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

LD78 is a small secreted protein that has a sequence similar to a number of other polypeptides, including murine macrophage inflammatory protein 1 alpha (MIP-1 alpha), interleukin 8 (IL-8), Act-2, monocyte chemoattractant protein 1 (MCP-1), and others. These polypeptides are members of a novel cytokine superfamily that is involved in the inflammatory response, wound healing, hematopoiesis, and tumorigenesis. Specific receptors for purified clonal LD78 protein were measured using four cell lines (HL-60, U937, Jurkat, and MJ). 125I-labeled recombinant LD78 bound most efficiently to U937 cells. We therefore characterized the receptors as being on the surface of U937 cells. Binding reached an equilibrium after incubation for 60 min at 4 degrees C. Scatchard analysis showed that there were two classes of binding sites on U937 cells, high affinity sites (Kd = 5.3 x 10(-9) M) and low affinity sites (Kd = 9.3 x 10(-8) M), with the average number of binding sites per cell being approximately 30,000 and approximately 90,000, respectively. These receptors for LD78 were distinct from the receptors for gamma-IFN and for IL-8. SDS-PAGE analysis of chemically crosslinked 125I-labeled LD78 receptor complexes identified a single band of 52 kDa. The ability to detect specific LD78 receptors should prove valuable in efforts to molecularly clone these receptors and to dissect the biological actions of LD78.
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PMID:Identification and characterization of specific receptors for the LD78 cytokine. 151 Nov 63

The proliferative status of the stem cell compartment is thought to be controlled by both positive and negative regulators of proliferation. These regulators have obvious clinical potential in manipulating the integrity and proliferative status of the stem cell in vivo during patient treatment for neoplastic disease. We have tested the ability of the human recombinant homologue of murine macrophage inflammatory protein-1 alpha (rhMIP1 alpha) to suppress the proliferation of primitive murine progenitors in vitro and in vivo. This recombinant protein (stem cell inhibitor, similar to the human homologue of MIP 1 alpha, LD78) is active in a dose-dependent manner in vitro on CFU-S measured at day 12 and to a slightly lesser extent on the more mature CFU-S that are measured at day 8. SCI/rhMIP1 alpha is also active in vivo in two separate models of bone marrow regeneration in which the high proliferative status of the CFU-S compartment is reduced to the quiescent state with a single inoculation of SCI/rhMIP1 alpha. The inhibitory activity of the recombinant protein was then tested in a relevant therapeutic model in which the observed protection of part of the stem cell compartment is reflected by a significant improvement in the kinetics of neutrophil recovery. These results establish the feasibility of testing SCI/rhMIP1 alpha in a range of chemotherapy regimes as a preliminary to clinical trials to attempt to protect the stem cell compartment during treatment for neoplastic disease.
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PMID:Demonstration of stem cell inhibition and myeloprotective effects of SCI/rhMIP1 alpha in vivo. 157 37

The gene for a murine macrophage inflammatory cytokine, MIP-1 alpha, belongs to a newly recognized superfamily encoding small, inducible peptides shown to be up-regulated in association with cellular activation or transformation (tentatively designated the scy, or small cytokine, gene family). Secreted scy family peptides as a group, and MIP-1 alpha in particular, have inflammatory and mitogenic activities, and the family has been divided into CXC and CC subfamilies according to the spacing of conserved cysteine residues in the primary amino acid sequences. We have isolated and characterized a genomic clone encoding the CC subfamily member MIP-1 alpha. The organization of the murine MIP-1 alpha gene into three exons interrupted by two introns is identical to that found for other members of the CC subfamily (e.g., huLD78, muJE, huJE/MCP-1, muTCA3, and hul-309), which has been taken as evidence of evolution from a common ancestral gene. With the exception of the ratPF4 gene, which shares the two-intron/three-exon pattern typical of the CC subfamily, sequenced genes encoding CXC subfamily peptides (e.g., hulL-8 and hulP-10) include an additional intervening sequence that creates a fourth exon. Genomic nucleotide sequences 5' of the MIP-1 alpha cap site are highly homologous to corresponding regions of the human gene encoding a CC peptide variously designated as LD78/GOS19/pAT464, including consensus regulatory motifs in common, reinforcing the contention that MIP-1 alpha and LD78 may be interspecies homologs.
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PMID:Genomic structure of murine macrophage inflammatory protein-1 alpha and conservation of potential regulatory sequences with a human homolog, LD78. 203 69

The response of normal and chronic myeloid leukemia (CML), CD34+ cells to human macrophage inflammatory protein-1 alpha (MIP-1 alpha or LD78) was assessed. In tritiated thymidine incorporation assays, stem cell factor plus granulocyte-macrophage colony-stimulating factor stimulated thymidine incorporation in normal CD34+ cells was reduced to 72% of control values in the presence of MIP-1 alpha, whereas incorporation by CML CD34+ cells exposed to the same factors was not altered. In clonogenic assays, the presence of MIP-1 alpha gave a level of colony formation that was 71% of control values for normal progenitor cells, whereas for CML CD34+ cells colony formation was enhanced by 25%. These results suggest that, in vitro, CML progenitor cells are relatively refractory to the growth inhibitory effects of MIP-1 alpha. Using flow cytometry, the specific binding of a biotinylated human MIP-1 alpha/avidin fluorescein (FITC) conjugate to normal and CML mononuclear and CD34+ cell populations was quantified. The data indicate that (for both normal and CML CD34+ cells) there was a single population of cells that express cell surface receptors for MIP-1 alpha and this receptor expression was independent of cell cycle status. CML progenitor cells may be refractory to the effects of MIP-1 alpha as a result of events downstream from receptor expression.
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PMID:Macrophage inflammatory protein-1 alpha receptors are present on cells enriched for CD34 expression from patients with chronic myeloid leukemia. 749 87

Macrophage inflammatory protein-1 alpha (MIP-1 alpha) and its human homologue GOS19.1/LD78 are members of the C-C chemokine/intercrine family of secreted proteins. They have proinflammatory properties and also inhibit cell cycle progression of hematopoietic stem cells. Characterization of MIP-1 alpha receptor(s) has been confused because of its reported aggregation to inactive forms. Using a defined monomeric form of MIP-1 alpha that is biologically active for stem cell inhibition and induction of oxidative metabolism in polymorphonuclear cells, we report the detection of high- and low-affinity receptor classes on human leukemic CD34+ blast cells, promyelocytic cells, monocytes, peripheral blood neutrophils, and T cells. Both high- and low-affinity classes are expressed simultaneously in promyelocytes and neutrophils. The calculated kd for high-affinity receptors correlates with the concentrations of MIP-1 alpha required to induce a biologic effect on stem cells and neutrophils. Cross-linking studies show that MIP-1 alpha associates with two cell surface proteins with apparent molecular masses of 92 kD and 52 kD. Direct competition binding studies combined with studies on the inhibition of stem cells show that human and murine MIP-1 alpha have different receptor-binding and biologic properties.
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PMID:The active monomeric form of macrophage inflammatory protein-1 alpha interacts with high- and low-affinity classes of receptors on human hematopoietic cells. 752 90

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

Trafficking to tissues and then to lymph nodes is a crucial aspect of the immunobiology of dendritic cells. The present study was designed to identify molecules able to direct the migration of human blood-derived dendritic cells. fMLP (representative of formyl peptides of bacterial origin), C5a, and the C-C chemokines monocyte chemotactic protein (MCP)-3, MIP-1 alpha/LD78, and RANTES elicited chemotactic migration and a rise of intracellular free calcium in dendritic cells. In contrast, the C-X-C chemokines IL-8 and IP-10 and the C-C chemokines MCP-1 and MCP-2 were inactive as chemoattractants. Thus, dendritic cells respond to classical chemotactic signals and to a set of chemokines distinct from that active on monocytes and neutrophils. Chemoattractants are likely to contribute to localization and trafficking of dendritic cells and provide tools to recruit these cells in the design of immunization strategies.
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PMID:Migration of dendritic cells in response to formyl peptides, C5a, and a distinct set of chemokines. 756 Oct 21

The effects of epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), insulin-like growth factor (IGF) I and II, acidic fibroblast growth factor (FGF), tumour necrosis factor alpha (TNF alpha), macrophage inhibitory protein 1 alpha (MIP-1 alpha) (LD78), and TGF beta-1 on cell proliferation in the crypts of the small intestine of mice were investigated. Various doses and dosing regimens were tested. Three in vivo assays were developed, in each case involving detailed cell positional analysis of methyl tritiated thymidine labelling and mitotic activity. These allowed deductions to be made about the regions of the crypt and hence regions of the proliferative hierarchy (stem cells versus dividing transit cells) that are affected by treatment with growth factors. The assays involved: (1) normal untreated mice (an assay most likely to be effective for detecting inhibitors); (2) mice shortly after whole body irradiation when compensatory proliferation has been endogenously triggered (another assay for inhibitory factors, possibly ones associated specifically with the regenerative process); and (3) mice at late times (96 hours) after irradiation in the regression phase after a proliferative overshoot (an assay designed to detect stimulators). Little effect was seen after treatment with acidic FGF, TNF alpha, or MIP-1 alpha but EGF, IGF-I and II, and TGF alpha can all be seen to exert some stimulatory effects on labelling or mitosis. EGF and IGF-I stimulate both unirradiated mice and 96 hour recipients, while TGF alpha had a greater effect on the 96 hour animals. In all cases, multiple doses were used. TGF beta-1 was an effective inhibitor of proliferation in unirradiated and early regenerating (18 hour) animals. EGF was the most effective of the stimulators, raising the levels of proliferation at all positions in the crypt, but particularly in the upper crypt. IGF-I also exerted its effect predominantly in the upper crypt, while TGF alpha raised proliferation at all cell positions. TGF beta-1 tended to have its strongest inhibitory effects in the lower (stem cell) regions of the crypt.
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PMID:Stimulation and inhibition of proliferation in the small intestinal crypts of the mouse after in vivo administration of growth factors. 761 75

To study the effect of localised secretion of chemokines on tumour growth, the genes for human (hu) interleukin 8 (IL-8), hu-MCP-1 (MCAF), hu-MIP-1 alpha (LD78), murine (mu)-MCP-1 (JE), mu-MIP-1 alpha or mu-MIP-2 were introduced, via mammalian expression vectors, into Chinese hamster ovary (CHO) cells, and the ability of transfected cells to form tumours in vivo was evaluated. The production of hu-IL-8, hu-MIP-1 alpha or mu-MIP-1 alpha by transfected clones did not influence the growth rate in vitro, but drastically suppressed tumour growth when injected subcutaneously (s.c.) into nude mice. However, clones transfected with hu-MCP-1, mu-MCP-1 or mu-MIP-2 did not show any significant difference in growth rate in vivo compared with clones transfected with vector alone. Histological examination of the site of injection of CHO clones transfected with hu-IL-8, hu-MIP-1 alpha or mu-MIP-1 alpha showed predominantly neutrophilic infiltration. These results indicate that chemokines have potent anti-tumour activity when released, even at low doses, at the tumour site, which may be mediated by recruitment and targeting of neutrophilic granulocytes to chemokine-releasing cells. Our studies highlight the potential usefulness of localised chemokine secretion in inducing potent host anti-tumour defensive responses.
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PMID:Chemokine gene transfection into tumour cells reduced tumorigenicity in nude mice in association with neutrophilic infiltration. 766 85

Murine macrophage inflammatory protein 1 alpha (MIP-1 alpha) and its human equivalent (GOS19, LD78, or AT464) are members of the -C-C family of low-molecular-weight chemokines. Secreted from activated T cells and macrophages, bone marrow-derived MIP-1 alpha/GOS19 inhibits primitive hematopoietic stem cells and appears to be involved in the homeostatic control of stem cell proliferation. It also induces chemotaxis and inflammatory responses in mature cell types. Therefore, it is important to understand the mechanisms which control the expression of MIP-1 alpha/GOS19. Previous work has shown that in Jurkat T cells, a set of widely expressed transcription factors (the ICK-1 family) affect the GOS19 promoter. One member, ICK-1A, behaves as a strong negative regulator. In this communication, we provide evidence that the pathway of induction in the macrophage cell line U937 is different from that in Jurkat cells. Furthermore, we show that the ICK-1 binding site does not confer negative regulation in U937 cells. We provide evidence for an additional binding site, the MIP-1 alpha nuclear protein (MNP) site, which overlaps the ICK-1 site. Interaction of nuclear extracts from various cell lines and tissue with the MNP site leads to the formation of fast-migrating protein-DNA complexes with similar but distinct electrophoretic mobilities. A mutation of the MNP site which does not abrogate ICK-1 binding inactivates the GOS19.1 promoter in U937 cells and reduces its activity by fourfold in Jurkat cells. We propose that the MNP protein(s) binding at the MNP site constitutes a novel transcription factor(s) expressed in hematopoietic cells.
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PMID:MIP1 alpha nuclear protein (MNP), a novel transcription factor expressed in hematopoietic cells that is crucial for transcription of the human MIP-1 alpha gene. 776 Aug 7


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