Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-10, an anti-inflammatory cytokine, has been shown to exhibit stimulatory functions including CD14 up-regulation on human monocytic cells. CD14-mediated signaling following LPS stimulation of monocytic cells results in the synthesis of proinflammatory cytokines. Our results show that LPS-induced CD14 expression on monocytic cells may be mediated by endogenously produced IL-10. To investigate the molecular mechanism by which IL-10 enhances CD14 expression, both human monocytes and the promyelocytic HL-60 cells were used as model systems. IL-10 induced the phosphorylation of PI3K and p42/44 ERK MAPK. By using specific inhibitors for PI3K (LY294002) and ERK MAPKs (PD98059), we demonstrate that LY294002 either alone or in conjunction with PD98059 inhibited IL-10-induced phosphorylation of STAT-1 and consequently CD14 expression. However, IL-10-induced STAT-3 phosphorylation remained unaffected under these conditions. Finally, STAT-1 interfering RNA inhibited IL-10-induced CD14 expression. Taken together, these results suggest that IL-10-induced CD14 up-regulation in human monocytic cells may be mediated by STAT-1 activation through the activation of PI3K either alone or in concert with the ERK MAPK.
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PMID:STAT-1 mediates the stimulatory effect of IL-10 on CD14 expression in human monocytic cells. 1594 87

Mesenchymal stem cells (MSC) can be isolated from many sites adults and the fetus. Cells with osteoblastic, chondrogenic, leiomiogenic and stromogenic potentials have been obtained from the bovine artery wall, and we now show that MSC can be isolated also from the adult human vein wall. Cells detached from internal surface of the saphenous vein are cultured in vitro for 2-3 weeks and replated weekly. The culture forms a semi-confluent layer of spindle-shaped cells that are CD13(+), CD29(+), CD44(+), CD34(-), CD45(-), CD14(-), CD133(-), CD31(-), CD33(-), CD54(+), CD106(-), CD90(+), KDR(-), cadherin-5-, HLA class I(+) and HLA-DR- and differentiate in vitro into osteoblasts, chondrocytes and adipocytes. Gene expression, when compared with seven other normal tissues, shows strong similarity with MSC obtained from other sources. Three genes more expressed in saphenous MSC than in the other two MSC are related to angiogenesis, and the expression of two of them is shared by endothelial cells. These results demonstrate that the human vein wall contains mesenchymal cells with morphologic features, immunophenotypic markers, gene expression profile and differentiation potential that are similar to MSC obtained from the bone marrow and from the umbilical vein.
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PMID:Mesenchymal stem cells can be obtained from the human saphena vein. 1601 99

The evidence for the promising potential for derivatives of Vitamin D (deltanoids) in the treatment of myeloid leukemias is increasing, but currently is not matched by the understanding of the precise mechanisms by which these anti-neoplastic effects are achieved. Unlike solid tumors in which growth retardation by deltanoids appears to result from inhibition of cell proliferation and the promotion of cell death by apoptosis, control of myeloid leukemia proliferation by deltanoids results from the induction of differentiation of the immature myelo-monocytic cells towards functional monocytic cells. We present here the accumulating evidence that a pathway that is initiated by deltanoid activation of Vitamin D receptor (VDR) and leads to monocytic differentiation of human myeloblastic HL60 cells, includes the MEK-ERK and JNK mitogen-activated protein kinases (MAPKs), their positive and negative regulators and a downstream effector C/EBPbeta. As in other cells, the abundance of VDR protein increases shortly after an exposure of HL60 cells to 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2) D(3)). Other early events include a parallel upregulation of kinase suppressor of Ras (KSR-1) and the activation of the ERK MAPK pathway and data suggest that KSR-1 acts to amplify the signal provided by low concentrations of 1alpha,25(OH)(2) D(3). Maintenance of monocytic differentiation may be enhanced by JNK, but diminished by p38, MAPK signaling. Downstream, one of the targets of these pathways is C/EBPbeta, which can directly interact with the promoter for CD14, a gene characteristically expressed in monocytes. Importantly, in freshly obtained acute myeloid leukemia (AML)-M2 cells exposed to PRI-2191, a novel deltanoid with a modified side chain, upregulation of C/EBPbeta paralleled the induction of monocytic differentiation. These data provide a basis for the hypothesis that deltanoid-induced upregulation of C/EBPbeta bypasses the block to granulocytic differentiation in myeloid leukemia cells by redirecting the cells to monocytic differentiation.
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PMID:The rationale for deltanoids in therapy for myeloid leukemia: role of KSR-MAPK-C/EBP pathway. 1604 62

Tyrosine phosphorylation is an early step in lipopolysaccharide (LPS) stimulated monocytes and macrophages that appears to play a key role in signal transduction. We have demonstrated that LPS purified from Actinobacillus actinomycetemcomitans also increases protein tyrosine phosphorylation in human gingival fibroblasts (HGF). This effect was elicited rapidly after LPS stimulation at concentrations that stimulate anti-bacterial responses in human gingival fibroblasts. Two main proteins, with an apparent molecular weight of 44 and 42 kDa, were phosphorylated after LPS stimulation of the human gingival fibroblasts. The phosphorylation was detected after 5 to 15 min and reached the maximum at 30 min of treatment. The increase in tyrosine phosphorylation was apparent following stimulation with LPS at 10 ng/ml and the response was dose dependent up to 10 microg/ml. Pretreatment with the tyrosine kinase inhibitors, herbimycin A and genistein inhibited the LPS-stimulated phosphorylation of p44 and p42 MAP kinases in a dose dependent manner. Pretreatment of human gingival fibroblasts with antibodies anti-CD14 or anti-TLR-4 but not anti-TLR-2 inhibited the LPS-induced tyrosine phosphorylation of p44 and p42. Additionally, LPS-induced p44 and p42 phosphorylation was inhibited by polymyxin treatment. These findings demonstrate that LPS from A. actinomycetemcomintans increases rapidly p44 and p42 phosphorylation (ERK 1 and ERK 2, respectively) in human gingival fibroblasts. Our data also suggest that CD14 and TLR-4 receptors are involved in the LPS effects in human gingival fibroblasts.
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PMID:Actinobacillus actinomycetemcomitans lipopolysaccharide stimulates the phosphorylation of p44 and p42 MAP kinases through CD14 and TLR-4 receptor activation in human gingival fibroblasts. 1631 59

Endothelial progenitor cells (EPCs) contribute to blood vessel formation in ischemic and tumorous tissues, but comprise only a small population in circulation. We attempted to immortalize putative EPCs from human cord blood. Human CD34+ cord blood cells were cultured in the presence of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF), and transfected with a retroviral vector encoding the simian virus 40 large T (SV40T) antigen. This resulted in the immortalization of cord blood cells, leading to the establishment of several cell lines. One of these lines, HYCEC-1, exhibited a phenotype characteristic of the endothelial lineage, including expression of von Willebrand factor and VEGF receptor-2 (VEGFR-2/KDR/Flk-1) and uptake of acetylated-low density lipoprotein. Flow cytometric analysis revealed that HYCEC-1 cells were strongly positive for CD31 and CD146, moderately positive for CD144, weakly positive for CD133 and CD34, and negative for CD14 and CD45. HYCEC-1 cells formed capillary-like structures on basement matrix gel in vitro. Upon transplantation into the ischemic hind limb of nude rats, HYCEC-1 cells efficiently participated in neovascularization and augmented blood flow. The immortalized HYCEC-1 cells are suggested to be a class of EPCs that can efficiently participate in postnatal neovasculogenesis in the ischemic hind limb, and may also be a useful tool for studying tumor vessel formation.
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PMID:Postnatal neovascularization by endothelial progenitor cells immortalized with the simian virus 40T antigen gene. 1652 29

Mobilization of endothelial progenitor cells has been suggested to contribute to neo-vascularization of ischemic organs. Aim of this study was to investigate whether the combination of granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage (GM)-CSF may influence the expansion of circulating KDR+ cells in patients with acute myocardial infarction (AMI). KDR+ cells significantly increased in peripheral blood of AMI patients treated with G-CSF and GM-CSF compared to untreated patients. This KDR+ cells population was CD14+ but not CD34+ or CD133+. CD14+/KDR+ cells were also obtained in vitro by culturing mononuclear cells from healthy donors in a Rotary Cell Culture System in the presence of G-CSF + GM-CSF, but not of the individual growth factors. CD14+/KDR+ cells, obtained from patients or from in vitro culture, co-expressed hematopoietic (CD45, CD14) and endothelial markers (CD31, CD105, and VE-cadherin). CD14+/KDR+, but not CD14+/KDR- cells, stimulated the organization of human microvascular endothelial cells into capillary-like structures on Matrigel both in vitro and in vivo. The combination of G-CSF and GM-CSF induced a CD14+/KDR+ cell population with potential pro-angiogenic properties.
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PMID:Combined administration of G-CSF and GM-CSF stimulates monocyte-derived pro-angiogenic cells in patients with acute myocardial infarction. 1669 75

The hierarchy of endothelial progenitor cells (EPCs) in human umbilical cord blood has been disclosed. In this study we compare, for the first time, the angiogenic potential difference between two types of EPCs. We cultured mononuclear cells (MNCs) isolated from human umbilical cord blood using endothelial cell-conditioned medium and obtained two types of EPCs, referred to as circulating angiogenic cells (CACs) and high proliferative potential endothelial progenitor cells (HPP-EPCs). Both types of cells possess characteristics of EPCs, including expressing CD31, VE-cadherin, KDR and von Willebrand factor, uptake of Ac-LDL and binding to lectin. However, unlike CACs, which express CD14 but not CD133, HPP-EPCs express CD133 but not CD14. Also, unlike CACs, HPP-EPCs display stronger proliferation and clonogenic potential in vitro and show stronger ability to promote vascular growth in the hind-limb model of ischemia in mice (BALB/C-nu) in vivo.
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PMID:Angiogenic potential difference between two types of endothelial progenitor cells from human umbilical cord blood. 1702 Aug 9

Lactoferrin (LF) is a component of innate immunity and is known to interact with accessory molecules involved in the TLR4 pathway, including CD14 and LPS binding protein, suggesting that LF may activate components of the TLR4 pathway. In the present study, we have asked whether bovine LF (bLF)-induced macrophage activation is TLR4-dependent. Both bLF and LPS stimulated IL-6 production and CD40 expression in RAW 264.7 macrophages and in BALB/cJ peritoneal exudate macrophages. However, in macrophages from congenic TLR4(-/-) C.C3-Tlr4(lps-d) mice, CD40 was not expressed while IL-6 secretion was increased relative to wild-type cells. The signaling components NF-kappaB, p38, ERK and JNK were activated in RAW 264.7 cells and BALB/cJ macrophages after bLF or LPS stimulation, demonstrating that the TLR4-dependent bLF activation pathway utilizes signaling components common to LPS activation. In TLR4 deficient macrophages, bLF-induced activation of NF-kappaB, p38, ERK and JNK whereas LPS-induced cell signaling was absent. We conclude from these studies that bLF induces limited and defined macrophage activation and cell signaling events via TLR4-dependent and -independent mechanisms. bLF-induced CD40 expression was TLR4-dependent whereas bLF-induced IL-6 secretion was TLR4-independent, indicating potentially separate pathways for bLF mediated macrophage activation events in innate immunity.
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PMID:Lactoferrin activates macrophages via TLR4-dependent and -independent signaling pathways. 1703 74

Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is an important mediator of innate immunity and septic shock, but the exact mechanisms mediating cellular LPS recognition and the subsequent translation to inflammatory gene expression remain incompletely understood. CD14 has been established as a receptor that confers high sensitivity to LPS in cells of the myeloid lineage, probably by presenting LPS to Toll receptors. We use an anti CD14 blocking antibody to define a LPS stimulus that activates only this high affinity component of the LPS receptor and then examine CD14 dependent signaling events that are activated in response to LPS stimulation. We describe a novel LPS activated signaling pathway in human PBMC that leads to cytokine production and is mediated by PI3 kinase through Ras and the MEK/ERK cassette. Moreover, we show the PI3 kinase effectors PKB and PKC(zeta) are also activated by PI3 kinase in a CD14 dependent manner in LPS stimulated human PBMC. Thus, PI3 kinase appears to be an essential component in LPS signal transduction.
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PMID:Phosphatidyl inositol-3-phosphate kinase mediates CD14 dependent signaling. 1712 2

Fetal Alcohol Spectrum Disorders (FASD) are birth defects that result from maternal alcohol use. We used a non a priori approach to prioritize candidate pathways during alcohol-induced teratogenicity in early mouse embryos. Two C57BL/6 substrains (B6J, B6N) served as the basis for study. Dosing pregnant dams with alcohol (2x 2.9 g/kg ethanol spaced 4 hr on day 8) induced FASD in B6J at a higher incidence than B6N embryos. Counter-exposure to PK11195 (4 mg/kg) significantly protected B6J embryos but slightly promoted FASD in B6N embryos. Microarray transcript profiling was performed on the embryonic headfold 3 hr after the first maternal alcohol injection (GEO data series accession GSE1074). This analysis revealed metabolic and cellular reprogramming that was substrain-specific and/or PK11195-dependent. Mapping ethanol-responsive KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways revealed down-regulation of ribosomal proteins and proteasome, and up-regulation of glycolysis and pentose phosphate pathway in B6N embryos; and significant up-regulation of tight junction, focal adhesion, adherens junction, and regulation of the actin cytoskeleton (and near-significant up-regulation of Wnt signaling and apoptosis) pathways in both substrains. Expression networks constructed computationally from these altered genes identified entry points for EtOH at several hubs (MAPK1, ALDH3A2, CD14, PFKM, TNFRSF1A, RPS6, IGF1, EGFR, PTEN) and for PK11195 at AKT1. Our findings are consistent with the growing view that developmental exposure to alcohol alters common signaling pathways linking receptor activation to cytoskeletal reorganization. The programmatic shift in cell motility and metabolic capacity further implies cell signals and responses that are integrated by the mitochondrial recognition site for PK11195.
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PMID:Reprogramming of genetic networks during initiation of the Fetal Alcohol Syndrome. 1720 Sep 51


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