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)

Eosinophilic differentiation of a pro-eosinophilic HL-60 cell line resulted in the induction of a high affinity RANTES/macrophage inflammatory protein-1 alpha receptor. The induced receptor is biochemically indistinguishable in RANTES equilibrium-binding studies from the monocytic receptor expressed on THP-1 cell membranes. Continued expression of the receptor requires the continuous presence of the inducing stimulus, and receptor site number declines without a loss of binding affinity with a t1/2 of 11.5 h on withdrawal of the inducing stimulus. The induced receptor is capable of three physiologic measures of receptor coupling, namely, ligand-induced Ca2+ fluxes, priming of the respiratory burst, and chemotaxis. Dose-dependent Ca2+ fluxes were elicited upon increasing concentrations of RANTES and MIP-1 alpha whereas no response was measured upon addition of MIP-1 beta or MCP-1. In addition, desensitization studies demonstrated that previous exposure to either RANTES or MIP-1 alpha almost completely inhibits a Ca2+ flux upon subsequent exposure to either ligand. Priming of the respiratory burst to PMA in differentiated cells by human rRANTES was more effective than priming by IL-5 or granulocyte-macrophage-CSF, whereas undifferentiated cells failed to secrete superoxide anion. In addition, differentiated cells underwent chemotaxis in response to RANTES. This provides the first evidence for the induction of a C-C chemokine receptor upon eosinophilic differentiation of a leukocyte cell line, and is in keeping with the demonstrated ability of human RANTES to induce the rapid formation of eosinophilic inflammatory sites.
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PMID:Induction, characterization, and functional coupling of the high affinity chemokine receptor for RANTES and macrophage inflammatory protein-1 alpha upon differentiation of an eosinophilic HL-60 cell line. 751 65

The Duffy antigen (DARC) is a promiscuous chemokine receptor that also binds Plasmodium vivax. DARC belongs to a family of heptahelical chemokine receptors that includes specific (IL-8RA) and shared (IL-8RB) IL-8 receptors. Ligand binding specificity of IL-8 receptors was localized to the amino-terminal extracellular (E1) domain. To determine the basis for promiscuous chemokine binding by DARC, a chimeric receptor composed of the E1 domain of DARC and hydrophobic helices and loops from IL-8RB (DARCe1/IL-8RB) was constructed. Scatchard analysis of stable transfectants demonstrated that the DARCe1/IL-8RB chimeric receptor bound IL-8 and melanoma growth stimulating activity (MGSA) with KD values almost identical to the native receptors. The hybrid receptor also bound RANTES, MCP-1, and MGSA-E6A (which binds DARC, but not IL-8RB), but not MIP-1 alpha, similarly to DARC. Ligand binding to DARC transfectants was unaltered by anti-Fy3, but inhibited by Fy6, which binds an epitope in the E1 domain. The epitope recognized by Fy3 was localized to the third extracellular loop by analysis of insect cells expressing chimeric receptors composed of complementary portions of DARC and IL-8RB. These findings implicate the E1 domain of DARC in multispecific chemokine binding.
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PMID:The promiscuous chemokine binding profile of the Duffy antigen/receptor for chemokines is primarily localized to sequences in the amino-terminal domain. 759 30

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

The murine beta-chemokine TCA3 was purified to homogeneity. The biologic activities of the purified glycoprotein were evaluated in vivo and in vitro. Mice injected i.p. with 1- to 100-ng purified rTCA3 exhibited a rapid influx of neutrophils and macrophages. Increased numbers of neutrophils and monocytes were observed in peripheral blood within 15 min and peak at 45 min. After 45 min neutrophil and macrophage levels were increased in the peritoneal exudate with peak levels occurring at 2 h, followed by a subsequent decline by 24 h. Inflammatory responses were induced in a dose-dependent fashion. The in vivo inflammatory responses were mirrored by the pattern of TCA3-induced chemotaxis in vitro. Neutrophils and macrophages responded to similar concentrations of TCA3 (3 x 10(-9) to 10(-8) M). Lymph node cells responded to other chemokines but did not migrate to TCA3. We also demonstrated that rTCA3 stimulates a transient increase in cytoplasmic free calcium in monocytic cells through a PTX-sensitive pathway. Cross-desensitization studies indicate that TCA3 acts independently of other beta-chemokines (MIP-1 alpha and RANTES) and the alpha-chemokine IL-8. Furthermore, TCA3 does not induce a Ca2 lux in cells transfected with cDNA for the C-C CKR-1 chemokine receptor, supporting the conclusion that there are distinct receptors for TCA3.
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PMID:Biologic activities of the murine beta-chemokine TCA3. 796 34

Macrophage inflammatory protein-1 alpha (MIP-1 alpha) and RANTES are members of the beta chemokine family of leukocyte chemoattractants. We have previously cloned three mouse genes by cross-hybridization with the human MIP-1 alpha/RANTES receptor gene CMKBR1. One of the mouse genes, Scya3r, encodes a functional MIP-1 alpha receptor. The functions of the other two, Scya3r-rs1 and Scya3r-rs2, are not known. We have now mapped Scya3r, Scya3r-rs1, and Scya3r-rs2 to chromosome 9, in a region of conserved synteny with the location of CMKBR1. Thus, like chemokine genes and alpha chemokine receptor genes, this group of beta chemokine receptor genes arose by tandem duplication.
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PMID:Mapping of the mouse macrophage inflammatory protein-1 alpha receptor gene Scya3r and two related mouse beta chemokine receptor-like genes to chromosome 9. 853 91

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

Several studies have shown that CC chemokines attract T lymphocytes, and that CD45RO+, memory phenotype cells are considered to be the main responders. The results, however, have often been contradictory and the role of lymphocyte activation and proliferation has remained unclear. Using CD45RO+ blood lymphocytes cultured under different stimulatory conditions, we have now studied chemotaxis as well as chemokine receptor expression. Expression of the RANTES/MIP-1 alpha receptor (CC-CKR1) and the MCP-1 receptor (CC-CKR2) was highly correlated with migration toward RANTES, MCP-1, and other CC chemokines, and was strictly dependent on the presence of IL-2 in the culture medium. Migration and receptor expression were rapidly downregulated when IL-2 was withdrawn, but were fully restored when IL-2 was added again. The effect of IL-2 could be partially mimicked by IL-4, IL-10, or IL-12, but not by IL-13, IFN gamma, IL-1 beta, TNF-alpha, or by exposure to anti-CD3, anti-CD28 or phytohemagglutinin. Activation of fully responsive lymphocytes through the TCR/CD3 complex and CD28 antigen actually had the opposite effect. It rapidly downregulated receptor expression and consequent migration even in the presence of IL-2. In contrast to the effects on CC chemokine receptors, stimulation of CD45RO+ T lymphocytes with IL-2 neither induced the expression of the CXC chemokine receptors, IL8-R1 and IL8-R2, nor chemotaxis to IL-8. The prominent role of IL-2 in CC chemokine responsiveness of lymphocytes suggests that IL-2-mediated expansion is a prerequisite for the recruitment of antigen-activated T cells into sites of immune and inflammatory reactions.
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PMID:Interleukin-2 regulates CC chemokine receptor expression and chemotactic responsiveness in T lymphocytes. 876 Jul 84

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

Chemokines are small proteins that selectively activate and recruit leukocytes to sites of inflammation. Several of them, including the CC chemokines RANTES, MIP-1 alpha, MIP-1 beta, MCP-1, and the CXC chemokines IL-8, GRO-alpha, ENA-78 have been identified in rheumatoid synovium, implicating a potential role for these molecules in rheumatoid arthritis. We have investigated the expression patterns of CC chemokine receptors in the joints of mice with collagen-induced arthritis, a model for human rheumatoid arthritis. In addition, we have investigated the incidence and severity of arthritis in mice receiving administration of MetRANTES, a modified chemokine which is a nanomolar antagonist of certain CC chemokine receptors. The mRNA expression pattern of the chemokines and their receptors in the joints of arthritic mice was investigated using reverse transcriptase-PCR and in situ hybridization. An upregulation of the CC chemokine receptors mCCR1, mCCR2; mCCR3 and mCCR5 was found in the joints from arthritic mice, compared to control animals. In addition, injections of MetRANTES reduced the incidence of disease in a dose dependent manner. Furthermore, in MetRANTES-treated mice that did develop arthritis a significantly lower severity of disease was observed compared with control animals. Our data clearly demonstrate a role for CC chemokines and their receptors in inflammatory joint destruction and support the use of chemokine receptor antagonists as potential tools to control inflammatory diseases such as rheumatoid arthritis.
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PMID:Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. 923 36

Elevated levels of chemokines have been observed in various diseases of the CNS. Little is known, however, about how these chemokines affect parenchymal cells of the CNS. The current studies examine astrocyte chemotaxis to the mouse chemokine macrophage inflammatory protein-1alpha (MIP-1alpha). Murine astrocytes demonstrate directed migration along a chemical gradient in response to 10(-10)-10(-8) M MIP-1alpha. Peak chemotactic responses are noted at 10(-9) M. MIP-1alpha-induced astrocyte migration is specifically inhibitable with pertussis toxin, suggesting a role for Galphai proteins in the signaling process. RT-PCR and in situ hybridization were used to identify expression of the murine CCR1 MIP-1alpha receptor on astrocytes. Astrocytes contain mRNA for CCR1, but messages for CCR4 and the orphan chemokine receptor MIP-1alphaR-like#1 were not detected. The combined results suggest that a functional chemokine receptor is expressed on resident cells of the CNS. We speculate that the interactions of chemokines with astrocytes are involved in inflammatory reactions of the CNS.
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PMID:Murine astrocytes express a functional chemokine receptor. 925 64


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