Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P80098 (monocyte chemoattractant protein)
 1,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A polymerase chain reaction (PCR) strategy with degenerate primers was used to identify novel G-protein-coupled receptor-encoding genes from human genomic DNA. One of the isolated clones, termed V28, showed high sequence similarity to the genes encoding human chemokine receptors for monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1 alpha (MIP-1 alpha)/RANTES, and to the rat orphan receptor-encoding gene RBS11. When RNA was analyzed by Northern blot, V28 was found to be most highly expressed in neural and lymphoid tissues. Myeloid cell lines, particularly THP.1 cells, showed especially high expression of V28. We have mapped V28 to human chromosome 3p21-3pter, near the MIP-1 alpha/RANTES receptor-encoding gene.
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PMID:The orphan G-protein-coupled receptor-encoding gene V28 is closely related to genes for chemokine receptors and is expressed in lymphoid and neural tissues. 759 Feb 84

Equilibrium binding studies with recombinant human chemoattractant cytokines Rantes and monocyte chemoattractant protein 1 (MCP-1) on monocytic THP-1 cells have allowed the functional identification of two distinct receptors for C-C chemokines. One is a novel oligospecific receptor with high affinity for Rantes (50% maximal inhibitory concentration [IC50], 0.68 nM) and low affinity (IC50, 35 nM) for MCP-1, while the other is the previously described specific receptor for MCP-1 (IC50, 0.5 nM). Receptor affinity for Rantes is enhanced on preparation of isolated membranes with a 12-fold decrease in receptor Kd. The basis of this enhancement is not understood. The Rantes receptor appears to be G protein linked, as binding activity is abolished by guanosine 5'-O-(3-thiotriphosphate) (IC50, 7.3 nM). In contrast to the consequences of MCP-1 binding, we were unable to demonstrate ligand-dependent calcium fluxes on binding of Rantes to human monocytes or THP-1 cells. The binding of Rantes and MCP-1 to mononuclear cells from dog, rabbit, and rat were tested. While high affinity binding could be demonstrated in dog and rabbit, differences in ligand-induced Ca2+ fluxes could be shown between species. This suggests that receptor-ligand interactions and receptor coupling is best examined with autologous receptors and cytokine.
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PMID:Characterization and species distribution of high affinity GTP-coupled receptors for human rantes and monocyte chemoattractant protein 1. 767 12

Antagonists of multiple chemokines could be more effective than inhibitors of specific chemokines for controlling cell migration and inflammation. To attempt to identify such antagonists we characterized a number of truncated analogs of regulated on activation normal T cell expressed protein (RANTES), monocyte chemoattractant protein (MCP)-3, and MCP-1. On the basis of their ability to compete for binding of their parent chemokines, three analogs were selected for cross-reactivity studies: RANTES (9-68), MCP-3 (10-76), and MCP-1 (9-76). These analogs bound to THP-1 monocytic cells with dissociation constants that were within 4-6-fold of their native counterparts, but they did not promote detectable chemotaxis of THP-1 cells or enzyme release from purified human monocytes. The RANTES (9-68) analog competed for the binding and inhibited the activities of all three chemokines. In contrast, native RANTES was specific for RANTES binding sites. However, truncation of either MCP-1 or MCP-3 did not change their respective binding specificity. MCP-3 and MCP-3 (10-76) competed for binding of all three labeled chemokines. MCP-1 (9-76) competed strongly for binding of labeled MCP-1, but only weakly for the other two labeled ligands and inhibited the activities induced by MCP-1 and MCP-3 but not RANTES. Although RANTES (9-68) and MCP-3 (10-76) inhibited all three chemokines, the RANTES analog was significantly more potent for RANTES-induced activity. The results indicate that NH2-terminal residues partly determine the receptor specificity of RANTES, and deletions within this region permit binding to multiple chemokine receptors. The findings suggest the feasibility of design of high affinity multi-specific CC chemokine antagonists.
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PMID:RANTES and MCP-3 antagonists bind multiple chemokine receptors. 863 50

Bicyclams are a novel class of antiviral compounds that are highly potent and selective inhibitors of the replication of HIV-1 and HIV-2. Surprisingly, however, when the prototype compound AMD3100 was tested against M-tropic virus strains such as BaL, ADA, JR-CSF, and SF-162 in human peripheral blood mononuclear cells, the compound was completely inactive. Because of the specific and potent inhibitory effect of AMD3100 on T-tropic viruses, but not M-tropic viruses, it was verified that AMD3100 interacts with the CXC-chemokine receptor CXCR4, the main coreceptor used by T-tropic viruses. AMD3100 dose dependently inhibited the binding of a specific CXCR4 monoclonal antibody to SUP-T1 cells as measured by flow cytometry. It did not inhibit the binding of the biotinylated CC-chemokine macrophage inflammatory protein (MIP) 1alpha or MIP-1beta, ligands for the chemokine receptor CCR5 (the main coreceptor for M-tropic viruses). In addition, AMD3100 completely blocked (a) the Ca2+ flux at 100 ng/ml in lymphocytic SUP-T1 and monocytic THP-1 cells, and (b) the chemotactic responses of THP-1 cells induced by stromal cell-derived factor 1alpha, the natural ligand for CXCR4. Finally, AMD3100 had no effect on the Ca2+ flux induced by the CC-chemokines MIP-1alpha, regulated on activation normal T cell expressed and secreted (RANTES; also a ligand for CCR5), or monocyte chemoattractant protein 3 (a ligand for CCR1 and CCR2b), nor was it able to induce Ca2+ fluxes by itself. The bicyclams are, to our knowledge, the first low molecular weight anti-HIV agents shown to act as potent and selective CXCR4 antagonists.
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PMID:Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. 933 78

The chemokine monocyte chemoattractant protein (MCP)-1 plays a role in regulating the lymphocyte and macrophage infiltrate in ovarian cancer, but macrophages also accumulate in necrotic areas of the tumors where there is little MCP-1 expression (Negus, R. P. M. et al., Am. J. Pathol. 1997. 150: 1723-1734). Necrotic regions are likely to be hypoxic. In this study we show that hypoxia inhibits MCP-1-induced migration of THP-1 monocytic cells and human macrophages. In contrast, lymphocytes from peripheral blood migrate normally to an MCP-1 gradient in hypoxic conditions. The inhibition of monocyte migration by hypoxia is rapid and reversible. At the exposure times studied (30-90 min) hypoxia does not affect expression of the MCP-1 receptor CCR2B and cells exposed to hypoxia still respond to MCP-1 with an elevation of intracellular calcium. Although hypoxia is known to modulate gene expression, the inhibition of migration reported here was not due to the production of soluble factors, and mRNA expression of macrophage migration inhibitory factor was unchanged. Hypoxia-induced inhibition of chemotaxis was not limited to MCP-1. Hypoxia also inhibited the chemotactic response to macrophage inflammatory protein-1alpha, RANTES and the chemoattractant N-formyl-met-leu-phe, but hypoxic cells were still able to phagocytose opsonized red blood cells. We suggest that inhibition of migration by hypoxia is not due to gene regulation but is a reflection of metabolic changes in the cell. Transient hypoxia may regulate the distribution of macrophages in tumors and other inflammatory conditions.
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PMID:Hypoxia inhibits macrophage migration. 1042 91

THP-1 monocytic/macrophage cells were stimulated via their FcgammaR receptors with insoluble aggregates of human IgG and the production of the C-C chemokine monocyte chemoattractant protein (MCP)-1 assayed. A dose- and time-dependent production of MCP-1 comparable to that produced by the most potent agonists could be detected in the culture medium by a sensitive ELISA assay. This was accompanied by a parallel activation of the transcription factor NF-kappaB as judged from both the appearance of kappaB-binding activity containing p50/p65 NF-kappaB/Rel complexes in the nuclear extract and the disappearance of the NF-kappaB inhibitor IkappaB-alpha in the cell lysate. In contrast, IkappaB-beta and IkappaB-epsilon expression was not modified, thus pointing to the occurrence of a selective degradation of IkappaB-alpha under those conditions. Attempts to modulate MCP-1 production with compounds that display inhibitory effects on the activation of NF-kappaB such as the proteasome inhibitor N-acetyl-leucinyl-leucinyl-norleucinal, the antioxidant pyrrolidine dithiocarbamate and the salicylate derivative 2-hydroxy-4-trifluoromethylbenzoic acid showed a parallel effect on both MCP-1 production and NF-kappaB activation, thus pointing to the involvement of kappaB-binding sites on the transcriptional regulation of MCP-1 production. Our findings suggest the existence in monocytic cells of a signaling mechanism initiated by cross-linking of low-affinity FcgammaR, most likely of the FcgammaRII family since THP-1 cells do not express FcgammaRIII receptors, that involves activation of NF-kappaB associated to the proteolytic degradation of IkappaB-alpha and leads to the transcriptional up-regulation of MCP-1.
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PMID:Stimulation of Fc gamma R receptors induces monocyte chemoattractant protein-1 in the human monocytic cell line THP-1 by a mechanism involving I kappa B-alpha degradation and formation of p50/p65 NF-kappa B/Rel complexes. 1074 56

Amphotericin B is known to elicit immunomodulatory effects on neutrophil, monocyte, and lymphocyte function. It also has been shown to induce the release of proinflammatory cytokines from human monocytes and macrophages. Release of these cytokines has been associated with the infusion-related toxicity observed after administration of this drug. The present study demonstrates that amphotericin B increases mRNA for the chemokines interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1beta, as well as the cell adhesion molecules intercellular adhesion molecule (ICAM)-1 and CD44 in the human monocytic cell line THP-1. Amphotericin B increased the concentrations of IL-8, MCP-1, and MIP-1beta in a dose-dependent fashion. Amphotericin B also induced expression of ICAM-1 but not CD44 in these cells. Production of these proteins in response to amphotericin B may play a role in the immunomodulatory activity and toxicity of this antifungal agent.
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PMID:Amphotericin B induces expression of genes encoding chemokines and cell adhesion molecules in the human monocytic cell line THP-1. 1097 35

Macrophages secrete matrix metalloproteinase 9 (MMP-9), an enzyme that weakens the fibrous cap of atherosclerotic plaques, predisposing them to plaque rupture and subsequent ischemic events. Recent work indicates that statins strongly reduce the possibility of heart attack. Furthermore, these compounds appear to exert beneficial effects not only by lowering plasma low-density-lipoprotein cholesterol but also by directly affecting the artery wall. To evaluate whether statins influence the proinflammatory responses of monocytic cells, we studied their effects on the chemotactic migration and MMP-9 secretion of human monocytic cell line THP-1. Simvastatin dose dependently inhibited THP-1 cell migration mediated by monocyte chemoattractant protein 1, with a 50% inhibitory concentration of about 50 nM. It also inhibited bacterial lipopolysaccharide-stimulated secretion of MMP-9. The effects of simvastatin were completely reversed by mevalonate and its derivatives, farnesylpyrophosphate and geranylgeranyl pyrophosphate, but not by ubiquinone. Additional studies revealed similar but more profound inhibitory effects with L-839,867, a specific inhibitor of geranylgeranyl transferase. However, alpha-hydroxyfarnesyl phosphonic acid, an inhibitor of farnesyl transferase, had no effect. C3 exoenzyme, a specific inhibitor of the prenylated small signaling Rho proteins, mimicked the inhibitory effects of simvastatin and L-839,867. These data supported the role of geranylgeranylation in the migration and MMP-9 secretion of monocytes.
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PMID:Statins suppress THP-1 cell migration and secretion of matrix metalloproteinase 9 by inhibiting geranylgeranylation. 1140 82

Homocysteinaemia is an independent risk factor for atherosclerosis. The development of atherosclerosis involves monocyte chemoattractant protein 1 (MCP-1)-mediated monocyte recruitment to the lesion site. The action of MCP-1 is mostly via its interaction with MCP-1 receptor (CCR2), which is the major receptor for MCP-1 on the surface of monocytes. The objective of the present study was to investigate the effect of homocysteine on CCR2 expression in human THP-1 monocytes. Cells were incubated with various concentrations of homocysteine for 6, 12, 24 and 48 h. The expression of CCR2 mRNA was determined by nuclease protection assay and the CCR2 protein was measured by Western immunoblotting analysis. The binding of MCP-1 to CCR2 as a functional receptor on the monocyte surface was determined by flow cytometry. Homocysteine (0.05-0.2 mM) significantly enhanced the expression of CCR2 mRNA (129-209% of the control) and CCR2 protein (up to 183% of control) in these cells after 24 h of incubation. Stimulation of CCR2 expression was associated with a parallel increase in the binding activity of CCR2 (129-191% of control) as well as an enhanced chemotactic response of homocysteine-treated monocytes. Further investigation revealed that the levels of superoxide were significantly elevated in cells incubated with homocysteine for 12-48 h. The addition of superoxide dismutase, a scavenger of superoxide, to the culture medium abolished the stimulatory effect of homocysteine on CCR2 expression as well as the binding activity of the receptor. The stimulatory effect of homocysteine on the expression of CCR2 mRNA and the levels of CCR2 protein was also observed in human peripheral blood monocytes. In conclusion, the present study has clearly demonstrated that homocysteine stimulates CCR2 expression in monocytes, leading to an enhanced binding activity and chemotatic response. Homocysteine-induced superoxide formation might serve as one of the underlying mechanisms for this effect.
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PMID:Homocysteine stimulates the expression of monocyte chemoattractant protein-1 receptor (CCR2) in human monocytes: possible involvement of oxygen free radicals. 1141 54

Despite sharing considerable homology with the members of the monocyte chemoattractant protein (MCP) family, the CC chemokine eotaxin (CCL11) has previously been reported to signal exclusively via the receptor CC chemokine receptor 3 (CCR3). Using the monocyte cell line THP-1, we investigated the relative abilities of eotaxin and MCPs 1-4 to induce CCR2 signaling, employing assays of directed cell migration and intracellular calcium flux. Surprisingly, 1 microm concentrations of eotaxin were able to recruit THP-1 cells in chemotaxis assays, and this migration was sensitive to antagonism of CCR2 but not CCR3. Radiolabeled eotaxin binding assays performed on transfectants bearing CCR2b or CCR3 confirmed eotaxin binding to CCR2 with a K(d) of 7.50 +/- 3.30 nm, compared with a K(d) of 1.68 +/- 0.91 nm at CCR3. In addition, whereas 1 microm concentrations of eotaxin were able to recruit CCR2b transfectants, substimulatory concentrations of eotaxin inhibited MCP-1-induced chemotaxis of CCR2b transfectants and also inhibited MCP-1-induced intracellular calcium flux of THP-1 cells. Collectively, these findings suggest that eotaxin is a partial agonist of the CCR2b receptor. A greater understanding of the interaction of CCR2 with all of its ligands, both full and partial agonists, may aid the rational design of specific antagonists that hold great promise as future therapeutic treatments for a variety of inflammatory disorders.
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PMID:The CC chemokine eotaxin (CCL11) is a partial agonist of CC chemokine receptor 2b. 1155


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