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)

The haemopoietic system has three main compartments: multi-potential stem cells, intermediate stage progenitor cells and mature cells. The availability of simple reproducible culture systems has made possible the characterization and purification of regulators of the progenitor cells, including colony-stimulating factors and interleukins. In contrast, our knowledge of the regulators involved in the control of stem cell proliferation is limited. The steady-state quiescent status of the haemopoietic stem cell compartment is thought to be controlled by locally acting regulatory elements present in the stromal microenvironment, but their purification has been hampered by the lack of suitable culture systems. We have recently developed a novel in vitro colony assay that detects a primitive cell (CFU-A) which has similar proliferative characteristics, in normal and regenerating bone marrow, to the CFU-S (haemopoietic stem cells, as defined by the spleen colony assay) and which responds to CFU-S-specific proliferation regulators. We have now used this assay to purify to homogeneity a macrophage-derived reversible inhibitor of haemopoietic stem cell proliferation (stem cell inhibitor, SCI). Antibody inhibition and sequence data indicate that SCI is identical to a previously described cytokine, macrophage inflammatory protein-1 alpha (MIP-1 alpha), and that SCI/MIP-1 alpha is functionally and antigenically identical to the CFU-S inhibitory activity obtained from primary cultures of normal bone marrow cells. The biological activities of SCI/MIP-1 alpha suggest that it is a primary negative regulator of stem cell proliferation and that it has important therapeutic applications in protecting haemopoietic stem cells from damage during cytotoxic therapies for cancer.
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PMID:Identification and characterization of an inhibitor of haemopoietic stem cell proliferation. 232 Jan 11

Cytokines mediate many host responses to bacterial infections. We determined the inflammatory activities of five cytokines in the central nervous system: TNF-alpha, IL-1 alpha, IL-1 beta, macrophage inflammatory protein 1 (MIP-1), and macrophage inflammatory protein 2 (MIP-2). Using a rabbit model of meningeal inflammation, each cytokine (except IL-1 beta) induced enhanced blood brain barrier permeability, leukocytosis in cerebrospinal fluid, and brain edema. Homologous antibodies to each mediator inhibited leukocytosis and brain edema, and moderately decreased blood brain barrier permeability. In rabbits treated with anti-CD-18 antibody to render neutrophils dysfunctional for adhesion, each cytokine studied lost the ability to cause leukocytosis and brain edema. After intracisternal challenge with pneumococci, antibodies to TNF or IL-1 prevented inflammation, while anti-MIP-1 or anti-MIP-2 caused only a 2-h delay in the onset of inflammation. We suggest these cytokines have multiple inflammatory activities in the central nervous system and contribute to tissue damage during pneumococcal meningitis.
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PMID:The role of cytokines in the generation of inflammation and tissue damage in experimental gram-positive meningitis. 240 63

Eosinophil accumulation is a prominent feature of allergic inflammatory reactions, such as those occurring in the lung of the allergic asthmatic, but the endogenous chemoattractants involved have not been identified. We have investigated this in an established model of allergic inflammation, using in vivo systems both to generate and assay relevant activity. Bronchoalveolar lavage (BAL) fluid was taken from sensitized guinea pigs at intervals after aerosol challenge with ovalbumin. BAL fluid was injected intradermally in unsensitized assay guinea pigs and the accumulation of intravenously injected 111In-eosinophils was measured. Activity was detected at 30 min after allergen challenge, peaking from 3 to 6 h and declining to low levels by 24 h. 3-h BAL fluid was purified using high performance liquid chromatography techniques in conjunction with the skin assay. Microsequencing revealed a novel protein from the C-C branch of the platelet factor 4 superfamily of chemotactic cytokines. The protein, "eotaxin," exhibits homology of 53% with human MCP-1, 44% with guinea pig MCP-1, 31% with human MIP-1 alpha, and 26% with human RANTES. Laser desorption time of flight mass analysis gave four different signals (8.15, 8.38, 8.81, and 9.03 kD), probably reflecting differential O-glycosylation. Eotaxin was highly potent, inducing substantial 111In-eosinophil accumulation at a 1-2 pmol dose in the skin, but did not induce significant 111In-neutrophil accumulation. Eotaxin was a potent stimulator of both guinea pig and human eosinophils in vitro. Human recombinant RANTES, MIP-1 alpha, and MCP-1 were all inactive in inducing 111In-eosinophil accumulation in guinea pig skin; however, evidence was obtained that eotaxin shares a binding site with RANTES on guinea pig eosinophils. This is the first description of a potent eosinophil chemoattractant cytokine generated in vivo and suggests the possibility that similar molecules may be important in the human asthmatic lung.
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PMID:Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation. 750 65

The allogeneic mixed lymphocyte reaction (MLR) is regarded as an effective model for examining the events which occur during an allospecific immune response. Numerous studies have delineated the role of adherence molecule interactions during the MLR response. In the present study we have identified VCAM-1 as having a contribution to the generation of an allogeneic MLR response. These findings may have broad implications in vivo during antigen-specific and allograft rejection events. RT-PCR analysis was initially used to examine whether VCAM-1 mRNA expression was observed during MLR responses and demonstrated peak expression between 12 and 48 hr of culture. Immunolocalization of VCAM-1 on adherent mononuclear phagocytes, but not nonadherent lymphocytes, from MLR cultures verified its expression during this response. Addition of anti-VCAM-1 mAbs to MLR assays inhibited the proliferative response by over 70%, while addition of anti-VCAM-1 as late as Day 2 of the assay allowed significant inhibition of the proliferative response. This correlated with peak expression of VCAM-1 mRNA observed as late as 48 hr in RT-PCR analyses. In further studies, anti-VCAM-1 significantly inhibited peak expression of IL-2 on Days 3 and 4, while TNF-alpha production was diminished at 30 min and 1, 96, and 120 hr of culture, compared to control cultures. The production of macrophage inflammatory protein-1 alpha (MIP-1 alpha), a chemotactic cytokine which has an important role in vivo for the recruitment of leukocytes to a site of inflammation, was also significantly inhibited during peak production on Days 4 and 5 of the MLR assay. This study demonstrates novel findings of VCAM-1 expression during an allogeneic MLR response. The expression of VCAM-1 may have important implications during allospecific immune responses for the activation and proliferation of T lymphocytes as well as cytokine production.
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PMID:VCAM-1 influences lymphocyte proliferation and cytokine production during mixed lymphocyte responses. 750 30

Chemokines/intercrines are structurally and functionally related cytokines that induce specific actions on the immune system and are released in response to infection, inflammation, and trauma. These pathological processes are frequently accompanied with food intake suppression. In the present study, the action of chemokines/intercrines on the regulation of feeding was investigated using the intracerebroventricular microinfusion of chemokine/intercrine-alpha subfamily members [interleukin-8 (IL-8); growth-related cytokine/melanoma growth-stimulating activity (GRO-alpha/MGSA); platelet factor-4 (PF-4); beta-thromboglobulin (beta-TG); and interferon-inducible protein-10 (IP-10)] and beta-subfamily members [monocyte chemotactic protein-1/monocyte chemotactic and activating factor (MCP-1/MCAF); regulated upon activation normal T-cell expressed and presumably secreted (RANTES); macrophage inflammatory protein-1 alpha (MIP-1 alpha); and macrophage inflammatory protein-1 beta (MIP-1 beta)]. The doses administered were 1.0, 20, and 100 ng/rat of the chemokine/intercrine. The intracerebroventricular administration of three members of the alpha-subfamily (IL-8, PF-4, and IP-10) and two members of the beta-subfamily (MCP-1/MCAF and RANTES) decreased the short-term (2-h) food intake. These effective chemokines/intercrines, however, were significantly less potent than IL-1 beta in decreasing feeding. The results support the hypothesis that only a subset of immunomodulators released during pathological processes may participate in the regulation of feeding with different potencies.
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PMID:Chemokines/intercrines and central regulation of feeding. 751 92

Endothelial cells express adhesion molecules and release free forms (e.g., sELAM-1, sGMP-140, sICAM-1 and sVCAM-1). Compared with controls, the serum levels of these soluble adhesion molecules (SAM) were significantly increased in patients with rheumatoid arthritis. We investigated whether this was associated with the circulating cytokines and changes in peripheral blood T-lymphocyte (T-PBL) subsets. In healthy subjects, sELAM-1 correlated with the serum levels of Il-1 beta, Il-1 receptor antagonist (Il-1RA) and Il-6, while sGMP-140 was associated with Il-8, and sVCAM-1 was related to Il-7 and Il-8. Thus, already in controls, relations exist between the levels of SAM and circulating cytokines. The rheumatoid arthritis patients with low and high serum levels of IgA- and/or IgM-rheumatoid factors (RF) were separately analyzed. They have different cytokine profiles and showed distinct correlations. In patients with low RF, sGMP-140 and sVCAM-1 correlated with Il-1 beta, while sICAM-1 was associated with Il-7 and TNF-alpha. In patients with high RF, sELAM-1 correlated with Il-1RA, and sGMP-140 was associated with many cytokines (e.g., GM-CSF, MIP-1 alpha and TNF-alpha). In addition, lymphopenia (less than 1000 lymphocytes/microliters) was shown in 30% of the patients, and 20% (mostly with low RF levels) had reduced levels of "primed" CD45RO+ cells among T-PBL. In controls, cytokines (Il-7, Il-8 and GM-CSF), but not SAM, were associated with less CD45RO+ T-PBL. In patients with low RF only, sGMP-140 and sELAM-1 correlated with the depletion of "primed" CD4+ and CD8+ T-PBL respectively. In such patients, Il-1 beta and GM-CSF also correlated with less CD8+, CD45RO+ T-PBL. Thus, particularly in patients with low RF, increased SAM, possibly released by the endothelial cells, might reflect the cytokine-induced activation of the vascular endothelium and the extravasation of some CD45RO+ T-PBL.
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PMID:Increased soluble endothelial adhesion molecules in rheumatoid arthritis correlate with circulating cytokines and depletion of CD45RO+ T-lymphocytes from blood stream. 753 32

Liver and kidney injury following acute or chronic exposure to cadmium is well characterized. While hepatocytes and endothelial cells of the sinusoids are thought to be the primary cellular targets in the liver, ultrastructural changes may vary depending upon the exposure regimen and the time following administration. Since acute and chronic liver disease is often associated with the presence of cytokines, we investigated the role of proinflammatory cytokines in cadmium-induced hepatotoxicity. Supernatants from cultured liver slices obtained from acute or subchronic cadmium-exposed rats and mice were collected and cytokine secretion was examined. In addition, mRNA transcripts for IL-1 alpha, IL-1 beta, IL-6, TNF-alpha, MIP-2, IFN-gamma, and ICAM-1 from livers of treated mice were quantitated by reverse transcription-polymerase chain reaction. Modest increases in secretion of TNF-alpha, IL-1 alpha, and IL-6 were observed in response to cadmium which were enhanced in LPS-primed mice. Additionally, cadmium exposure increased IL-1 alpha, IL-1 beta, TNF-alpha, MIP-2, IL-6, and ICAM-1 mRNA transcripts in the liver. Immunohistochemical analysis revealed that TNF-alpha was associated with nonparenchymal cells in livers of cadmium-treated mice. Cadmium exposure produced a marked increase in plasma hepatocellular enzyme levels (i.e., AST, LDH, SDH), acute phase proteins (i.e., serum amyloid A), and foci formation in the liver, while focal inflammation and serum amyloid A (SAA) secretion, but not plasma enzymes, were further increased in cadmium-exposed mice primed with LPS. SAA secretion and focal inflammation were prevented by pretreatment with antibodies to TNF-alpha, indicating that these pathological manifestations are cytokine dependent. These data indicate that TNF-alpha, released from nonparenchymal cells as well as associated cytokines, are responsible for certain manifestations observed with cadmium-induced hepatotoxicity.
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PMID:Role of tumor necrosis factor-alpha in cadmium-induced hepatotoxicity. 753 60

We have previously characterized the proliferative response of primitive CD34+ cells, purified from adult bone marrow, umbilical cord blood, and fetal liver, to a mixture of hematopoietic stimulators (steel factor [SF], interleukin-3 [IL-3], IL-6, and erythropoietin [Epo]) in serum-free liquid cultures. In the present study, we assessed the effects of the hematopoietic inhibitors, macrophage inflammatory protein-1 alpha (MIP-1 alpha), transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha), on the cytokine-induced proliferation of three different CD34+ cell subpopulations derived from cord blood and on total CD34+ cells derived from fetal liver. In cultures of cord blood cells, addition of MIP-1 alpha inhibited the numerical expansion of primitive CD34+ cells (CD34+ CD45RAlow CD71low cells) without inhibiting the proliferation of more mature subpopulations enriched for myeloid (CD34+ CD45RA+ CD71low cells) or erythroid (CD34+ CD45RAlow CD71+ cells) progenitors. TGF-beta significantly reduced the proliferation of all three subpopulations, although its effects were more pronounced on cells of the erythroid lineage, particularly immature erythroid progenitors. Similarly, TNF-alpha preferentially inhibited total nucleated and CD34+ cell production in the subpopulation enriched for erythroid cells. However, in contrast to TGF-beta, TNF-alpha preferentially inhibited the proliferation of more mature erythroid progenitors. In a separate set of experiments, MIP-1 alpha, TGF-beta, and TNF-alpha were added to cultures of total CD34+ cells purified from fetal liver. In keeping with the fact that the majority of the progenitors contained in these cells were erythroid progenitors, the inhibitory effects of the three cytokines were similar to those observed in cultures of CD34+ CD45RAlow CD71+ cord blood cells. The results of the present study demonstrate that MIP-1 alpha, TGF-beta, and TNF-alpha have the capacity to modulate cytokine-induced proliferation of cord blood and fetal liver progenitors. The differential effects of these three cytokines confirm their pleiotropic nature as regulators of hematopoiesis.
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PMID:Differential effects of the hematopoietic inhibitors MIP-1 alpha, TGF-beta, and TNF-alpha on cytokine-induced proliferation of subpopulations of CD34+ cells purified from cord blood and fetal liver. 753 84

Pulmonary fibrosis is the end point of a chronic inflammatory process characterized by leukocyte recruitment and activation, fibroblast proliferation, and increased extracellular matrix production. Previous studies of models of pulmonary fibrosis have investigated the role of cytokines in the evolution of the fibrotic response. The involvement of tumor necrosis factor and interleukin-1 in bleomycin-induced lung injury, a model of idiopathic pulmonary fibrosis, has been well established, suggesting that cytokines mediate the initiation and maintenance of chronic inflammatory lesions. However, the aforementioned cytokines alone cannot account for the recruitment and activation of specific leukocyte populations found in the bleomycin model. Recently, a family of novel proinflammatory cytokines (chemokines) was cloned and characterized, yielding many putative mediators of leukocyte functions. Macrophage inflammatory protein-1 alpha (MIP-1 alpha) and monocyte chemoattractant protein-1 (MCP-1) belong to the C-C chemotactic cytokine family, a group of low-molecular-weight peptides. These molecules modulate chemotaxis, proliferation, and cytokine expression in leukocyte subsets. Our group has investigated the roles of MCP-1 and MIP-1 alpha in the bleomycin model. Both MCP-1 and MIP-1 alpha are expressed in a time-dependent manner after bleomycin challenge, and passive immunization of these animals with either anti-MIP-1 alpha or anti-MCP-1 antibodies attenuated leukocyte accumulation. In addition, we have identified specific cell types expressing MCP-1 or MIP-1 alpha by in situ hybridization and immunohistochemical localization, respectively. Furthermore, our results indicate that MIP-1 alpha expression is mediated by alveolar macrophage-derived tumor necrosis factor, identifying an important cytokine pathway in the initiation of pulmonary fibrosis. Finally, anti-MIP-1 alpha therapy attenuated fibrosis, providing direct evidence for its involvement in fibrotic pathology. Our work has clearly established that the C-C chemokines MCP-1 and MIP-1 alpha are expressed and contribute to the initiation and maintenance of the bleomycin-induced pulmonary lesion.
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PMID:A role for C-C chemokines in fibrotic lung disease. 753 30

We have demonstrated the detection of proallergic cytokines in the nasal secretions after antigen challenges. Our aim was to determine the secretion kinetics of chemokines (interleukin [IL]-8, macrophage inflammatory protein-1 alpha [MIP-1 alpha], and RANTES) and other cytokines (IL-1 beta and granulocyte/macrophage colony-stimulating factor [GM-CSF] after allergen challenges and their inhibition by steroid therapy. Ten allergic patients were given either beclomethasone dipropionate (BDP) or placebo in a double-blind, randomized, crossover manner. Allergen challenges were performed after 1 wk of treatment. Nasal secretions were collected serially for 11 h after allergen challenge by a matrix method. Subjects maintained symptom scores at each time point of nasal secretion recovery. Cytokines were measured by specific enzyme-linked immunosorbent assays. The mean peak values for each cytokine and total symptom scores during the early (ER) and/or late-phase reactions (LPR) were significantly reduced during the BDP treatment period (p < 0.05). The levels of cytokine correlated (p < 0.05) with corresponding total symptom scores during ER (IL-1 beta and MIP-1 alpha) and LPR (all cytokines). Our findings document local elevations of IL-1 beta, GM-CSF, and chemokines in the nasal secretions after allergen challenges and their inhibition by steroids. We speculate that the inhibition of cytokine production and secretion in the nasal mucosa may contribute to the clinical efficacy of topical steroids.
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PMID:Secretion of chemokines and other cytokines in allergen-induced nasal responses: inhibition by topical steroid treatment. 754 59


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