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

beta or C-C chemokines including RANTES, MCP-3, MIP-1 alpha, and eotaxin have been implicated in the pathogenesis of eosinophilic inflammation. Two human beta chemokine receptors have been cloned and characterized: the MIP-1 alpha/RANTES receptor or C-C chemokine receptor 1 (CCR-1) and the MCP-1 receptor or C-C chemokine receptor 2 (CCR-2). However, no murine beta chemokine receptors have thus far been reported. Molecular cloning from mouse genomic DNA and cDNA libraries yielded two murine beta chemokine receptors with 79% and 65% sequence identity with human CCR-1, and 50% and 55% with human CCR-2. COS cells transiently transfected with the murine homologue of human CCR-1 bind murine MIP-1 alpha and human RANTES with Kds of 3.4 nM and 4.2 nM and murine MIP-1 beta with an EC50 of 8.9 nM. The other murine beta chemokine receptor, which we have designated murine CCR-3, also binds murine MIP-1 alpha. The mRNAs for both receptors are expressed in eosinophils from IL-5 transgenic mice. The level of murine CCR-3 mRNA in these mouse eosinophils exceeds that of CCR-1 mRNA and approaches actin levels. Murine MIP-1 alpha was found to be a potent chemoattractant for murine eosinophils. Our findings suggest that the murine MIP-1 alpha ligand/receptor system is an important mediator of murine eosinophil trafficking.
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PMID:Molecular characterization of two murine eosinophil beta chemokine receptors. 759 43

Although there is a mounting body of evidence that eosinophils are recruited to sites of allergic inflammation by a number of beta-chemokines, particularly eotaxin and RANTES, the receptor that mediates these actions has not been identified. We have now cloned a G protein-coupled receptor, CC CKR3, from human eosinophils which, when stably expressed in AML14.3D10 cells bound eotaxin, MCP-3 and RANTES with Kds of 0.1, 2.7 and 3.1 nM, respectively. CC CKR3 also bound MCP-1 with lower affinity, but did not bind MIP-1 alpha or MIP-1 beta. Eotaxin, RANTES, and to a lessor extent MCP-3, but not the other chemokines, activated CC CKR3 as determined by their ability to stimulate a Ca(2+) -flux. Competition binding studies on primary eosinophils gave binding affinities for the different chemokines which were indistinguishable from those measured with CC CKR3. Since CC CKR3 is prominently expressed in eosinophils we conclude that CC CKR3 is the eosinophil eotaxin receptor. Eosinophils also express a much lower level of a second chemokine receptor, CC CKR1, which appears to be responsible for the effects of MIP-1 alpha.
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PMID:Cloning, expression, and characterization of the human eosinophil eotaxin receptor. 864 44

The recent discovery of a chemokine receptor, fusin (fusin/CXCR-4), as the long-sought human immunodeficiency virus type 1 (HIV-1) coreceptor opened an entirely new field of aquired immunodeficiency syndrome (AIDS) research on mechanisms of viral entry, tropism and pathogenesis. It was soon followed by the identification of the chemokine receptor CCR-5 as the major macrophage-tropic (M-tropic) HIV-1 coreceptor and the demonstration that other chemokine receptors, CCR-3 and CCR-2b, also may serve as coreceptors, albeit at somewhat lower efficiency. Very recently it was demonstrated that the mechanism of the coreceptor function involves the formation of a complex on the cell surface between the HIV-1 envelope, the primary receptor CD4 and the coreceptor. Thus the prevention of the HIV-1 envelope glycoprotein-mediated fusion by the chemokines RANTES, macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta, as well as by the recently identified fusin/CXCR-4 ligand, stromal cell-derived factor-1 (SDF-1) could be explained by disruption of that complex. Interestingly, the identification of the HIV-1 coreceptor CCR-5 not only provided new insights into the mechanisms of viral entry and tropism, but also may help in explaining why some people with genetic alterations in CCR-5 are protected from HIV-1 infection.
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PMID:HIV and the 7-transmembrane domain receptors. 903 25

The beta-chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) is chemotactic for many hemopoietic cell types and can inhibit hemopoietic stem cell (HSC) proliferation, effects mediated through G-protein coupled heptahelical receptors. We have isolated cDNAs for seven chemokine receptors, CCR-1 to -5, MIP-1alphaRL1, and a novel cDNA, D6. Chinese hamster ovary cells expressing CCR-1, -3, -5, and D6 bound 125I-murine MIP-1alpha: the order of affinity was D6 > CCR-5 > CCR-1 > CCR-3. Each bound a distinct subset of other beta-chemokines: the order of competition for 125I-murine MIP-1alpha on D6 was murine MIP-1alpha > human and murine MIP-1beta > human RANTES approximately JE > human MCP-3 > human MCP-1. Human MIP-1alpha and the alpha-chemokines did not compete. Like other chemokine receptors, D6 induced transient increases in [Ca2+] in HEK 293 cells upon ligand binding. D6 mRNA was abundant in lung and detectable in many other tissues. Bone marrow cell fractionation demonstrated T-cell and macrophage/monocyte expression of D6, and CCR-1, -3, and -5. Moreover, we could detect expression of CCR-3, CCR-5, and to a greater extent D6 in a cell population enriched for HSCs. Thus, we have characterized four murine beta chemokine receptors that are likely involved in mediating the pro-inflammatory functions of MIP-1alpha and other chemokines, and we present D6, CCR-3, and CCR-5 as candidate receptors in MIP-1alpha-induced HSC inhibition.
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PMID:Cloning and characterization of a novel murine beta chemokine receptor, D6. Comparison to three other related macrophage inflammatory protein-1alpha receptors, CCR-1, CCR-3, and CCR-5. 913 99

Following the identification of the C-C chemokines RANTES, MIP-1alpha and MIP-1beta as major human immunodeficiency virus (HIV)-suppressive factors produced by CD8+ T cells, several chemokine receptors were found to serve as membrane co-receptors for primate immunodeficiency lentiretroviruses. The two most widely used co-receptors thus far recognized, CCR5 and CXCR4, are expressed by both activated T lymphocytes and mononuclear phagocytes. CCR5, a specific RANTES, MIP-1alpha and MIP-1 receptor, is used preferentially by non-MT2-tropic HIV-1 and HIV-2 strains and by simian immunodeficiency virus (SIV), whereas CXCR4, a receptor for the C-X-C chemokine SDF-1, is used by MT2-tropic HIV-1 and HIV-2, but not by SIV. Other receptors with a more restricted cellular distribution, such as CCR2b, CCR3 and STRL33, can also function as co-receptors for selected viral isolates. The third variable region (V3) of the gp120 envelope glycoprotein of HIV-1 has been fingered as a critical determinant of the co-receptor choice. Here, we document a consistent pattern of evolution of viral co-receptor usage and sensitivity to chemokine-mediated suppression in a longitudinal follow-up of children with progressive HIV-1 infection. Viral isolates obtained during the asymptomatic stages generally used only CCR5 as a co-receptor and were inhibited by RANTES, MIP-1alpha and MIP-1beta, but not by SDF-1. By contrast, the majority of the isolates derived after the progression of the disease were resistant to C-C chemokines, having acquired the ability to use CXCR4 and, in some cases, CCR3, while gradually losing CCR5 usage. Surprisingly, most of these isolates were also insensitive to SDF-1, even when used in combination with RANTES. An early acquisition of CXCR4 usage predicted a poor prognosis. In children who progressed to AIDS without a shift to CXCR4 usage, all the sequential isolates were CCR5-dependent but showed a reduced sensitivity to C-C chemokines. Discrete changes in the V3 domain of gp120 were associated with the loss of sensitivity to C-C chemokines and the shift in co-receptor usage. These results suggest an adaptive evolution of HIV-1 in vivo, leading to escape from the control of the antiviral C-C chemokines.
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PMID:In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. 935 2

Chemokines belong to an expanding family of cytokines the primary function of which is recruitment of leukocytes to inflammatory sites. Recent evidence has shown their presence in the central nervous system. Because inflammatory responses have been implicated in the pathogenesis of Alzheimer's disease (AD), we studied the expression of CCR3, CCR5, and their ligands in normal and AD brains by immunohistochemistry. CCR3 and CCR5 are present on microglia of both control and AD brains, with increased expression on some reactive microglia in AD. Immunohistochemistry for MIP-1beta, MIP-1alpha, RANTES, eotaxin, and MCP-3 (ligands for CCR5 and/or CCR3) revealed the presence of MIP-1beta predominantly in a subpopulation of reactive astrocytes, which were more widespread in AD than control brains, and MIP-1alpha predominantly in neurons and weakly in some microglia in both AD and controls. Many of the CCR3+ or CCR5+ reactive microglia and MIP-1beta+ reactive astrocytes were found associated with amyloid deposits. Immunoreactivity for eotaxin, RANTES, and MCP-3 were not detected. Detection of these beta-chemokine receptors on microglia and some of their ligands in reactive astrocytes and neurons as well as microglia suggests a role for this system in glial-glial and glial-neuronal interactions, potentially influencing the progression of AD.
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PMID:Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer's disease brains. 966 62

The selective recruitment of eosinophils in tissue is a striking feature of allergic diseases. Recently, a family of chemoattractant molecules, namely chemokines, has been described which potently activates eosinophil function in vitro. We have developed a murine model of eosinophil recruitment to compare the relative potency and efficacy of chemokines in vivo. Of the chemokines tested, only eotaxin and MIP-1 alpha induced significant accumulation of eosinophils in vivo, but eotaxin was more effective than MIP-1 alpha. Chemokines, especially eotaxin acting via the CCR-3 receptor, may have a fundamental role in determining selective eosinophil recruitment in vivo.
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PMID:Eosinophil-active chemokines: assessment of in vivo activity. 968 75

The human CC chemokine leukotactin-1 (Lkn-1) is both a strong chemoattractant for neutrophils, monocytes, and lymphocytes and a potent agonist for CCR1 and CCR3. However, human neutrophils do not migrate when the cells are stimulated with other human CC chemokines, such as human macrophage inflammatory protein-1 alpha (hMIP-1 alpha) and eotaxin, which also use the CCR1 and CCR3 as their receptors. In this report, we demonstrate that while hMIP-1 alpha induced a negligible level of calcium flux and chemotaxis, Lkn-1 produced a high level of calcium flux and chemotaxis in human neutrophils. Lkn-1 cross-desensitized hMIP-1 alpha-induced calcium flux, but hMIP-1 alpha had little effect on the Lkn-1-induced response in human neutrophils. The same pattern was observed in peritoneal neutrophils from wild-type mice, whereas neutrophils from CCR1-/- mice failed to respond to either MIP-1 alpha or Lkn-1. Scatchard analysis revealed a single class of receptor for both hMIP-1 alpha and Lkn-1 on human neutrophils with dissociation constants (Kd) of 3.2 nM and 1.1 nM, respectively. We conclude that CCR1 is a receptor mediating responses to both MIP-1 alpha and Lkn-1 on neutrophils and produces different biological responses depending on the ligand bound.
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PMID:Differential effects of leukotactin-1 and macrophage inflammatory protein-1 alpha on neutrophils mediated by CCR1. 1020 40

Experimental autoimmune encephalomyelitis (EAE) is a T helper 1 (Th1) cell mediated demyelinating disease and the principal animal model for multiple sclerosis. Spinal cords from SJL mice primed with proteolipid protein peptide 139-151 (pPLP) expressed the chemokines RANTES, MCP-1, MIP-2, KC, MIP-1alpha, MIP-1beta, Mig, and fractalkine. We also identified IP-10 in these samples and described a sequence polymorphism in this transcript. Chemokine expression was specific for tissues of the central nervous system. MCP-1, IP-10, and MIP-2 RNA expression significantly correlated with clinical score. Chemokine receptor expression generally correlated with ligand expression. pPLP-primed mice expressed the Th1-associated markers CCR5 and CXCR3 on mononuclear cells. In addition, cells expressing CCR1, CCR2, CCR3, CCR4, CCR8, and CXCR2 were detected. Here we demonstrate that altered peptide ligand (APL)-induced protection from EAE was accompanied by modulation of chemokine and chemokine receptor expression. Spinal cord tissue sections from APL-protected mice showed greatly reduced levels of all chemokines and of CCR1, CCR5, CCR8, CXCR2 and CXCR3. The Th2-associated chemokine receptors CCR3 and CCR4 were found in protected mice, supporting the hypothesis that Th1 but not Th2 cells are down-regulated by APL treatment. This report concludes that chemokines and chemokine receptors can be useful tools to follow modulation of autoimmune disease.
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PMID:Modulation of experimental autoimmune encephalomyelitis: effect of altered peptide ligand on chemokine and chemokine receptor expression. 1102 50

CCR5 and CXC chemokine receptor 4 (CXCR4) are coreceptors for CD4 as defined by HIV-1 glycoprotein (gp) 120 binding. Pretreatment of T cells with gp120 results in modulation of both CCR5 and CXCR4 responsiveness, which is dependent upon p56(lck) enzymatic activity. The recent findings that pretreatment of T cells with a natural CD4 ligand, IL-16, could alter cellular responsiveness to macrophage-inflammatory protein-1ss (MIP-1ss) stimulation, prompted us to investigate whether IL-16 could also alter CXCR4 signaling. These studies demonstrate that IL-16/CD4 signaling in T lymphocytes also results in loss of stromal derived factor-1alpha (SDF-1alpha)/CXCR4-induced chemotaxis; however, unlike MIP-1ss/CCR5, the effects were not reciprocal. There was no effect on eotaxin/CCR3-induced chemotaxis. Desensitization of CXCR4 by IL-16 required at least 10-15 min pretreatment; no modulation of CXCR4 expression was observed, nor was SDF-1alpha binding altered. Using murine T cell hybridomas transfected to express native or mutated forms of CD4, it was determined that IL-16/CD4 induces a p56(lck)-dependent inhibitory signal for CXCR4, which is independent of its tyrosine catalytic activity. By contrast, IL-16/CD4 desensitization of MIP-1ss/CCR5 responses requires p56(lck) enzymatic activity. IL-16/CD4 inhibition of SDF-1alpha/CXCR4 signals requires the presence of the Src homology 3 domain of p56(lck) and most likely involves activation of phosphatidylinositol-3 kinase. These studies indicate the mechanism of CXCR4 receptor desensitization induced by a natural ligand for CD4, IL-16, is distinct from the inhibitory effects induced by either gp120 or IL-16 on CCR5.
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PMID:Desensitization of CXC chemokine receptor 4, mediated by IL-16/CD4, is independent of p56lck enzymatic activity. 1108 73


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