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)

Hematopoietic stem cells are capable of self-replication and differentiation to lineage-committed progenitor cells. The progenitors proliferate and differentiate to lineage-specific, morphologically recognizable precursors and, finally, to terminal circulating blood cells. These homeostatic mechanisms are regulated by a complex set of interacting growth stimulatory and inhibitory factors that are produced by, or in collaboration with, the tissue's regulatory microenvironment. A number of well-characterized cytokines have been implicated in the negative regulation of hematopoiesis: ferritin H-subunit (HF), lactoferrin (Lf), prostaglandin E (PGE), tumor necrosis factor (TNF), interferon (IFN), transforming growth factor-beta (TGF beta), acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) or thymosin-beta 4, pyroGlu-Glu-Asp-Cys-Lys (pEEDCK), macrophage inflammatory protein-1 alpha (MIP-1 alpha), inhibin, superoxide dismutase (SOD), glutathione (GSH) and others not well-known yet. The role of inhibitors in restraining stem cells from entering the cell cycle and protecting them from the toxic side effects of chemotherapeutic drugs is opening an alternate strategy for the treatment of cancer patients.
 ...
PMID:[Biomolecules suppressing myelopoiesis]. 134 39

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.
 ...
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

The aim of this study was to compare the inhibitory effect of the tetrapeptide AcSDKP, tumor necrosis factor-alpha (TNF-alpha), which contains the sequence of the peptide, transforming growth factor-beta (TGF-beta), and macrophage inflammatory protein-1 alpha (MIP-1 alpha) on sorted CD34+ cells using both proliferation and clonogenic assays. Although a short treatment with any of the molecules decreased the growth of colony-forming unit granulocyte/macrophage (CFU-GM) and burst-forming unit-erythroid (BFU-E) progenitors (except for TNF-alpha as it is a greater inhibitor for CFU-GM), further experiments using a 6-day liquid culture in the presence of a combination of growth factors (recombinant human interleukin-3 [rhIL-3], IL-6, IL-1 beta, GM colony-stimulating factor [GM-CSF], G-CSF, erythropoeitin [Epo], and stem cell factor [SCF]) allowed us to determine a number of differences between their effects: 1) TGF-beta and TNF-alpha induced a stronger decrease in the proliferation and clonogenicity of CD34+ subsets than MIP-1 alpha and AcSDKP, 2) the dose-response curves appeared different, and 3) contrary to TGF-beta and TNF-alpha, AcSDKP and MIP-1 alpha required repeated addition to induce inhibition. Therefore, our data clearly show that while the inhibitory effect of TNF-alpha and AcSDKP appeared to be different, there is a close similarity in the effect of AcSDKP and MIP-1 alpha on normal human progenitor response to the combination of growth factors used.
 ...
PMID:Comparison of the inhibitory effect of AcSDKP, TNF-alpha, TGF-beta, and MIP-1 alpha on marrow-purified CD34+ progenitors. 753 83

The long-term marrow culture (LTC) system allows the sustained production of primitive normal and neoplastic (chronic myeloid leukemia [CML]) hematopoietic cells in vitro for many weeks. This is achieved in the absence of exogenously added hematopoietic growth factors because of the presence in the cultures of supportive "stromal" cells of the fibroblast-endothelial-adipocyte lineages. These latter cells form a confluent adherent layer with which the most primitive hematopoietic cells become associated and which locally regulates their behavior. The LTC system has thus been considered as a model of the microenvironment of the bone marrow and used to delineate potentially physiologically relevant mechanisms that regulate the proliferation, self-renewal and differentiation of primitive normal hematopoietic cells. It has also been used to analyze the molecular basis of the altered proliferative behavior that characterizes primitive neoplastic cells from patients with CML. Most of the information obtained to date has emerged from experiments designed to shift the balance of stimulatory and inhibitory factors present in order to favor either the cycling or quiescence of primitive normal or CML cells in LTC. This has been achieved either by addition of soluble factors (or antagonists) to the LTC medium or by the use of genetically engineered factor-producing stromal cells. Such experiments have allowed the identification of a number of cytokines that promote one or the other of these responses (i.e., primitive progenitor cycling or quiescence), including some that are involved in control mechanisms endogenous to the LTC system. Recent studies suggest that the retention of primitive normal cells in a reversible G(o) state in this system is mediated by the cooperating action of limiting concentrations of at least two endogenously produced inhibitory factors (transforming growth factor-beta (TGF-beta) and macrophage inflammatory protein-1 alpha (MIP-1 alpha)), either of which, however, if added exogenously at a sufficient concentration, can exert this action on its own. Interestingly, the heightened turnover characteristic of primitive CML cells appears to be due to a selective unresponsiveness to only one of these two inhibitors (MIP-1 alpha). These findings are consistent with a complex model of the extrinsic regulation of primitive hematopoietic cells in which a multiplicity of intracellular signaling intermediates within the target cells converge at different points ultimately to control their entry into S phase. Our findings further suggest that only some of these pathways may be affected by intracellular expression of the BCR-ABL fusion gene.
 ...
PMID:Differential manipulation of normal and chronic myeloid leukemia stem cell proliferation in vitro. 799 64

The aim of this study was to measure the level of cytokines produced by peripheral blood mononuclear cells (PBMNC) in patients with aplastic anemia (AA) and to determine their effect on the clonal growth of normal bone marrow (BM) cells. Twenty-one patients with AA and 11 normal controls were enrolled in this study. Medium conditioned by PBMNC of AA patients in the presence of lipopolysaccharide (LPS) was found to be suppressive to the colony growth of normal BM cells. Thus, we further determined the presence in the PBMNC-conditioned medium (CM) of both inhibitory cytokines: macrophage inflammatory protein-1 alpha (MIP-1 alpha), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta 2 (TGF-beta 2), and interferon-gamma (IFN-gamma), and stimulatory cytokines: interleukin-3 (IL-3) and stem cell factor (SCF). Spontaneous production of MIP-1 alpha was higher in the AA patients than the normal controls (1887 +/- 174 pg/ml vs 1643 +/- 93 pg/ml), but the difference was not significant. After LPS stimulation, the production of MIP-1 alpha was markedly increased in the AA patients, and its level was significantly higher than that of the normal controls (2360 +/- 149 pg/ml vs 1517 +/- 92 pg/ml, p = 0.0022). The level of TNF alpha was also higher in the AA patients. However, IFN-gamma, TGF-beta 2, SCF, and IL-3 were not detectable in the PBMNC-CM of either AA patients or normals. The myelopoietic suppressing effect of AA-PBMNC-CM from each AA patient was significantly blocked by pretreatment with anti-TNF-alpha, resulting in a colony-forming enhancement of 174% +/- 12%. A similar effect was noted in six of 11 AA patients by pretreatment with anti-MIP-1 alpha. We conclude that TNF alpha and MIP-1 alpha can be overproduced by the PBMNC of some AA patients, which may play a role in the progression of AA.
 ...
PMID:Overproduction of inhibitory hematopoietic cytokines by lipopolysaccharide-activated peripheral blood mononuclear cells in patients with aplastic anemia. 853 59

The aim of this study was to measure the level of cytokines produced by peripheral blood mononuclear cells (PBMNC) in patients with aplastic anemia (AA) and determine their effect on normal bone marrow (BM) colony growth. Thirty-five patients with AA and 21 normal controls were enrolled in the study. Medium conditioned by PBMNC of AA patients in the presence of phytohemagglutinin (PHA) was found to be suppressive to the clonal growth of normal BM cells. Thus, we further determined the presence in the PBMNC conditioned medium (CM) of inhibitory cytokines (macrophage inflammatory protein-1 alpha [MIP-1 alpha], transforming growth factor-beta 2 [TGF-beta 2], interferon-gamma [IFN-gamma], and tumor necrosis factor-alpha [TNF-alpha]) and stimulatory cytokines (granulocyte-macrophage colony-stimulatory factor [GM-CSF], interleukin-3 [IL-3], and stem cell factor [SCF]). The results show no significant difference between AA patients and normal controls in the spontaneous production of all cytokines by PBMNC. After PHA stimulation, the production of MIP-1 alpha, IFN-gamma, TNF-alpha, and GM-CSF significantly increased in the cultures of AA patients (p = 0.0009, 0.0002, 0.0022, and 0.0156, respectively). However, both TGF-beta 2 and SCF were undetectable in most of the tested samples. IL-3 was measured in the conditioned medium only after PHA stimulation, but without significant difference between the two groups (p = 0.67). Furthermore, the myelopoietic suppressing effect of AA-PBMNC CM could be significantly blocked by pretreatment with specific antibodies to the corresponding inhibitory cytokines (MIP-1 alpha, IFN-gamma, and TNF-alpha). After antibody neutralization, an apparent change occurred in the clonal growth of normal BM cells incubated with AA-PBMNC CM, resulting in colony enhancement of 205, 131, and 237% by anti-MIP-1 alpha, anti-IFN-gamma, and anti-TNF-alpha, respectively. These results suggest that overproduction of inhibitory cytokines, rather than underproduction of stimulating cytokines, may play a role in the progression of at least some patients with AA.
 ...
PMID:Production of hematopoietic regulatory cytokines by peripheral blood mononuclear cells in patients with aplastic anemia. 853 89

The tachykinins are a family of neuropeptides that share a common carboxyl terminus. Substance P (SP) and neurokinin-A (NK-A) are derived from the preprotachykinin l gene. Although SP and NK-A can bind to either NK-1, NK-2, or NK-3 receptors (R), they have preferences for NK-1R and NK-2R, respectively. We have reported that SP stimulates erythroid (E) (burst-forming unit [BFU]-E and colony-forming unit [CFU]-E) and myeloid (CFU-granulocyte-macrophage [GM]) progenitors partly through the induction of growth factors. We have now investigated the hematopoietic effects of NK-A using short-term bone marrow (BM) cultures and found that NK-A (10(-7) to 10(-12) mol/L) inhibits CFU-GM proliferation but stimulates erythroid progenitors. Release of soluble factors by the stroma appears to mediate the inhibition because direct contact with the stroma was not required. We have found that NK-A, through NK-2-like receptors induces increased levels of macrophage inflammatory protein-1 alpha (MIP-1 alpha) and transforming growth factor-beta (TGF-beta) (transcriptional and posttranscriptional) in BM stroma. Clonogenic assays with NK-A (10(-9) mol/L) and either anti-MIP-1 alpha or anti-TGF- beta 1 indicate that these cytokines partly contribute to the inhibition, suggesting that these two negative hematopoietic regulators exert part of the inhibition by NK-A on CFU-GM. The findings of two closely related neuropeptides, derived from the same gene, exerting opposite effects on myeloid colonies suggest that neuropeptides, by themselves could be important factors in hematopoietic regulation.
 ...
PMID:Induction of negative hematopoietic regulators by neurokinin-A in bone marrow stroma. 870 7

We investigated the effects of transforming growth factor-beta (TGF-beta) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) on very primitive CD34++CD38- and on more mature CD34++CD38+ human hematopoietic progenitor cells by means of a two stage pre-colony-forming cell (pre-CFC) assay. The first (liquid) stage of this assay allows evaluation of the effects of TGF-beta and MIP-1 alpha on the "primary" proliferation of the progenitors under study and on the generation of "secondary" colony-forming cells (CFC, cells for which a second stage semisolid clonogenic assay was used as a read-out). TGF-beta inhibited the proliferation and CFC generation of CD34++CD38- and CD34+CD38+ cells, showing the strongest inhibitory activity on CD34++CD38- cells. MIP-1 alpha exerted a weaker inhibitory activity on CD34+2CD38- cells, whereas it enhanced the primary proliferation of CD34+CD38+ cells and generation of secondary CFC in this subpopulation. Thus, TGF-beta, and MIP-1 alpha both inhibit very primitive CD34+2)CD38- cells, but they are not equally potent. The effects of TGF-beta and MIP-1 alpha on more mature progenitor cells are more complex. Our results and data from the literature indicate that, as progenitor cells mature, they reach a "pivotal point" at a certain stage in their differentiation pathway, depending on the inhibitor, where they are no longer inhibited or where they may even be stimulated by the former inhibitor to proliferate.
 ...
PMID:TGF-beta and MIP-1 alpha exert their main inhibitory activity on very primitive CD34+2CD38- cells but show opposite effects on more mature CD34+CD38+ human hematopoietic progenitors. 895 Feb 34

We have demonstrated that phagocytosis of late apoptotic cells by mouse macrophages leads to the production of proinflammatory cytokines, notably macrophage-inflammatory protein (MIP-2), and therefore, a yet-unknown mechanism(s) should keep our body free of inflammation. In this study, we examined the effect of the addition of immature dendritic cells (iDCs) to a coculture of macrophages and apoptotic cells on MIP-2 production and phagocytosis by macrophages. The addition of iDCs to the coculture reduced MIP-2 production significantly but unexpectedly enhanced the phagocytosis by macrophages. Further study revealed that the reduction of MIP-2 production was dependent on cell-to-cell contact partly involving the beta(2) integrin family Mac-1. In addition, anti-inflammatory cytokines, interleukin-10 and transforming growth factor-beta, were involved in the reduction of MIP-2 production, as antibodies against these cytokines recovered MIP-2 production. Both cytokines were expressed by iDCs more significantly than macrophages at the mRNA levels, although they were hardly detected in the supernatant at the protein levels, suggesting that minute amounts of these anti-inflammatory cytokines were produced mainly by iDCs to block MIP-2 production in a cell-to-cell contact-dependent manner. Thus, this study reveals a new mechanism by which MIP-2 production by macrophages phagocytosing apoptotic cells is prevented.
 ...
PMID:Immature dendritic cells reduce proinflammatory cytokine production by a coculture of macrophages and apoptotic cells in a cell-to-cell contact-dependent manner. 1476 36

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
 ...
PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84


1 2 Next >>