to fibronectin (FN) and to endothelial-secreted ECM but not to purified ICAM-1 or VCAM-1, or to activated endothelium. The MCP-1-induced binding of T lymphocytes to FN was rapid, dose dependent, and resulted from activation of both VLA-4 and VLA-5. Like MCP-1, the chemokines RANTES and MIP-1 beta induced T lymphocyte binding to FN, but not to ICAM-1. We suggest therefore, that these T lymphocyte chemokines may be most important, not in initiating integrin-dependent firm adhesion of T lymphocytes to the vascular wall, but rather, in subsequent adhesive interactions during migration into tissue.
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PMID:The C-C chemokine MCP-1 differentially modulates the avidity of beta 1 and beta 2 integrins on T lymphocytes. 862 8

The proteolytic cleavage product of complement component 3, (C3a), is like C4a and C5a, is a potent anaphylatoxin and induces the production of inflammatory mediators in phagocytes. Notably, mast cells respond to C3a with the release of vasoactive substances, including histamine. We have examined the function and receptor binding of C3a in a human leukemic mast cell line, HMC-1. Similar to chemoattractant agonists in leukocytes, C3a induced rapid cytosolic free calcium concentration increases in HMC-1 cells. EGTA did not diminish this response, indicating that mobilizable Ca2+ was from intracellular stores. Receptors of C3a in HMC-1 cells couple in part to Bordetella pertussis toxin-sensitive G-proteins and, therefore, appear to belong to the family of serpentine receptors that require G-proteins for signal transduction. HMC-1 cells express two types of C3a receptors, C3aR1 and C3aR2, that were shown to bind 125I-C3a with high-(Kd1 = 2.1-4.8 nM) or low-affinity (Kd2 = 30-150 nM), and both receptors are expressed at high level: 3 x 10(5)-6 x 10(5) C3aR1/cell and 5 x 10(5)-2.3 x 10(6) C3aR2/cell. Results from cross-linking experiments with 125I-C3a fully agree with the presence of two different classes of C3a receptors in HMC-1 cells. Two membrane proteins with apparent molecular masses of 54-61 kDa (p57) and 86-107 kDa (p97) could be covalently modified with 125I-C3a, and this cross-linking was inhibited with an excess of unlabeled C3a. Many of the known agonists for leukocytes including 13 chemokines (IL-8, NAP-2, GRO alpha, ENA-78, IP10, PF4, MCP-1, 2 and 3, RANTES, MIP-1 alpha, MIP-1 beta and I309), three neuropeptides (neuropeptide Y, somatostatin and calcitonin), as well as C5a, did not activate HMC-1 cells, indicating that C3a is one of a few protein ligands for which this cell line expresses specific receptors. The apparent selectivity for C3a and the abundant expression of C3a receptors make the HMC-1 cell line an excellent choice for the cloning of the receptor genes.
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PMID:Expression of high- and low-affinity receptors for C3a on the human mast cell line, HMC-1. 862 64

Monocyte chemotactic protein (MCP)-1, a member of the C-C (or beta) branch of the chemokine superfamily, at chemotactic concentrations, induced a rapid release of [3H]arachidonic acid but not of [14C]oleic acid from prelabeled human monocytes. This effect was associated with an increase in the intensity of the immunoreactive band corresponding to the phosphorylated form of cytosolic phospholipase A2, (cPLA2). To address the role of cPLA2 in the induction of monocyte chemotaxis, cells were treated with a specific antisense oligonucleotide. Monocytes cultured in the presence of 10 microM antisense oligonucleotide for 48 h showed a marked decrease (57 +/- 5%; n = 4) of cPLA2 expression, as evaluated by Western blot analysis and a nearly complete inhibition (81.8 +/- 4.2%; n = 3) of [3H]arachidonic acid release in MCP-1-stimulated cells. Monocyte chemotaxis in response to MCP-l also was inhibited in a concentration-dependent manner by cPLA2 antisense oligonucleotide (IC50 = 1.9 +/- 1.1 microM; n = 3), with complete inhibition observed between 3 and 10 microM. No inhibition of chemotactic response was observed in monocytes treated with a control oligonucleotide. Monocyte migration in response to MCP-3, RANTES (regulated on activation normal T cells expressed and secreted), and MIP-1 alpha/LD78 also was inhibited (>70%) in antisense oligonucleotide-treated cells. On the contrary, the chemotactic response elicited by formyl-methionyl-leucyl-phenylalanine and C5a, two "classical" chemotactic agonists, was minimally affected (<20%) by antisense oligonucleotide treatment. These data show that cPLA2 plays a major role in [3H]arachidonic acid release by MCP-1 in human monocytes and provide direct evidence for the involvement of cPLA2 in C-C chemokine-induced monocyte chemotaxis.
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PMID:Inhibition of monocyte chemotaxis to C-C chemokines by antisense oligonucleotide for cytosolic phospholipase A2. 862 84


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