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)

We examined the effect of diffusible factors generated during the culture of the KM102 stromal cell line as well as in long-term bone marrow culture (LTBMC) on K562 leukemia cells, with respect to proliferation of clonogenic cells as well as total cells, and compared it with the effect on normal myeloid progenitors (CFU-GM). Proliferation of K562 cells plated in diffusion chambers was inhibited by coculture for 3-5 days in the fluid phase of stromal cell cultures or stromal cell-conditioned medium (CM), while CFU-GM proliferation was not inhibited under the same culture conditions. The inhibitory action was not attributed to the exhaustion of nutrients or growth promoting factors such as stem cell factor. These findings suggest that bone marrow stromal cells secrete diffusible molecule(s) which exert a preferential inhibitory effect on K562 leukemic cells vs. normal CFU-GM. Neutralization with antibodies against hematopoiesis-inhibiting cytokines such as TGF-beta 1, IFN-gamma, MIP-1 alpha and IL-4 which were detected in stromal cell-CM, failed to abrogate the inhibitory effect of KM102-CM on K562 cells. IL-1, TNF-alpha, IFN-alpha and lipopolysaccharides, known as stimulators of various cytokines from stromal cells, could not enhance the inhibitory activity. Further characterization of the factors may have implications for the treatment of leukemias.
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PMID:Preferential inhibitory effect of soluble factor(s) in human bone marrow stromal cells on proliferation of K562 leukemia cells versus normal myeloid progenitor cells. 893 34

Myeloproliferative disorders (MPD) are characterized by several common clinical and biological features, although at the molecular level, each disease entity exhibits distinct abnormalities. IFN-alpha exerts beneficial therapeutic effects in chronic myelogenous leukemia, polycythemia vera and essential thrombocythemia, resulting in control of hematopoietic hyperplasia and, in a minority of patients, in induction of cytogenetic remission. The mechanism of action of IFN-alpha in MPD is poorly defined. Recently published in vitro findings suggest that IFN-alpha interacts with the regulation of hematopoiesis by multiple ways. Its antiproliferative activity is well known for more than a decade, however, substantial growth inhibition is achieved only at relatively high concentrations. Defective adhesion of hematopoietic progenitor cells in CML to bone marrow stromal cells is corrected by IFN-alpha, which might expose CML progenitors to inhibitory cytokines produced by the bone marrow microenvironment. Recent work from our group demonstrated, that IFN-alpha potently interacts with the production of hematopoietic cytokines in bone marrow stromal cells. Expression of stimulatory cytokines, such as GM-CSF, G-CSF, IL-1 and IL-11 is inhibited by IFN-ct, whereas the production of negative regulators, such as IL-1RA and MIP-1 alpha, is stimulated. The combined action of IFN-alpha on paracrine expression of cytokines suggests an indirect antihematopoietic effect, which might contribute to its clinical activity in MPD.
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PMID:Influence of interferon-alpha on cytokine expression by the bone marrow microenvironment--impact on treatment of myeloproliferative disorders. 895 83

Lipopolysaccharide (LPS) is a potent inducer of macrophage inflammatory protein-1 alpha (MIP-1 alpha) production in human polymorphonuclear leukocytes (PMN), and it was recently shown that Interferon- gamma (IFN gamma) transiently inhibits MIP-1 alpha mRNA accumulation in LPS-stimulated PMN. To elucidate the molecular basis of the regulation of MIP-1 alpha gene expression in PMN, we investigated the effects of LPS and IFN gamma at both transcriptional and post-transcriptional levels. Nuclear run-on analysis revealed that LPS increases the transcription rate of the MIP-1 alpha gene, and that IFN gamma markedly inhibits the rate of MIP-1 alpha gene transcription in LPS-activated neutrophils. IFN gamma did not affect MIP-1 alpha mRNA stability in LPS-treated PMN, indicating that the cytokine does not regulate the LPS-induced MIP-1 alpha gene expression through post-transcriptional events. These results demonstrate that human neutrophils can actively transcribe the MIP-1 alpha gene, and that transcriptional inhibition is the mechanism whereby IFN gamma inhibits MIP-1 alpha gene expression in PMN.
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PMID:Interferon-gamma inhibits the lipopolysaccharide-induced macrophage inflammatory protein-1 alpha gene transcription in human neutrophils. 896 14

We have previously reported that oral administration of hot water extract of Chlorella vulgaris (CVE) enhances resistance to Listeria monocytogenes through augmentation of Listeria-specific cell-mediated immunity in normal mice and mice with murine acquired immunodeficiency syndrome (MAIDS) caused by murine leukemia virus (MuLV) LP-BM5. To elucidate the mechanisms whereby CVE augments the cell-mediated immunity, we examined the expression patterns of mRNA for cytokines in normal and MAIDS mice given CVE orally after L. monocytogenes infection. The expression levels of IL-1 alpha, IL-12, GM-CSF, MIP and TNF alpha genes were significantly augmented in the peritoneal adherent cells by oral administration of CVE for 2 weeks before Listeria infection. The expression levels of gamma IFN and IL-12 mRNA were significantly higher in the spleen after Listeria infection in CVE-treated mice than in normal mice, while the expression of IL-10 mRNA in the spleen was decreased by CVE administration. In MAIDS mice, oral administration of CVE also augmented the expression of gamma IFN and IL-12 mRNA in the spleen after Listeria infection, while it rather reduced the expression of IL-10 mRNA. These results suggest that CVE may preferentially augment THI responses against Listeria via activation of macrophages to produce IL-12 and enhance host defence against Listeria infection both in normal and MAIDS mice.
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PMID:Effect of hot water extract of Chlorella vulgaris on cytokine expression patterns in mice with murine acquired immunodeficiency syndrome after infection with Listeria monocytogenes. 904 41

Herpesvirus saimiri (HVS), strain 488-77, was used to derive continuously growing transformed human CD8+ T cell lines that can suppress HIV replication in CD4+ cells via the production of an antiviral factor(s). Transformed CD8+ cell lines were obtained by HVS infection of peripheral blood mononuclear cells or purified CD8- T cells from HIV-infected or uninfected individuals. Suppression of primary or laboratory isolates of HIV was mediated by factor permeation of a transwell membrane or by cell-free culture supernatants. Suppressing and nonsuppressing cell lines were IL-2-dependent for good growth and showed a similar activated cell surface phenotype. The cell lines produced varying amounts of the cytokines IL-8, IL-10, TNF-alpha, TNF-beta, RANTES, MIP-1 alpha, and MIP-1 beta, but not IFN-alpha. No correlation was observed between the level of any of these cytokines and the presence or absence of antiviral activity in cell line culture supernatants. These cell lines have become an important resource for studying antiviral factors produced by CD8+ T cells from HIV-infected individuals.
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PMID:Derivation of herpesvirus saimiri-transformed CD8+ T cell lines with noncytotoxic anti-HIV activity. 907 51

Adult T cell leukemia (ATL) cells show a mature helper-inducer T cell phenotype and are thought to secrete many kinds of cytokines in vivo, complicating the clinical features in these patients. In an attempt to specify the cytokines produced by ATL cells, we measured the cytokine concentration in the culture supernatants of three ATL cell lines, all of which were confirmed to be true peripheral blood ATL cell in origin. All these cell lines showed the same cytokine production profile, secreting IL1-alpha, IL1-beta, LD78(MIP-l alpha), TNF-alpha, IFN-gamma, and GM-CSF, but not secreting IL-1 alpha, IL-1 beta, IL-1 receptor antagonist (IL-1 Ra), IL-4, IFN-alpha, and G-CSF irrespective of the stimulatory agents used. Such limited cytokine production may indicate the specific origin of ATL cells within the helper-inducer T cell subtypes. Moreover, these results explain some of the unusual clinical features of ATL patients.
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PMID:Features of the cytokines secreted by adult T cell leukemia (ATL) cells. 917 9

The increased migration of peripheral blood mononuclear cells (PBMNCs) across a fibronectin (FN) matrix in response to the chemokines RANTES, MIP-1 alpha and MCP-1 is antagonized by interferon-beta-1b (IFN beta-1b). MCP-1 treatment of PBMNCs elevates their mRNA level and secretion of a matrix degrading enzyme, matrix metalloproteinase (MMP)-9, which is abrogated by IFN beta-1b. The clinical benefits of IFN beta-1b treatment in multiple sclerosis patients may in part be a result of this drug's ability to decrease the migration of PBMNCs in spite of a chemotactic gradient. Furthermore, the elevation of MMP-9 production by PBMNCs may be an important mechanism of action of chemokines.
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PMID:Chemokine-enhanced migration of human peripheral blood mononuclear cells is antagonized by interferon beta-1b through an effect on matrix metalloproteinase-9. 941 58

The macrophage occupies a central role in the host response to invasion, exerting its control over the developing inflammatory response largely through the elaboration of an assortment of endogenous mediators including many cytokines. The beta chemokine peptides, macrophage inflammatory protein [MIP]-1 alpha and MIP-1 beta, are two such effectors markedly up-regulated in macrophages following exposure to bacterial lipopolysaccharide (LPS). These highly homologous peptides, like the other members of the beta chemokine family, exhibit diverse but partially overlapping biological activity profiles, suggesting that the cellular participants and intensity of an inflammatory response may in part be regulated by selective expression of these chemokines. Studies reported here demonstrate that, in contrast to the "balanced" MIP-1 alpha/MIP-1 beta chemokine responses of LPS-stimulated macrophage cultures in vitro, circulating levels of MIP-1 beta are significantly higher than those of MIP-1 alpha following LPS administration in vivo. Further studies have revealed that several immunomodulatory cytokines known to be up-regulated in vivo as a consequence of exposure to an invasive stimulus (gamma-IFN, IL-10, IL-4, and transforming growth factor [TGF]-beta) down-regulated the LPS-induced release of MIP-1 alpha by macrophages in vitro, but spared the MIP-1 beta response. This altered pattern of secretion may explain, at least in part, the high circulating levels of MIP-1 beta relative to MIP-1 alpha observed in vivo in response to LPS challenge.
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PMID:Induction of the chemokine beta peptides, MIP-1 alpha and MIP-1 beta, by lipopolysaccharide is differentially regulated by immunomodulatory cytokines gamma-IFN, IL-10, IL-4, and TGF-beta. 984 81

Flt3-ligand (FL) is a cytokine that is of paramount importance in the proliferation of primitive hematopoietic progenitors. In this study, we show that endothelial cells (EC) produce large amounts of soluble FL and express a membrane-bound form of the molecule. Bone marrow microvascular EC also produce FL, suggesting that EC are an important source of FL in the bone marrow. High concentrations of FL in EC supernatants contrast with its undetectable levels in long-term bone marrow cultures. A single mRNA for FL is detected, suggesting that soluble FL derives from the membrane-bound species by proteolytic release. FL mRNA is stable with a half-life of about 3 h. II-1alpha increases FL mRNA levels and membrane and soluble FL expression. Glucocorticoids, known inhibitors for many hematopoietic growth factors do not down-regulate the expression of FL. On the contrary, GC increase the expression of both species of FL. The neutralization of FL in cocultures EC/ hematopoietic progenitors results in an acceleration of the maturation of the progenitors. IFN-alpha, MIP-1 alpha and TGF-beta stimulate production of membrane-bound and soluble FL. This stimulation is essential to explain their modulatory effect on the generation of clonogenic cells in cocultures EC/hematopoietic progenitors. Leukemia (2000) 14, 153-162.
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PMID:Expression of Flt3-ligand by the endothelial cell. 1063 91

The effect of porcine reproductive and respiratory syndrome (PRRS) virus infection on the synthesis and secretion of TNF-alpha and other pro-inflammatory cytokines by porcine alveolar macrophages (PAM) was investigated as well as the effect that TNF-alpha has on the replication of this virus. A clear reduction of phorbol myristate acetate (PMA)-induced expression of TNF-alpha mRNA was observed in cells incubated with PRRS virus. Moreover, the presence of PRRS virus also induced a decrease in IL-1 alpha and MIP-1 beta mRNAs expression with respect to PMA-stimulated uninfected cells. According to these results, exposure to the PRRS virus led to a reduction of the TNF-alpha protein in supernatants of PMA-stimulated PAM. On the other hand, addition of recombinant porcine TNF-alpha to cultures clearly reduced virus replication; however the addition of TNF-alpha to cultures containing IFN-alpha did not result in a further reduction of the produced by IFN-alpha alone. This indicates the lack of synergy in the effect of these cytokines on viral replication.
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PMID:Porcine reproductive and respiratory syndrome (PRRS) virus down-modulates TNF-alpha production in infected macrophages. 1098 84


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