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)

Interleukin-8 (IL-8) is a member of the CXC branch of the chemokine superfamily and activates neutrophils but not monocytes. The related CC chemokine branch, which includes monocyte chemoattractant protein-1 (MCP-1) and RANTES are potent chemoattractants for monocytes but not neutrophils. Examination of the sequences of the CXC chemokines reveals that the highly conserved leucine, corresponding to Leu25 in IL-8, is always replaced by tyrosine in CC chemokines. There is also a high degree of conservation among the CXC chemokines of the adjacent Val27 residue, which points out from the same side of the beta-sheet as Leu25. In RANTES, Val27 is also replaced by a tyrosine. In order to investigate the role of these residues in controlling cell specificity, we have made the single mutants Leu25-->Tyr, Val27-->Tyr and the double mutant Leu25-->Tyr, Val27--> Tyr of IL-8. These proteins have been expressed in Escherichia coli and purified to homogeneity from inclusion body material. All three mutants have lower potency and efficacy in chemotaxis and calcium mobilization assays using neutrophils. The mutants also show lowered affinity to both IL-8 receptors A and B expressed recombinantly in HL-60 cells and to neutrophils in [125I]IL-8 competition assays. Additionally, the Leu25-->Tyr mutation introduces a novel monocyte chemoattractant activity into IL-8. We therefore studied the displacement of [125I]MIP-1 alpha by IL-8 Leu25-->Tyr from the CC-CKR-1 receptor. The mutant displaces MIP-1 alpha ligand with an affinity only 12-fold less than MIP-1 alpha itself. This suggests that mutations in this region of IL-8 are involved in receptor binding and activation and in the control of specificity between CC and CXC chemokines.
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PMID:Mutation of Leu25 and Val27 introduces CC chemokine activity into interleukin-8. 753 92

The CD44 cell surface glycoprotein is expressed on a broad range of different tissues as multiple isoforms containing from one to ten alternatively spliced exons v1-v10 inserted within the extracellular domain. Differential glycosylation generates still further variability, yielding both N- and O-glycan-modified forms of CD44 in addition to proteoglycan-like variants containing chondroitin sulphate and heparan sulphate. These high molecular mass proteoglycan-like variants, previously identified in lymphocytes, melanomas, and keratinocytes have been implicated in cell-matrix adhesion, cell motility, and invasiveness. More recently, monocyte CD44 molecules presumed to carry glycosaminoglycan chains were shown to bind the chemokine MIP-1 beta (Tanaka, Y.,D. H. Adams, S. Hubscher, H. Hirano, U. Siebenlist, and S. Shaw. 1993. Nature (Lond). 361:79-82.) raising the intriguing possibility that proteoglycan-like CD44 variants might play a role in regulating inflammatory responses. Here we have investigated the molecular identity of these proteoglycan-like CD44 variants by generating a panel of recombinant CD44 isoforms using a novel cassette cloning strategy. We show that both chondroitin and heparan sulphate modifications are associated specifically with isoforms (CD44v3-10 and CD44v3,8-10) containing the v3 alternative exon which encodes a consensus motif SGXG for GAG addition. Other isoforms (CD44v10, CD44v8-10, CD44v7-10, and CD44v6-10) are shown to lack these GAG chains but to carry extensive O-glycan modifications, most likely within the mucin-like alternative exon inserts. We also demonstrate that the majority of endogenous GAG-modified CD44 isoforms present in epithelial cells constitute v3 isoforms thus establishing that in these cells the majority of proteoglycan-like CD44 variants are generated by alternative splicing. Finally we present evidence using transfected B lymphoma cells that the GAG-modified CD44 isoforms CD44v3-10 and CD44v3,8-10, unlike CD44H, bind only weakly to hyaluronan. Together with the demonstration in the accompanying paper (Bennett, K., D. G. Jackson, J.C. Simon, E. Tanczos, R. Peach, B. Modrell, I. Stamenkovic, G. Plowman, and A. Aruffo. 1995. J. Cell Biol. 128:687-698.), that CD44 molecules containing the v3 exon bind growth factors, these results highlight a new and potentially important role for CD44 alternative splicing in the control of cell-surface proteoglycan expression.
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PMID:Proteoglycan forms of the lymphocyte homing receptor CD44 are alternatively spliced variants containing the v3 exon. 753 75

The immunoregulatory C-C chemokine, macrophage inflammatory protein-1 alpha (MIP-1 alpha) has suppressive activity on proliferation of stem cells and early subsets of myeloid progenitor cells. A receptor for C-C chemokines that binds MIP-1 alpha has been characterized, cloned, and shown to be related structurally to neuropeptide receptors that couple through G-proteins to phospholipase-C and adenyl cyclase. Yet, very little information on the intracellular mechanisms of action of MIP-1 alpha is available. We show here that the human factor-dependent cell line M07e is responsive to the cell cycle-suppressive effects of MIP-1 alpha, has specific membrane-binding sites for MIP-1 alpha, and that treatment of these cells with this chemokine increases the phosphatidylcholine (PC) and phosphocholine turnover rates in cells that are synergistically stimulated by the combination of granulocyte-macrophage colony-stimulating factor and steel factor but not these factors acting singly. Additional, MIP-1 alpha treatment induces a dose- and time-dependent increase in intracellular cAMP levels in M07e cells. Both exogenous PC and dibutyryl cAMP were found to suppress the proliferation of M07e colony-forming cells to a level similar to that of MIP-1 alpha, further implicating cAMP and PC metabolism in MIP-1 alpha-induced M07e suppression. RANTES, a related chemokine, with weak or incomplete binding to the cloned MIP-1 alpha receptor, did not suppress M07e colony-forming cells, nor did it increase intracellular cAMP levels, but it did enhance growth factor-induced PC turnover, further supporting the involvement of cAMP in MIP-1 alpha suppression while demonstrating that increased PC turnover alone is not sufficient for suppression. These findings support the idea that the human MIP-1 alpha receptor is coupled to phospholipid and cAMP metabolism in a manner similar to other 7-transmembrane, G-protein-linked receptors and suggest that a phosphatidylcholine hydrolytic cycle and an associated increase in cAMP are part of the mechanisms of action of MIP-1 alpha.
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PMID:Macrophage inflammatory protein-1 alpha enhances growth factor-stimulated phosphatidylcholine metabolism and increases cAMP levels in the human growth factor-dependent cell line M07e, events associated with growth suppression. 753 66

The chemokines macrophage inflammatory protein 1 alpha (MIP 1 alpha), interleukin-8 (IL-8) and RANTES are potent regulators of leukocyte trafficking. Examination of chemokine secretion by human peripheral blood lymphocytes after stimulation with anti-CD3 or phorbol 12, 13 myristate acetate and ionomycin showed CD8+ cells were the dominant source of MIP 1 alpha and RANTES. Although production of MIP 1 alpha and IL-8 were similar in pharmacologically stimulated CD4+ CD45RA+, CD4+ CD45RO+, and CD8+ CD45RA+ cells, the largest amounts of MIP 1 alpha and RANTES were secreted by CD8+ CD45RO+ lymphocytes. A parallel pattern of prolonged chemokine mRNA expression for at least 18 h after activation was observed in the T cells subsets. These results confirm that human T lymphocytes have a unique capacity for secretion of these three chemokines. In addition, CD8+ cells have an unrecognized role in recruiting cells to sites of inflammation, and adult human CD45RA+ cells have a physiologically significant secretory capacity.
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PMID:CD8+ and CD45RA+ human peripheral blood lymphocytes are potent sources of macrophage inflammatory protein 1 alpha, interleukin-8 and RANTES. 753 2

Expression of mRNA for the C-X-C chemokine, macrophage inflammatory protein-2 (MIP-2), is induced during acute inflammation in rat models of disease. We have characterized the phlogistic potential of rat recombinant MIP-2 (rMIP-2) protein in vitro and in vivo. Recombinant MIP-2 caused marked PMN chemotaxis in vitro, with peak chemotactic activity at 10 nM. Incubation of whole blood with rMIP-2 caused a significant loss of L-selectin and a significant increase in Mac-1 expression on the PMN surface. Under similar conditions rMIP-2 also caused a modest respiratory burst in PMNs. The intratracheal instillation of 10 and 50 micrograms of rMIP-2 caused a significant influx of PMNs into the airspace of the lungs. Rat MIP-2 is a potent neutrophil chemotactic factor capable of causing neutrophil activation and is likely to function in PMN recruitment during acute inflammation in rat disease models.
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PMID:Functional characterization of rat chemokine macrophage inflammatory protein-2. 753 49

It is known that the HTLV-I-transformed cell line MT4 releases chemotactic activity for monocytes spontaneously. The MT4 monocyte chemoattractant was purified to homogeneity and sequencing of 25 amino acids revealed identity with the C-C chemokine macrophage inflammatory protein-1 alpha (MIP-1 alpha/LD78). An anti-MIP-1 alpha/LD78 rabbit antiserum substantially inhibited chemotaxis of the MT4 chemoattractant. MT4 cells constitutively expressed MIP-1 alpha/LD78 but not the C-C chemokines MCP-1, RANTES, and MIP-1 beta/Act2 and the C-X-C chemokines IL-8, gro alpha, and gro beta. MT4-derived MIP-1 alpha/LD78 was active on monocytes but was a weak chemoattractant for polymorphonuclear leukocytes. Thus, MIP-1 alpha/LD78 is a major monocyte chemoattractant released by HTLV-I-transformed T cells. Expression of MIP-1 alpha/LD78, a leukocyte chemotactic and myelosuppressive molecule, may play an important role in the manifestations of HTLV-I-related diseases.
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PMID:Identification of MIP-1 alpha/LD78 as a monocyte chemoattractant released by the HTLV-I-transformed cell line MT4. 753 10

Chemokines are a family of low molecular mass proteins with chemotactic and cell activating activities. Reverse transcription-polymerase chain reaction and Northern hybridization were used to examine their expression during murine experimental allergic encephalomyelitis (EAE), an autoimmune disease used as a model of multiple sclerosis. The mRNAs encoding RANTES, MIP-1 alpha, MIP-1 beta, TCA3 (I-309), IP-10, JE (MCP-1), KC (MGSA/gro), and MARC (MCP-3) were induced in the spinal cord 1-2 days before clinical signs were apparent. SDF, a cDNA predicted to encode a chemokine-like product, was expressed in normal as well as diseased spinal cords. No expression of C10 or MIP-2 was detected. Activated encephalitogenic T cells expressed message for RANTES, MIP-1 alpha, MIP-1 beta, and TCA3. These results define a subset of chemokines that may play an important role in the inflammatory process during murine EAE.
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PMID:Chemokine expression in murine experimental allergic encephalomyelitis. 753 12

We investigated the effect of interleukin-1 (IL-1) activation of human umbilical vein endothelium (HUVE) on human monocyte transendothelial migration induced by chemotactic factors. Monocyte migration across unactivated endothelium in response to macrophage inflammatory protein-1 alpha (MIP-1 alpha), RANTES, platelet-activating factor (PAF), or monocyte chemoattractant protein-1 (MCP-1) was completely inhibited (90%) by monoclonal antibodies (mAbs; 60.3) to CD18 of the CD11/CD18 complex on the monocyte and partially inhibited (by 75%) in response to C5a. When the HUVE was stimulated with IL-1 alpha (5 h, 0.1 ng/ml), monocyte migration in response to C5a, MIP-1 alpha, RANTES, or PAF was no longer inhibited by mAb to CD18. However, migration was blocked by the combination of mAb to the alpha 4-integrin (CD49d) chain of very late antigen-4 (CD49d/CD29) with the mAb to CD18. In contrast to the above stimuli, activation of the HUVE with IL-1 alpha inhibited the transendothelial migration of monocytes in response to MCP-1. mAbs to the adhesion molecules up-regulated on HUVE by IL-1, i.e., E-selectin (CD62E), intercellular adhesion molecule-1 (CD54) or vascular cell adhesion molecule-1 (CD106), did not reverse the inhibitory effect. Transendothelial migration in response to MCP-1 but not to C5a was inhibited by the treatment of monocytes with culture supernatant from IL-1 alpha-stimulated (but not from unstimulated) HUVE. Such supernatant contained chemotactic activity for monocytes, and a mAb to MCP-1 blocked the migration inhibitory effect of IL-1 activation of the HUVE monolayer, as well as the chemotactic activity in the supernatant from IL-1-stimulated HUVE. The inhibitory effect on migration of IL-1-stimulated HUVE was specific for monocytes because polymorphonuclear leukocyte transendothelial migration in response to IL-8 (a related chemokine) was not inhibited by IL-1 activation of HUVE.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:IL-1 activation of endothelium supports VLA-4 (CD49d/CD29)-mediated monocyte transendothelial migration to C5a, MIP-1 alpha, RANTES, and PAF but inhibits migration to MCP-1: a regulatory role for endothelium-derived MCP-1. 754 7

The solution structure of the chemokine RANTES (regulated on activation, normal T-cell expressed and secreted) has been determined using NMR spectroscopy. Backbone and side-chain 1H and 15N assignments have been obtained using a combination of two-dimensional homonuclear and three-dimensional heteronuclear spectra. Regular elements of secondary structure have been identified on the basis of a qualitative interpretation of NOE data, J(NH-H alpha) coupling constants, and amide exchange rates. Three-dimensional structures were calculated from a total of 2146 experimental restraints using a combination of distance geometry and simulated annealing protocols. For the 13 best structures the average backbone (N, C alpha, C) atomic rmsd from the mean coordinates for residues 5-65 is 0.64 A (+/- 0.14 A) for the dimer and 0.50 A (+/- 0.08 A) for the individual monomers. Each monomer consists of a three-stranded antiparallel beta-sheet (residues 26-30, 38-43, 48-51) in a Greek key motif with a C-terminal helix (56-65) packed across the sheet, an arrangement similar to the monomeric structure of other members of this chemokine family (IL-8, PF4, MGSA/Gro alpha, and MIP-1 beta). Overall, the RANTES dimer resembles that previously reported for MIP-1 beta.
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PMID:The three-dimensional solution structure of RANTES. 754 19

The mechanisms by which interferon-alpha (IFN-alpha) restores normal hematopoiesis in chronic myelogenous leukemia (CML) are not well understood. We have recently demonstrated that IFN-alpha acts directly on CML hematopoietic progenitors to restore their adhesion to marrow stroma by modulating beta 1 integrin receptor function. In the present study we examined the effect of IFN-alpha treatment of marrow stroma on subsequent adhesion of CML progenitors. Stromal layers were preincubated with IFN-alpha (10,000 microns/ml) for 48 h. Subsequent coincubation with CML progenitors for 2 h resulted in significantly increased adhesion of CML progenitors. We demonstrated that alpha 4 beta 1 and alpha 5 beta 1 integrin receptors were involved in the enhanced adhesion of CML progenitors, suggesting that IFN-alpha-treated stroma can upregulate CML integrin function. This effect is due, at least in part, to IFN-alpha-induced increased stromal production of the chemokine macrophage inflammatory protein-1 alpha (MIP-1 alpha), which upregulates beta 1 integrin-dependent adhesion of CML progenitors to stroma. Thus, IFN-alpha treatment of marrow stroma restores beta 1 integrin-dependent adhesion of CML progenitors, at least in part through induction of MIP-1 alpha production. These observations provide further insights into mechanisms by which IFN-alpha may restore normal hematopoiesis in CML.
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PMID:Treatment of marrow stroma with interferon-alpha restores normal beta 1 integrin-dependent adhesion of chronic myelogenous leukemia hematopoietic progenitors. Role of MIP-1 alpha. 754 95


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