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)

An important process in the immune response is the migration of different populations of lymphocytes at the proper time to sites of antigenic challenge. Although several chemoattractants are known for broad classes of lymphocytes, such as T and B cells, the process by which lymphocytes of specific subsets, such as helper, cytotoxic or memory T cells, migrate to the appropriate sites remains obscure. Interleukin-8 is a chemoattractant for T cells and neutrophils and is a member of a superfamily of soluble molecules related by a conserved motif containing four cysteine residues. IL-8 and related molecules, including platelet factor 4, constitute the C-X-C class of the superfamily and a group of cytokines produced by haematopoietic cells constitute the RANTES/sis or C-C class. The roles of most of these molecules are not well known, although murine MIP-1 alpha of the C-C branch is a specific inhibitor of haematopoietic stem cell proliferation and some members of the C-X-C branch are neutrophil-targeted inflammatory agents. Here we report that the RANTES protein of the C-C class causes the selective migration of human blood monocytes and of T lymphocytes expressing the cell surface antigens CD4 and UCHL1. CD4+/UCHL1+T cells are thought to be prestimulated or primed helper T cells involved in memory T cell function. The preferential attraction of T-cell subsets by specific cytokines could in part explain how lymphocytes are targeted, and may provide insight into the workings of T cell memory.
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PMID:Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. 169 35

The regulation of CD4 expression on macrophages and its role in immune cell interactions remain obscure. In contrast with primary lymphocytes, primary macrophages express only low amounts of surface CD4, which is regulated differentially for example by adherence in vitro. We report that addition of LPS for 1-5 days to human blood monocyte tissue culture-derived macrophages (TCDM) down-regulates both surface CD4 expression and total cellular CD4 antigen content as measured by flow cytometry and Western blot analysis. TNF-alpha and IL-1 beta, proinflammatory cytokines which are both induced by LPS, also down-regulate surface and total CD4 expression in TCDM. This down-regulation of CD4 expression by LPS, TNF-alpha, and IL-1 beta occurs at the level of transcription. The decreased macrophage CD4 expression induced by LPS was blocked by MoAbs directed against human TNF-alpha and IL-1 beta, demonstrating that LPS acts on CD4 expression through induction of endogenous TNF-alpha and IL-1 beta. Conversely, neither LPS nor TNF-alpha and IL-1 beta were able to modulate surface CD4 expression on quiescent or phytohaemagglutinin (PHA)-activated lymphocytes. Of other cytokines and growth factors tested, Th2 cytokines (IL-4, IL-10, IL-13), chemokines (MCP-1, MIP-1 alpha, RANTES), and macrophage colony-stimulating factor did not alter CD4 expression in primary macrophages; granulocyte-monocyte colony-stimulating factor and the prototypal Th1 cytokine interferon-gamma (IFN-gamma) modulated surface CD4 expression only after prolonged treatment (5 days). Our results show that LPS, TNF-alpha and IL-1 beta selectively down-regulate CD4 expression in primary human macrophages, and that decreased CD4 expression induced by LPS results from endogenous secretion of TNF-alpha and IL-1 beta by the macrophages.
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PMID:Lipopolysaccharide (LPS) down-regulates CD4 expression in primary human macrophages through induction of endogenous tumour necrosis factor (TNF) and IL-1 beta. 758 2

Competitive polymerase chain reaction (PCR) is a sensitive method for quantification of cytokine mRNA expression. Co-amplification of an internal standard serves as control for comparing the efficiency of PCR in different samples. We have developed a novel control fragment for multiple analyses of rat cytokine gene expression containing primers for IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-alpha, TGF-beta 1, IFN-gamma and MIP-2. Additional primers were incorporated to analyse the content of T cells (CD3), activated T cells (CD25) and housekeeping genes (beta-actin and HPRT). As an example we demonstrate analysis of IL-2 mRNA expression in small pieces of kidney tissue obtained from rats after kidney allotransplantation. The IL-2 expression decreased tenfold during treatment with an anti-rat CD4 monoclonal antibody as compared to untreated animals.
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PMID:A novel multispecific competitor fragment for quantitative PCR analysis of cytokine gene expression in rats. 782 31

To date no hematopoietic progenitors of dendritic Langerhans' cells (DLC), which represent an highly efficient class of antigen presenting cells, have been identified or the cytokines they elaborate have been defined. Here we describe an acute leukemia patient whose blasts (90-96% in peripheral blood and bone marrow) had a phenotype consistent with putative progenitors of DLC. The patient was treated with ara-C and VP-16 but did not achieve remission. The blasts had lobulated nuclei, no cytoplasmic vacuolation or Auer rods and were weakly positive for acid phosphatase and non-specific esterase and negative for PAS, granzyme A, dipeptidyl aminopeptidase IV, ATPase/ADPase and lysozyme production. The blasts were positive for CD1a, CD4, CD16, CD35, HLADR, HLADQ, CD11b, CD11c, CD14, CD33, CD34, CD11a, CD71, CD19, CD25, IL-2R beta and negative for CD2, CD7, CD8, CD10, CD22, CD56, CD57, surface or cytoplasmic CD3, TCR delta and TCR beta, HTLV-1p19 and P-glycoprotein. On liquid culture with or without 5 x 10(-9) M 12-O-tetradecanoylphorbol-13-acetate (TPA) for 3 days, the blasts formed aggregates of proliferating and elongating cells on the wall of the flasks with a decline in CD34, numerous dendritic processes appeared on the cells and there was strong positivity for ATPase/ADPase, but no other changes in phenotype. No macrophages were observed, indicating derivation from separate DLCs. Cytogenetic analysis showed chromosomal abnormalities and electron microscopy showed Birbeck granules. Southern blotting of DNA showed rearrangement of one allele for both JH and TCR beta but no HTLV-1 related sequences. Culture supernatants from blasts cultured with or without TPA showed the production of large amounts of IL-8, IL-6, TNF-alpha, MIP-1 alpha, IL-10 and interferon gamma and modest amounts of IL-1 alpha, GM-CSF and stem cell factor. The presence not only of CD1a, HLADR, HLADQ and many other characteristics including Birbeck granules, but also differentiation along the lines of DLC with appearance of dendritic processes on the cells and expression of ATPase/ADPase activity, indicate that the leukemic blasts in our patient represented a leukemic counterpart of normal progenitors of DLC and the leukemia a new entity which could possibly be classified as AML-M8. Lastly, many pro-inflammatory cytokines produced by DLC could contribute to inflammation and IL-10 to immunosuppression.
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PMID:Phenotype, genotype and cytokine production in acute leukemia involving progenitors of dendritic Langerhans' cells. 791 55

The pX gene of human T-cell leukemia virus type I (HTLV-I) is known to be a potent transactivator of the viral gene and the host genes which are important for cell proliferation in vitro. It has been reported that various diseases occur in transgenic mice harboring either tax, pX, or env-pX gene, such as mesenchymal tumor, neurofibroma, thymic atrophy, muscle degeneration, exocrinopathy and arthropathy. We previously demonstrated that rat but not mouse CD4 positive T cells could be easily infected and immortalized by HTLV-I and infectious transmission of HTLV-I induced HAM/TSP-like myelopathy in WKAH rats after long incubation periods of 16 months. These observations prompted us to produce a series of transgenic rats that expressed the pX gene products under the control of mouse H-2Kd promotor in order to evaluate further the biological and pathological function of the pX gene in vivo. In various tissues of pX transgenic rats (pX rats), pX mRNA was constitutively expressed irrespective of age. PX rats developed mammary tumors with massive infiltration by neutrophils as early as 9 months of age. Pathological and immunohistochemical examination revealed that the tumors were undifferentiated carcinomas of the mammary gland origin. They were transplantable into pX rats, but not into normal syngenic rats. High levels of mRNA expression of not only the pX transgene but also the host genes such as Gro (melanoma growth-stimulatory activity/KC), MIP-2 (macrophage inflammatory protein-2) and IL-1 alpha were demonstrated in the tumor tissues. Gro and MIP-2 which were known as IL-8 families were likely to be produced by tumor cells and appeared to be responsible for neutrophil infiltration in the tumor tissues. Lastly, pX rats described here appear to be suitable animal models for elucidating mechanisms involved in the tumorigenesis and the transactivation of the cellular genes by HTLV-I, especially by the pX gene products in vivo.
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PMID:[Pathological and molecular analyses of mammary tumors induced in HTLV-I pX transgenic rats]. 792 76

We previously showed that superoxide (O2-) significantly enhanced human immunodeficiency virus type 1 (HIV-1)-induced syncytia formation in co-cultured infected and uninfected human T cells. In this study, we describe a novel chemotactic response of uninfected CD4+ T cells by stimulating infected T cells with O2-. Syncytia formation was amplified only when persistently infected cells were stimulated by O2-. When the infected cells in lower well of microplate were cultured with uninfected cells in the upper well of a Boyden chamber with 8.0 microns pores, uninfected cell migration to the porous membrane was significantly amplified by stimulating infected cells with O2-. In contrast, similar functions were slight under the same assay conditions in the presence of known chemokines such as human RANTES and macrophage inflammatory protein 1 (MIP-1 alpha and beta), which all activate T lymphocytes. In addition, it is unlikely that the O2(-)-induced chemotactic response is due to soluble HIV-1 proteins from infected cells or to amplified expression levels of cell surface functional molecules such as CD4 and LFA-1 (CD11a and CD18) as well as HIV-1 Env gp120 on uninfected and/or infected cells. Thus, an unknown chemotactic factor could be generated from infected T cells by stimulation with O2- and it might contribute to viral transmission by activating cell-to-cell interactions.
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PMID:Stimulation of human immunodeficiency virus type 1 infected cells with superoxide enhances the chemotactic motile response of CD4+ human T cells: implication for virus transmission by cell-to-cell interaction. 865 92

A putative chemokine receptor that we previously cloned and termed LESTR has recently been shown to function as a co-receptor (termed fusin) for lymphocyte-tropic HIV-1 strains. Cells expressing CD4 became permissive to infection with T-cell-line-adapted HIV-1 strains of the syncytium-inducing phenotype after transfection with LESTR/fusin complementary DNA. We report here the indentification of a human chemokine of the CXC type, stromal cell-derived factor 1 (SDF-1), as the natural ligand for LESTR/fusin, and we propose the term CXCR-4 for this receptor, in keeping with the new chemokine-receptor nomenclature. SDF-1 activates Chinese hamster ovary (CHO) cells transfected with CXCR-4 cDNA as well as blood leukocytes and lymphocytes. In cell lines expressing CXCR-4 and CD4, and in blood lymphocytes, SDF-1 is a powerful inhibitor of infection by lymphocyte-tropic HIV-1 strains, whereas the CC chemokines RANTES, MIP-1 alpha and MIP-1 beta, which were shown previously to prevent infection with primary, monocyte-tropic viruses, are inactive. In combination with CC chemokines, which block the infection with monocyte/macrophage-tropic viruses, SDF-1 could help to decrease virus load and prevent the emergence of the syncytium-inducing viruses which are characteristic of the late stages of AIDS.
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PMID:The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. 875 81

Seven of 112 hemophiliacs infected with human immunodeficiency virus type-1 (HIV-1) before 1986 through contaminated plasma products are currently healthy, with CD4 T-cell counts above 500 cells/microL, and have never received antiretroviral therapy (long-term nonprogressors [LTNPs]). Seven age and sex-matched hemophiliacs infected in the same period but who have progressive HIV disease (progressors) and one additional slow-progressing individual were also studied. One hundred-fold, 20-fold, and 10-fold lower levels of full-length HIV RNA in plasma, peripheral blood mononuclear cells (PBMCs), and proviral DNA in PBMCs, respectively, were found in LTNPs compared with progressors. Plasma and cell-associated HIV RNA and proviral DNA were lower in LTNPs who tested negative for viral isolation from PBMCs or who were positive only after removal of CD8+ cells. No substantial differences were observed in the in vitro production of chemokines including RANTES, MIP-1 alpha, MIP-1 beta, MCP-1, and interleukin-8 (IL-8) in supernatants of activated PBMCs or CD8-depleted PBMCs of LTNPs, even when HIV isolation was simultaneously accomplished exclusively after removal of CD8+ cells. Low levels of HIV load and replication in peripheral blood are the strongest correlates of nonprogression in this small number of infected hemophiliacs.
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PMID:Hemophilia and nonprogressing human immunodeficiency virus type 1 infection. 932 56

The recent discovery of a chemokine receptor, fusin (fusin/CXCR-4), as the long-sought human immunodeficiency virus type 1 (HIV-1) coreceptor opened an entirely new field of aquired immunodeficiency syndrome (AIDS) research on mechanisms of viral entry, tropism and pathogenesis. It was soon followed by the identification of the chemokine receptor CCR-5 as the major macrophage-tropic (M-tropic) HIV-1 coreceptor and the demonstration that other chemokine receptors, CCR-3 and CCR-2b, also may serve as coreceptors, albeit at somewhat lower efficiency. Very recently it was demonstrated that the mechanism of the coreceptor function involves the formation of a complex on the cell surface between the HIV-1 envelope, the primary receptor CD4 and the coreceptor. Thus the prevention of the HIV-1 envelope glycoprotein-mediated fusion by the chemokines RANTES, macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta, as well as by the recently identified fusin/CXCR-4 ligand, stromal cell-derived factor-1 (SDF-1) could be explained by disruption of that complex. Interestingly, the identification of the HIV-1 coreceptor CCR-5 not only provided new insights into the mechanisms of viral entry and tropism, but also may help in explaining why some people with genetic alterations in CCR-5 are protected from HIV-1 infection.
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PMID:HIV and the 7-transmembrane domain receptors. 903 25

Cyclosporin A (CsA) is a potent immunosuppressant affecting many components of cellular and humoral immunity. Its main action probably results from inhibition of T-lymphocyte activation and interference with secretion of cytokines like IL-2, IL-4, IFN-gamma and TNF-alpha. Correspondingly, CsA has beneficial effects on the course of several autoimmune diseases thought to be mediated by T-lymphocytes, including a mild effect on multiple sclerosis. We exposed CD4 + cytotoxic T-lymphocytes specific for myelin basic protein, a putative target autoantigen in MS, to CsA in vitro, and determined the drug's effects on proliferation, expression of high affinity IL-2R, secretion of the proinflammatory cytokines IFN-gamma and TNF-alpha as well as on the secretion of the chemokines MIP-1 alpha and MIP-1 beta. In all instances, we observed a partial to complete inhibition. In contrast, the response of activated cells to IL-2 was resistant to CsA. Our observations are in line with results obtained in different experimental systems. The discrepancy between the profound inhibition of T-cells and the modest therapeutic effects on MS is discussed.
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PMID:In vitro modulation of human, autoreactive MBP-specific CD4 + T-cell clones by cyclosporin A. 918 37


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