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)

A number of disease states are characterized by the accumulation of inflammatory cells at the site of tissue injury. Mononuclear phagocytes (M phi) represent key cellular mediators of inflammation via the production of regulatory and chemokinetic cytokines. One such cytokine, macrophage inflammatory protein-1 alpha (MIP-1 alpha), has been shown to be one of the major inducible chemotaxins expressed from murine macrophage cell lines (RAW 264.7). We postulated that MIP-1 alpha is a major monocyte chemoattractant produced by resident M phi, and the magnitude of production of this chemotaxin may depend upon the specific population of M phi studied. To test this hypothesis, we isolated alveolar macrophages (AM phi) and peritoneal macrophages (PM phi) from CD-1 mice by bronchoalveolar and peritoneal lavage, respectively. Recombinant murine MIP-1 alpha accounted for significant neutrophil chemokinetic rather than chemotactic activity, as assessed by checkerboard analysis. LPS-stimulated AM phi-derived monocyte chemotactic activity (MCA) was significantly neutralized by specific rabbit anti-murine MIP-1 alpha serum. In contrast, PM phi-derived conditioned media failed to produce MCA attributable to MIP-1 alpha. The production of MIP-1 alpha was then characterized from both AM phi and PM phi. While unstimulated AM phi and PM phi failed to express MIP-1 alpha mRNA, both AM phi and PM phi challenged with lipopolysaccharide (LPS) expressed MIP-1 alpha mRNA in a time-dependent fashion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression and regulation of macrophage inflammatory protein-1 alpha by murine alveolar and peritoneal macrophages. 829 85

Factors that induce proliferation of the human hematopoietic stem cell are ill-defined. Primitive hematopoietic progenitors can be maintained and differentiate in stroma-dependent, long-term bone marrow cultures (LTBMC), originally described by Dexter et al. (Dexter, T. M., L. H. Coutinho, E. Spooncer, C. M. Heyworth, C. P. Daniel, R. Schiro, J. Chang, and T. D. Allen. 1990. Molecular Control of Haemopoiesis). However, 70-80% of primitive progenitors capable of reinitiating secondary stromal cultures (LTBMC-initiating cells [IC]) are lost over a period of 5 wk in such cultures. We have recently described a novel "stroma-noncontact" culture system, in which hematopoietic progenitors are separated from the stromal layer by a 0.4-micron microporous filter membrane. Primitive progenitors in such cultures can not only differentiate into committed progenitors, but are also maintained to a greater extent than in "Dexter" cultures. However, still only 50% of the originally seeded LTBMC-IC are recovered at week 5. Since maintenance of primitive progenitors may depend not only on growth-promoting factors but also on factors that inhibit differentiation and/or proliferation, we evaluated the effect of macrophage inflammatory protein 1 alpha (MIP-1 alpha) or "stem cell inhibitor" in combination with the growth-inducing factor interleukin 3 (IL-3) on the recovery of LTBMC-IC from stroma-noncontact cultures. We demonstrate that addition of MIP-1 alpha alone to stroma-noncontact cultures does not change the number of LTBMC-IC present after 8 wk, indicating that this factor may not directly inhibit or stimulate proliferation of primitive progenitors. Addition of the growth stimulatory cytokine, IL-3, alone results in exhaustion of LTBMC-IC after 8 wk of culture, possibly as a result of their terminal differentiation. However, LTBMC-IC can be maintained for at least 8 wk when grown in stroma-noncontact cultures supplemented with both MIP-1 alpha plus IL-3. This effect depends on soluble (ill-defined) stromal factors, and results from a direct interaction of these cytokines with the progenitor population or its progeny, but not the stroma.
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PMID:Macrophage inflammatory protein 1 alpha, interleukin 3 and diffusible marrow stromal factors maintain human hematopoietic stem cells for at least eight weeks in vitro. 829 73

Macrophage inflammatory protein-1 (MIP-1), a novel cytokine composed of alpha/beta subunits, is released from macrophages during infection. MIP-1 injected intravenously in the rabbit or into the anterior hypothalamic, preoptic area (AH/POA) of the rat causes an intense fever, which is not blocked by prostaglandin synthesis inhibitors, ibuprofin or indomethacin, respectively. The purpose of this study was to determine the role of de novo protein synthesis on the fever evoked by MIP-1 applied to thermosensitive cells of the AH/POA. Guide cannulae were implanted bilaterally above the AH/POA or ventral septal area (VSA) and medially above the third cerebral ventricle in each of 11 male Sprague-Dawley rats. Following postoperative recovery, body temperature (Tb) was monitored by a colonic thermistor probe. The bilateral microinjection of MIP-1 in a dose of 14 pg per 0.5 microliters into the AH/POA caused a biphasic elevation in Tb to 0.9 +/- 0.2 degrees C within 1.0 h, which reached 1.5 +/- 0.2 degrees C within 3.0 h, and persisted for over 6.0 h. An identical injection of MIP-1 into the VSA increased Tb biphasically to 0.1 +/- 0.1 degrees C within 1.0 h and to 0.8 +/- 0.3 degrees C within 3.0 h. The infusion into the third ventricle of 80 micrograms/10 microliters of the inhibitor of protein synthesis, anisomycin, either 10 or 30 min before the microinjection of MIP-1 into the AH/POA, attenuated significantly the rise in Tb for 1.0 to 3.0 h or 2.5 to 3.0 h, respectively. These results coincide with the earlier finding that anisomycin inhibits both endotoxin- and IL-1 beta-induced fevers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fever evoked by macrophage inflammatory protein-1 (MIP-1) injected into preoptic or ventral septal area of rats depends on intermediary protein synthesis. 831 99

The maintenance and regulation of continuously renewing tissues is ultimately controlled at the level of stem-cell proliferation. We have recently identified a reversible inhibitor of hemopoietic stem-cell proliferation (stem-cell inhibitor [SCI]), which is identical to the macrophage inflammatory protein, MIP-1 alpha, a 69-amino-acid heparin-binding cytokine. To test the cell/tissue specificity of the inhibition of proliferation by SCI/MIP-1 alpha, we have investigated its activity on epidermal keratinocytes, the principal cell type of another continuously renewing tissue. Here we show that SCI/MIP-1 alpha inhibits the proliferation of epidermal keratinocytes in vitro and that the MIP-1 alpha mRNA is present in epidermal Langerhans cells but not in keratinocytes. This suggests an important growth regulatory function for SCI/MIP-1 alpha in keratopoiesis, as well as hemopoiesis, and may also indicate a novel role for the epidermal Langerhans cell. As SCI/MIP-1 alpha can inhibit the proliferation of embryologically distinct precursor cells, this raises the possibility that it may also function in a number of other tissues.
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PMID:Hemopoietic stem cell inhibitor (SCI/MIP-1 alpha) also inhibits clonogenic epidermal keratinocyte proliferation. 834 11

Macrophage inflammatory protein 1 alpha (MIP-1 alpha) cytokine gene expression is restricted to a limited number of cells of hemopoietic origin and is rapidly and transiently induced by serum and endotoxin in macrophages. A single nuclear DNase I-hypersensitive site, which maps to the proximal promoter of the MIP-1 alpha gene, was identified in macrophage cells but was absent in cells which do not express basal levels of MIP-1 alpha mRNA. The proximal promoter sequences (+36 to -220 bp) are sufficient to confer cell-specific and inducible transcription in transfection assays. In vitro DNA-binding studies revealed five major nuclear protein binding sites in the proximal promoter which bind C/EBP, NF-kappa B, and/or c-Ets family members. Cell-specific differences in DNA binding by members of the NF-kappa B and c-Ets families correlate with the cell-specificity of MIP-1 alpha gene expression and the chromosomal conformation of the promoter. Changes in promoter binding by members of the C/EBP and NF-kappa B families correlate with the transcriptional up-regulation observed in serum- or endotoxin-stimulated macrophages in functional studies.
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PMID:C/EBP, NF-kappa B, and c-Ets family members and transcriptional regulation of the cell-specific and inducible macrophage inflammatory protein 1 alpha immediate-early gene. 835 82

Mononuclear phagocyte (M phi) recruitment and activation is a hallmark of a number of chronic inflammatory diseases of the lung, including sarcoidosis and idiopathic pulmonary fibrosis (IPF). We hypothesized that macrophage inflammatory protein-1 (MIP-1 alpha), a peptide with leukocyte activating and chemotactic properties, may play an important role in mediating many of the cellular changes that occur in sarcoidosis and IPF. In initial experiments, we demonstrated that human rMIP-1 alpha exerted chemotactic activities toward both polymorphonuclear leukocytes and monocytes, and these activities were inhibited by treatment with rabbit anti-human MIP-1 alpha antiserum. In support of the potential role of MIP-1 alpha in interstitial lung disease, we detected MIP-1 alpha in the bronchoalveolar lavage fluid of 22/23 patients with sarcoidosis (mean 443 +/- 76 pg/ml) and 9/9 patients with IPF (mean 427 +/- 81 pg/ml), whereas detectable MIP-1 alpha was found in only 1/7 healthy subjects (mean 64 +/- 64 pg/ml). In addition, we found a 2.5- and 1.8-fold increase in monocyte chemotactic activity in BALF obtained from patients with sarcoidosis and IPF respectively, as compared to healthy subjects, and this monocyte chemotactic activity, but not neutrophil chemotactic activity, was reduced by approximately 22% when bronchoalveolar lavage fluid from sarcoidosis and IPF patients were preincubated with rabbit antihuman MIP-1 alpha antibodies. To determine the cellular source(s) of MIP-1 alpha within the lung, we performed immunohistochemical analysis of bronchoalveolar lavage cell pellets, transbronchial biopsies, and open lung biopsies obtained from patients with IPF and sarcoidosis. Substantial expression of cell-associated MIP-1 alpha was detected in M phi, including both alveolar AM phi and interstitial M phi. In addition, interstitial fibroblasts within biopsies obtained from sarcoid and IPF patients also expressed immunoreactive MIP-1 alpha. Minimal to no detectable MIP-1 alpha was expressed in alveolar M phi from healthy subjects or interstitial cells in lung biopsy specimens obtained from patients undergoing thoracotomy for malignancy. Furthermore, pulmonary fibroblasts isolated from patients with IPF produced greater amounts of MIP-1 alpha after challenge with IL-1 beta than did similarly treated pulmonary fibroblasts recovered from patients without fibrotic lung disease. Our findings suggest that MIP-1 alpha is expressed in increased amounts within the airspace and interstitium of patients with sarcoidosis and IPF, and that this cytokine may be an important mediator of both M phi activation and recruitment that characterize these disease states.
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PMID:Macrophage inflammatory protein-1 alpha expression in interstitial lung disease. 836 Apr 96

The cytokines are important components of the brain-immune axis. Recent work has shown that [125I]IL-1 alpha and [125I]IL-1 beta are transported from the blood into the brain by a saturable system. Here we show that murine tumor necrosis factor alpha (mTNF alpha) labeled with 125I (I-mTNF alpha) crosses the blood-brain barrier (BBB) after i.v. injection by a transport system different from that for the interleukins. Self inhibition with mTNF alpha showed that this transport system was saturable, and lack of inhibition by IL-1 alpha, IL-1 beta, IL-6, or MIP-1 alpha showed selectivity of the system. High performance liquid chromatography (HPLC) of the radioactivity recovered from brain and from cerebrospinal fluid after the i.v. injection of I-mTNF alpha showed that the cytokine crossed the BBB largely in intact form. Capillary depletion showed that the accumulation of I-mTNF alpha in the cerebral cortex was due to passage across the BBB rather than to sequestration by capillaries. Transport rate was not changed by acute treatment with the neurotoxin aluminium or by acute and chronic treatment with the cationic chelator deferoxamine, but it was more than three times faster in neonatal rats. Efflux of I-mTNF alpha from the brain was slower than would have been predicted based on reabsorption of cerebrospinal fluid, suggesting that TNF alpha is sequestered by the brain. The BBB was not disrupted by up to 50 micrograms kg-1 of mTNF alpha i.v. in either adult mice or neonatal rats as assessed by the BBB's impermeability to radioactively labeled albumin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. 837 Jul 68

The BLR1 gene, isolated initially from Burkitt's lymphoma cells (Eur. J. Immunol. 1992. 22: 2795), encodes a G protein-coupled receptor with significant relationship to receptors for chemokines (IL-8, MIP-1 alpha) and neuropeptides. The murine homologue of human BLR1 was cloned and used to investigate its expression in vivo. blr1-specific transcripts are observed in secondary lymphatic organs and to a lesser extent in brain of adult mice but not in other tissues. RNA in situ hybridization localizes blr1 transcription to primary follicles and to the mantle zone of secondary follicles. SCID mice in which mature B cell development is severely impaired exhibit a strongly reduced level of blr1-specific RNA in the spleen. The analysis of murine lymphoid tumor cell lines representing distinct stages of the B cell lineage reveals elevated expression of blr1 in B cell lymphomas but not in pre-B lymphomas or plasmacytomas. Induction of differentiation of resting B cells by cytokines or mitogens down-regulates expression of blr1. RNA in situ hybridization using brain sections of adult mice detects blr1 transcription in the granule and Purkinje cell layer of the cerebellum. Interestingly, the blr1 gene is also expressed during late embryogenesis in fetal liver and brain. In view of the remarkable expression pattern in the B cell lineage we suggest that murine BLR1 may represent a cytokine/neuropeptide receptor exerting regulatory functions on recirculating mature B lymphocytes.
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PMID:The G protein-coupled receptor BLR1 is involved in murine B cell differentiation and is also expressed in neuronal tissues. 840 54

A unique subset of gamma delta T cells, termed dendritic epidermal T cells (DETC), resides in symbiosis with keratinocytes in mouse epidermis. We have shown previously that interleukin 7 (IL-7) which is produced by keratinocytes, promotes growth and prevents apoptosis in DETC. To extend this observation, we examined 12 cytokines, each of which is expressed by epidermal cells at mRNA and/or protein levels, for their capacities to modulate the growth of DETC. Cytokines examined included IL-1 alpha, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma), granulocyte/macrophage-colony stimulating factor (GM-CSF), and macrophage inflammatory protein-1 alpha (MIP-1 alpha). When tested individually, IL-2 and IL-7 promoted maximal growth of the long-term cultured DETC line 7-17. When tested in combinations, synergistic growth-promoting effects were seen with IL-2 and IL-4 or IL-7, and with IL-7 and IL-4 or TNF alpha. Dose-response experiments demonstrated that TNF alpha, which is produced by keratinocytes, enhances IL-7-induced DETC proliferation, but inhibits IL-2-induced proliferation. The mouse keratinocyte-derived cell line Pam 212 was used to test these cytokines for their capacities to regulate keratinocyte growth. Only gamma IFN, which is produced by DETC, inhibited proliferation in a dose-dependent fashion. These results illustrate three reciprocal pathways by which epidermal cytokines regulate the growth of epidermal cells: 1) a paracrine mechanism by which keratinocyte-derived cytokines (e.g., IL-7 and TNF alpha) promote the growth of DETC, 2) an autocrine mechanism by which DETC-derived cytokines (e.g., IL-2 and IL-4) support their own growth, and 3) a reciprocal pathway in which a cytokine produced by resident epidermal leukocytes (e.g., gamma IFN) modulates the growth of keratinocytes.
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PMID:Reciprocal cytokine-mediated cellular interactions in mouse epidermis: promotion of gamma delta T-cell growth by IL-7 and TNF alpha and inhibition of keratinocyte growth by gamma IFN. 840 21

The human macrophage inflammatory proteins-1 alpha and -beta (MIP-1 alpha and -beta), which are also known as LD78 and ACT2, respectively, are distinct but highly related members of the chemoattractant cytokine (chemokine) family. rMIP-1 alpha and -beta labeled with 125I specifically bind to human peripheral blood monocytes, the monocytic cell line THP-1, peripheral blood T cells, and the YT cell line. Steady state binding experiments revealed approximately 3000 high affinity binding sites/cell for MIP-1 alpha on human monocytes and on THP-1 cells, with Kd values of 383 pM and 450 pM, respectively. Human MIP-1 alpha and -beta had nearly identical affinities for the binding sites and each competed equally well for binding. Human monocyte chemotactic and activating factor (MCAF), a member of the same chemokine family, consistently displaced about 25% of human MIP-1 alpha and -beta binding on monocytes but not on YT cells, which did not bind MCAF. On the other hand, human rMIP-1 alpha and -beta partially inhibited binding of radiolabeled MCAF to monocytes. Both MIP-1 alpha and -beta were chemotactic for human monocytes. Preincubation of monocytes with human rMIP-1 alpha or -beta markedly reduced cell migration towards the other cytokine, whereas preincubation with human rMCAF only partially desensitized the monocyte chemotaxis response to human rMIP-1 alpha or -beta. These data suggest the existence of three subtypes of receptors, i.e., one unique receptor shared by MIP-1 alpha and -beta, a second unique receptor for MCAF, and a third species that recognizes both MCAF and MIP-1 peptides.
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PMID:Human recombinant macrophage inflammatory protein-1 alpha and -beta and monocyte chemotactic and activating factor utilize common and unique receptors on human monocytes. 845 71


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