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)

Equilibrium binding studies on canine mononuclear and granulocytic cells allow the identification of a single high affinity receptor for the human C-C chemokine RANTES (dissociation constant, 14 +/- 8 pM), that, in contrast to the human RANTES receptor, has no affinity for human macrophage inflammatory protein 1 alpha (hMIP-1 alpha). A single intradermal injection of hRANTES in dog resulted in eosinophil- and macrophage-rich inflammatory sites within 4 h. Cell infiltration peaked at 16-24 h after hRANTES injection. There was histological evidence of intravascular activation of eosinophils at 4 h, although eosinophils in the vasculature and interstitium contained apparently intact granules. Monocytes were the predominant cells adherent to venular endothelium at 16-24 h. Human MIP-1 alpha elicited no response in canine dermis, whereas monocyte chemoattractant protein 1 caused mild perivascular cuffing with monocytes. In contrast, human interleukin 8 induced a neutrophilic dermal infiltrate that was maximal by 4 h after challenge. This provides the first direct evidence in vivo that RANTES has significant proinflammatory activity and, in addition, could be a mediator in atopic pathologies characterized by eosinophilic and monocytic inflammatory responses.
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PMID:Formation of eosinophilic and monocytic intradermal inflammatory sites in the dog by injection of human RANTES but not human monocyte chemoattractant protein 1, human macrophage inflammatory protein 1 alpha, or human interleukin 8. 750 53

CC chemokines constitute a novel class of cytokines that attract and activate monocytes and lymphocytes, as well as basophil and eosinophil leukocytes, with distinct target cell profiles, and are believed to be involved in the regulation of different types of inflammation. The action of the recently identified monocyte chemotactic protein 3 (MCP-3) on human basophil and eosinophil function was studied and compared with that of other CC chemokines. In basophils, MCP-3, MCP-1, RANTES, and macrophage inflammatory protein (MIP)-1 alpha all induced cytosolic-free calcium concentration ([Ca2+]i) changes and, with different efficacies, chemotaxis (RANTES = MCP-3 >> MCP-1 > MIP-1 alpha), histamine release (MCP-1 = MCP-3 >> RANTES > MIP-1 alpha), and leukotriene C4 formation, after IL-3 pretreatment (MCP-1 = MCP-3 >> RANTES > MIP-1 alpha). Thus, MCP-3 was as effective as MCP-1 as an inducer of mediator release, and as effective as RANTES as a stimulus of basophil migration. In contrast to MCP-1, MCP-3 was also a stimulus for eosinophils, and induced [Ca2+]i changes and chemotaxis as effectively as RANTES, which is the most potent chemotactic cytokine for these cells. Desensitization of the transient changes in [Ca2+]i was used to assess receptor usage. In basophils, stimulation with MCP-3 prevented responsiveness to MCP-1 and RANTES, but not to MIP-1 alpha. No single CC chemokine (except for MCP-3 itself) affected the response to MCP-3, however, which was prevented only when the cells were prestimulated with both MCP-1 and RANTES. In eosinophils, by contrast, cross-desensitization between RANTES and MCP-3 was obtained. RANTES and to a lesser extent MCP-3 also desensitized eosinophils toward MIP-1 alpha. The desensitization data suggest the existence of three chemokine receptors: (a) a MCP-1 receptor expressed on basophils but not eosinophils that is activated by MCP-1 and MCP-3; (b) a RANTES receptor in basophils and eosinophils that is activated by RANTES and MCP-3; and (c) a MIP-1 alpha receptor that is activated by MIP-1 alpha, RANTES and, more weakly, by MCP-3. This study shows that MCP-3 combines the properties of RANTES, a powerful chemoattractant, and MCP-1, a highly effective stimulus of mediator release, and thus has a particularly broad range of activities toward both human basophil and eosinophil leukocytes.
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PMID:Monocyte chemotactic protein 3 is a most effective basophil- and eosinophil-activating chemokine. 750 12

Chronic rejection, the most important cause of long-term graft failure, is thought to result from both alloantigen-dependent and -independent factors. To examine these influences, cytokine dynamics were assessed by semiquantitative competitive reverse transcriptase-PCR and by immunohistology in an established rat model of chronic rejection lf renal allografts. Isograft controls develop morphologic and immunohistologic changes that are similar to renal allograft changes, although quantitatively less intense and at a delayed speed; these are thought to occur secondary to antigen-independent events. Sequential cytokine expression was determined throughout the process. During an early reversible allograft rejection episode, both T-cell associated [interleukin (IL) 2, IL-2 receptor, IL-4, and interferon gamma] and macrophage (IL-1 alpha, tumor necrosis factor alpha, and IL-6) products were up-regulated despite transient immunosuppression. RANTES (regulated upon activation, normal T-cell expressed and secreted) peaked at 2 weeks; intercellular adhesion molecule (ICAM-1) was maximally expressed at 6 weeks. Macrophage products such as monocyte chemoattractant protein (MCP-1) increased dramatically (to 10 times), presaging intense peak macrophage infiltration at 16 weeks. In contrast, in isografts, ICAM-1 peaked at 24 weeks. MCP-1 was maximally expressed at 52 weeks, commensurate with a progressive increase in infiltrating macrophages. Cytokine expression in the spleen of allograft and isograft recipients was insignificant. We conclude that chronic rejection of kidney allografts in rats is predominantly a local macrophage-dependent event with intense up-regulation of macrophage products such as MCP-1, IL-6, and inducible nitric oxide synthase. The cytokine expression in isografts emphasizes the contribution of antigen-independent events. The dynamics of RANTES expression between early and late phases of chronic rejection suggest a key role in mediating the events of the chronic process.
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PMID:Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1. 756 6

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

The chemokines are a large group of cytokines that are recognized to be important mediators of inflammation. In this study we show that the human mast cell leukemia line HMC-1 is a source of multiple chemokines, including I-309, monocyte chemoattractant protein 1, macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, RANTES, and interleukin-8. I-309 and MCP-1 transcripts are expressed at low levels in unstimulated HMC-1. However, phorbol ester treatment up-regulates these and other chemokine transcript levels and also up-regulates chemokine protein synthesis and secretion. Induction of chemokine transcripts in HMC-1 requires de novo protein synthesis. We compared the effects of anti-inflammatory glucocorticoids on the expression of chemokine genes in HMC-1 to their effects in activated T-cells. We find that methyl-prednisolone reduces MCP-1 but not other chemokine transcripts in HMC-1, even though there are distinct and more general effects on chemokine transcripts in activated T-cells. These effects are attributed to inhibition of transcription rather than transcript stability. Our results suggest that human mast cells may be a source of multiple chemokines, that glucocorticoids may inhibit the expression of only a subset of these chemokines, and that mast cells and T-cell chemokine expression may occur via distinct regulatory pathways.
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PMID:Expression of multiple chemokine genes by a human mast cell leukemia. 818 67

The chemoattractant cytokines, MCP-1 (monocyte chemoattractant protein) and MIP-1alpha (macrophage inflammatory protein), are recognized by highly homologous but distinct receptors. To identify receptor domains involved in determining ligand specificity, we created a series of chimeric MCP-1 and RANTES (regulated on activation, normal T cell expressed and secreted)/MIP-1alpha receptors that progressively interchanged the amino terminus and each of the three extracellular loops. Radiolabeled MCP-1 bound with high affinity to the wild-type MCP-1 receptor, but not to the RANTES/MIP-1alpha receptor (C-C CKR-1). Chimeras that retained the amino-terminal extension of the MCP-1 receptor bound MCP-1 with high affinity. In contrast, chimeric MCP-1 receptors, in which the wild-type amino terminus was replaced with the corresponding portion of the RANTES/MIP-1alpha receptor, bound MCP-1 with low affinity. These data indicate that the amino terminus of the MCP-1 receptor is necessary for high affinity binding of the ligand. Very different results were obtained using the RANTES/MIP-1alpha receptor. Radiolabeled MIP-1alpha bound with high affinity to chimeras that expressed the extracellular loops of the RANTES/MIP-1alpha receptor. In contrast to the MCP-1 receptor, substitution of the wild-type amino-terminal extension had little or no effect on MIP-1alpha binding. For the MCP-1, but not the RANTES/MIP-1alpha receptor, the presence of the wild-type amino terminus also significantly lowered the ligand concentration required for maximal signaling. We conclude that the amino-terminal extension of the MCP-1 receptor, but not the RANTES/MIP-1alpha receptor, is critically involved in ligand binding and signal transduction. These data reveal significant functional differences between the two C-C chemokine receptors and suggest a two-step mechanism for activation of the MCP-1 receptor.
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PMID:The amino-terminal extracellular domain of the MCP-1 receptor, but not the RANTES/MIP-1alpha receptor, confers chemokine selectivity. Evidence for a two-step mechanism for MCP-1 receptor activation. 870 81

The present study compares the activity of TCA3 with other beta-chemokines (macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and monocyte chemoattractant protein (MCP)-1) on rat vascular smooth muscle cells. TCA3, MIP-1 alpha, and MCP-1 (but not MIP-1 beta) treatment stimulates chemotaxis of vascular smooth muscle cells. TCA3-mediated chemotactic responses are sensitive to treatment with pertussis toxin, suggesting that G alpha-i proteins are involved in TCA3 signaling of smooth muscle. In addition, TCA3, MIP-1 alpha, and MCP-1 increase vascular smooth muscle cell adhesiveness to type III collagen. In contrast, stimulation with TCA3, but not other beta-chemokines, induces proliferation of vascular smooth muscle cells. TCA3 receptors were identified on rat vascular smooth muscle cells by direct binding of radiolabeled ligand. TCA3 binds to this receptor with high affinity (3 nM). Rat vascular smooth muscle cells display approximately 75,000 binding sites/cell. Competitive inhibition studies indicated that murine MIP-1 alpha, murine MCP-1, and human RANTES are weak partial competitors of TCA3 binding, demonstrating the existence of a unique receptor for TCA3. Murine MIP-1 beta, which fails to stimulate any biologic functions in vascular smooth muscle cells, also does not inhibit TCA3 binding. The combined data demonstrate that TCA3 and other beta-chemokines can modulate vascular smooth muscle cell function.
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PMID:Beta-chemokine TCA3 binds to and activates rat vascular smooth muscle cells. 875 39

T cells expressing gamma delta TCR may have evolved to recognize Ag in a different manner as well as perform a broader set of functions than T cells with alpha beta TCR. In this study, we tested the hypothesis that dendritic epidermal T cells (DETC) bearing the invariant V gamma 3V delta 1 TCR may be able to signal the migration of peripheral alpha beta T cells to the epidermis by secreting specific chemokines. Expression of macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, RANTES, and lymphotactin was inducible in DETC 7-17 cells, whereas mRNA for monocyte chemoattractant protein (MCP)-1 could not be detected. Strikingly, lymphotactin was the most abundant chemokine produced by activated DETC 7-17 cells. Activated primary DETC cultures also produced copious amounts of lymphotactin mRNA. Similarly, freshly isolated and activated intestinal intraepithelial T cells (i-IEL) with gamma delta TCR expressed high levels of lymphotactin mRNA. In contrast, lymphotactin mRNA was present in activated spleen gamma delta T cells at low basal levels. Migration of CD8+ T cells induced by culture supernatants from stimulated DETC 7-17 cells was strongly reduced in the presence of a neutralizing anti-lymphotactin antiserum and to a lesser extent by neutralizing anti-MIP-1 alpha, anti-MIP-1 beta, or anti-RANTES antiserum. The presence of lymphotactin in supernatants from activated DETC 7-17 cultures was directly demonstrated by Western blot analysis. These observations are consistent with a model in which gamma delta IEL play an active multi-faceted role in the maintenance of epithelia homeostasis.
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PMID:Chemokine expression by intraepithelial gamma delta T cells. Implications for the recruitment of inflammatory cells to damaged epithelia. 875 1

Leukocyte emigration possibly requires dynamic regulation of integrin adhesiveness for endothelial and extracellular matrix ligands. Adhesion assays on purified vascular cell adhension molecule (VCAM)-1, fibronectin, and fibronectin fragments revealed distinct kinetic patterns for the regulation of very late antigen (VLA)-4 (alpha 4 beta 1) and VLA-5 (alpha 5 beta 1) avidity by the CC chemokines monocyte inflammatory protein (MIP)-1 alpha, RANTES (regulated on activation, normal T expressed and secreted), or monocyte chemoattractant protein (MCP)-1 in monocytes. CC chemokines induced early activation and subsequent deactivation of VLA-4, whereas upregulation of VLA-5 avidity occurred later and persisted. Controlled detachment assays in shear flow suggested that adhesive strength of VLA-4 for VCAM-1 or the 40-kD fragment of fibronectin (FN40) is more rapidly increased and subsequently reduced by MCP-1 than by MIP-1 alpha, and confirmed late and sustained activation of the adhesive strength of VLA-5 for the 120-kD fragment of fibronectin (FN120). Mn2+ or the stimulating beta 1 mAb TS2/16 strongly and stably enhanced monocyte binding to VCAM-1 or fibronectin, and locked beta 1 integrins in a high avidity state, which was not further modulated by CC chemokines. Mn2+ and mAb TS2/16 inhibited CC chemokine-induced transendothelial migration, particularly chemotaxis across stimulated endothelium that involved VLA-4 and VCAM-1. VLA-4 on Jurkat cells is of constitutively high avidity and interfered with migration across barriers expressing VCAM-1. Low but not high site densities of VCAM-1 or FN40 promoted, while FN120 impaired, beta 1 integrin-dependent monocyte chemotaxis to MCP-1 across filters coated with these substrates. Thus, we show that CC chemokines can differentially and selectively regulate avidity of integrins sharing common beta subunits. Transient activation and deactivation of VLA-4 may serve to facilitate transendothelial diapedesis, whereas late and prolonged activation of VLA-5 may mediate subsequent interactions with the basement membrane and extracellular matrix.
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PMID:Sequential regulation of alpha 4 beta 1 and alpha 5 beta 1 integrin avidity by CC chemokines in monocytes: implications for transendothelial chemotaxis. 876 27

Intrinsic (nonatopic) asthma is considered to be a distinct pathogenetic variant of asthma since, unlike extrinsic (atopic) asthma, patients are skin-prick test negative to common aeroallergens and have total serum immunoglobulin E concentrations within the normal range. However both atopic and nonatopic asthma are characterized by chronic inflammation of the bronchial mucosa in which eosinophils are prominent and are believed to be associated with local tissue damage. Therefore, specific eosinophil chemoattractants acting in concert with factors which prolong eosinophil survival may at least partly account for selective eosinophil recruitment to the asthmatic bronchial mucosa. The CC chemokines RANTES and monocyte chemotactic protein 3 (MCP-3) are potent eosinophil chemotactic factors, while the cytokines interleukin (IL)-5, granulocyte macrophage-colony-stimulating factor (GM-CSF), and IL-3 prolong eosinophil survival. We have tested the hypothesis that elevated numbers of cells expressing mRNA for RANTES and MCP-3, as well as IL-5, GM-CSF, and IL-3 are present in bronchial biopsies from atopic and nonatopic asthmatics compared with atopic and nonatopic nonasthmatic controls. The technique of in situ hybridization using 35S-labeled riboprobes was employed to detect mRNA+ bronchial mucosal cells. Compared with controls we observed significant increases in the numbers of cells expressing RANTES and MCP-3, as well as IL-5, GM-CSF, and IL-3 (all P values < 0.001) in atopic and nonatopic asthmatics. These observations support the view that atopic and nonatopic asthma are associated with combined bronchial mucosal expression of CC chemokines (RANTES and MCP-3), together with eosinophil-active cytokines (IL-5, GM-CSF, and IL-3). These cytokines might contribute to the bronchial mucosal accumulation of activated eosinophils in both atopic and nonatopic variants of asthma.
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PMID:Bronchial mucosal expression of the genes encoding chemokines RANTES and MCP-3 in symptomatic atopic and nonatopic asthmatics: relationship to the eosinophil-active cytokines interleukin (IL)-5, granulocyte macrophage-colony-stimulating factor, and IL-3. 899 72


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