Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is known that Notch activation promotes the self-renewal of hematopoietic cells. However, we have previously found that the growth of a myeloid leukemia cell line, OCI/AML-6, was suppressed by Notch activation induced by stimulation with a recombinant Notch ligand, Delta-1 protein. We recently found that the growth of another leukemia cell line, THP-1, was also suppressed by the ligands Delta-1 and Jagged-1. In this study, we tried to clarify the cellular and molecular mechanism of the growth suppression induced by Notch activation. Flow cytometric analysis showed that Delta-1 stimulation increased the expression of differentiation markers such as CD11b and CD13 while it decreased the expression of CD117 (c-KIT), a marker for primitive cells in THP-1 cells. In OCI/AML-6 cells, Delta-1 stimulation decreased the expression of CD11b and CD14 and increased CD34 expression. Namely, Delta-1 showed the opposite effects on the differentiation markers of each cell line. Delta-1 stimulation did not increase the binding of annexin V, a marker for apoptotic cells in either cell line. Since the growth of myeloid cells is regulated by MAP kinase and JAK/STAT pathways, we investigated the effects of the ligand stimulation on these pathways. Delta-1 stimulation did not induce the phosphorylation of ERK1/2 and STAT3 proteins in either cell line. Pre-exposure to Delta-1 did not affect the phosphorylation of ERK1/2 and STAT3 induced by G-CSF in OCI/AML-6 cells, either. Namely, it is thought that these pathways are not involved in the growth suppression caused by Notch ligands. Our study revealed several findings on Notch function. However, the precise mechanism remains to be elucidated.
Int J Mol Med 2004 Aug
PMID:Cellular analysis of growth suppression induced by the Notch ligands, Delta-1 and Jagged-1 in two myeloid leukemia cell lines. 1525 69

We have previously shown that 17beta-estradiol (E2) prevents the activation of brain macrophages, i.e. microglia cells, both in vitro and in vivo. Hormone exerts this inhibitory effect by inhibiting pro-inflammatory gene expression. In this study we further investigated on the molecular mechanism of E2 action in the RAW 264.7 macrophage cell line. We show here that these cells express the alpha-isoform of the estrogen receptor (ERalpha) and not ERbeta. Similarly to its activity in brain macrophages, E2 is able to inhibit the activation program induced by lipopolysaccharide (LPS) in RAW 264.7 cells, as shown by the inhibitory effect of hormone on the morphological conversion and matrix metalloproteinase-9 (MMP-9) expression induced by the endotoxin. In addition, we demonstrate that hormone treatment is not associated with a reduction in the steady-state expression of Toll-like receptor-4 (TLR-4) and CD14, two components of the LPS receptor complex. Our results further confirm the anti-inflammatory role of ERalpha in macrophages and propose that the mechanism of hormone action on macrophage reactivity involves signaling molecules which are down-stream effectors of the LPS membrane receptors.
J Steroid Biochem Mol Biol 2004 Jun
PMID:Regulation of the lipopolysaccharide signal transduction pathway by 17beta-estradiol in macrophage cells. 1526 8

The involvement of cytosolic free calcium (Ca2+) as a second messenger in lipopolysaccharide (LPS)-activated cellular pathways remains controversial. Using human monocyte-like THP-1 cells stably transfected with glycosylphosphatidylinositol-anchored human CD14, we have monitored the concentration of intracellular Ca2+ after sequential addition of LPS, ATP, and ionomycin. Whereas ATP and ionomycin induced rapid elevations of cytosolic Ca2+, no such changes were observed after LPS addition. These data argue against the participation of cytosolic Ca2+ in the CD14-dependent LPS activation pathway.
Mol Immunol 2004 Aug
PMID:Lipopolysaccharide-mediated cell activation without rapid mobilization of cytosolic free calcium. 1530 64

The collectin surfactant protein (SP)-A has been implicated in multiple immunoregulatory functions of innate pulmonary host defense via modulating immune responses both in vitro and in vivo. The aim of the present study was to investigate mechanisms responsible for the anti-inflammatory effects of human (hu) SP-A on the inhibitory kappaB (IkappaB)/nuclear factor (NF)-kappaB signaling pathway in alveolar macrophages (AMs). Initial CD25 expression analysis by flow cytometry of CD14/hu Toll-like receptor 4-transfected Chinese hamster ovary reporter cells demonstrated that SP-A alone does not induce any NF-kappaB-dependent CD25 expression in these cells. In AMs, SP-A pretreatment caused a marked inhibition of lipopolysaccharide (LPS)-induced NF-kappaB activation independent of the LPS chemotype used as determined by electrophoretic mobility shift assay. Western blot analysis revealed that SP-A by itself increased the protein expression of IkappaB-alpha, the predominant regulator for rapidly induced NF-kappaB, in a dose- and time-dependent manner without enhancing IkappaB-alpha messenger RNA as determined by reverse transcription-polymerase chain reaction. SP-A did not interfere with LPS-induced serine(32) phosphorylation of IkappaB-alpha but significantly enhanced IkappaB-alpha abundance under LPS-coupled conditions. The data suggest that anti-inflammatory effects of SP-A on LPS-challenged AMs are associated with a SP-A-mediated direct modulation of the IkappaB-alpha turnover in these cells.
Am J Respir Cell Mol Biol 2004 Dec
PMID:Accumulation of inhibitory kappaB-alpha as a mechanism contributing to the anti-inflammatory effects of surfactant protein-A. 1530 5

An altered inflammatory activity due to functionally relevant polymorphisms of the innate immune system may influence pathways leading to labour and, therefore, impact on the frequency of preterm birth. We examined five polymorphisms of the innate immune system in a large cohort of preterm very-low-birth-weight (VLBW, n = 909) and term-born infants (n = 491) and their mothers (n = 747). The primary outcome was preterm versus term birth. Frequencies of polymorphisms in mothers of term-born infants versus mothers of VLBW infants and term infants versus preterm VLBW infants (singletons) are given. Homozygous CD14-159T: 18.5 versus 21.8% (mothers) and 19.6 versus 21.2% (infants). Homozygous interleukin IL-6-174G: 28.8 versus 38% (P = 0.018, mothers) and 30 versus 32.7% (infants). Homozygous or heterozygous nuclear oligomerization domain NOD2-3020insC: 6.9 versus 6.1% (mothers) and 5.7 versus 5.1% (infants). Heterozygous or homozygous toll-like-receptor TLR2-Arg753Gln: 6.9 versus 6.1% (mothers) and 5.7 versus 5.1% (infants). Homozygous or heterozygous TLR4-896G: 8.1 versus 11.5% (mothers) and 11.6 versus 10.5% (infants). Although the homozygous maternal IL-6-174G genotype was found to be independently associated with preterm delivery in multivariate regression analysis, the incidence of intrauterine infection was not significantly increased in mothers of preterm VLBW-infants, carrying this or other polymorphisms of the innate immune system. The overall influence of the investigated polymorphisms on the development of preterm delivery seems moderate, since only the maternal IL6-174G genotype was associated with preterm birth and none of the polymorphisms were associated with intrauterine infection as the cause of preterm birth.
Mol Hum Reprod 2004 Dec
PMID:Polymorphisms of genes involved in innate immunity: association with preterm delivery. 1551 60

A novel triple co-culture model of the human airway barrier was designed to simulate the cellular part of the air-blood barrier of the respiratory tract represented by macrophages, epithelial cells, and dendritic cells. When epithelial cells (A549 cells) were grown on filter inserts with pores of 3.0 mum in diameter in a two-chamber system, they formed monolayers with polarization into apical and basolateral domains. The epithelial cell cultures were then supplemented with human blood monocyte-derived macrophages and dendritic cells on the apical and basal aspect, respectively. The single-cell cultures as well as the triple co-cultures were characterized in terms of a number of typical features, for example, morphology of cell types, integrity of epithelial layer, and expression of specific cell surface markers (CD14 for macrophages and CD86 for dendritic cells). The interplay of epithelial cells with macrophages and dendritic cells during the uptake of polystyrene particles (1 mum in diameter) was investigated with confocal laser scanning and conventional transmission electron microscopy. Particles were found in all three cell types, although dendritic cells were not directly exposed to the particles. More investigations are needed to understand the translocation pathway.
Am J Respir Cell Mol Biol 2005 Apr
PMID:A three-dimensional cellular model of the human respiratory tract to study the interaction with particles. 1564 Apr 37

Nuclear hormone receptors have been shown to be important transcription factors for regulating lipid metabolism in myeloid cells and were also implicated in differentiation processes of the myeloid lineage and macrophages. Peroxisome proliferator-activated receptor gamma (PPARgamma) seems to be a key component of lipid uptake by inducing the scavenger receptor CD36 that mediates oxidized low-density lipoprotein uptake in macrophages. Retinoic acid receptors, on the other hand, were also shown to play important roles in myeloid cell differentiation. In this study, we present evidence for a cross-talk between these two nuclear receptor pathways in myeloid cells. We show that expression level of PPARgamma increases with the degree of monocyte/macrophage commitment during maturation. Activation of PPARgamma leads to the increased expression of maturation markers (e.g., CD14, CD36). It is interesting that retinoid treatment potentiates PPARgamma's ability to induce transcription of its target genes. Retinoid-increased PPARgamma response is sufficient for enhancing lipid uptake. Our data, taken together, indicate that the expression level of PPARgamma increases during monocyte/macrophage development. PPARgamma activity can be enhanced by retinoids at least in part via increasing PPARgamma expression level. These observations can be exploited to enhance therapeutically beneficial PPAR responses in myeloid cells.
Mol Pharmacol 2005 Jun
PMID:Retinoids potentiate peroxisome proliferator-activated receptor gamma action in differentiation, gene expression, and lipid metabolic processes in developing myeloid cells. 1574 3

Immunosuppressive drugs such as glucocorticoids (dexamethasone (Dexa)), cyclosporin A (CsA) and tacrolimus (Tacro) have been shown to impair differentiation and/or function of immunostimulatory dendritic cells (DC(ims)). Phenotypes and functions of the resultant myeloid dendritic cells, however, have not yet been thoroughly elucidated. We show here that all DC subsets generated by treatment with immunosuppressive agents exhibited considerably reduced allostimulatory properties as measured in the primary mixed lymphocyte reaction (tacrolimus>cyclosporin A>dexamethasone, used at equimolar concentrations). In the MLR, all these DC subsets furthermore inhibited secretion of the T-helper type 1 cytokine IFN-gamma; in addition, DC-Tacro and, less so, DC-CsA induced the T-helper type 2 cytokine IL-4. Upon FACS analysis, DC-Tacro and DC-CsA exhibited phenotypic features similar to DC(ims). In addition, DC-CsA and, to a smaller extent, DC-Tacro were characterized by increased mRNA expression of the novel costimulatory molecule B7-H2 (ICOS-ligand). In contrast, dexamethasone induced the generation of DC characterized by decreased expression of CD83 and CD86, by de novo expression of plasmacytoid and myeloid cell markers CD123 and CD14, respectively, and by sustained expression of Toll-like receptor 2. Interestingly, activation of DC-Dexa with a specific TLR2 ligand induced a strong up-regulation of IL-10 along with TNF-alpha and IL-6, a combination of cytokines that allow amplification of regulatory DC populations. In conclusion, myeloid DC induced by dexamethasone as well as by CsA or tacrolimus show reduced allostimulatory properties; however, they are equipped with different molecular repertoires to exert these functions.
Mol Immunol 2005 Aug
PMID:Immunosuppressive agents mediate reduced allostimulatory properties of myeloid-derived dendritic cells despite induction of divergent molecular phenotypes. 1595 Jul 46

The capsule of Cryptococcus neoformans, the principal virulence factor of this fungus, is composed primarily of polysaccharide. The predominant component of the polysaccharide capsule is glucuronoxylomannan (GXM), a compound with potent immunoregulatory properties. GXM is bound and internalized by natural immune cells affecting innate and subsequent adaptive immune response. The cellular pattern recognition receptors involved in GXM binding include toll-like receptor (TLR)4, CD14, TLR2, CD18, Fc gamma receptor II (FcgammaRPi). This multiple cross-linking leads to a suppressive outcome that is arrested and even reversed by protective antibodies to GXM. This review analyzes the immunosuppressive effects induced by capsular material, considering its pattern recognition receptors, and dissects the mechanism of monoclonal antibody shifting to immunoactivation.
Curr Mol Med 2005 Jun
PMID:The cellular responses induced by the capsular polysaccharide of Cryptococcus neoformans differ depending on the presence or absence of specific protective antibodies. 1597 97

Acute promyelocytic leukemia (APL) is a human cancer generated by a chromosomal translocation t(15;17) involving the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARalpha) genes. The PML/RARalpha oncoprotein expressing blasts show two of the most important biological features of neoplastic progression: block of differentiation, at the promyelocytic state, and increased survival. Although PML/RARalpha interferes with the normal maturation of myeloid precursors to granulocytes, pharmacological doses of retinoic acid are sufficient to restore the differentiation processes. We designed an assay based on the Real-Time reverse transcriptase polymerase chain reaction (RT-PCR) to experimentally follow the differentiation response of leukemic cells even after short-time differentiating treatments. Amplifying CD11b, CD11c, and CD14 mRNAs, as specific markers of differentiation, by the real-time RT-PCR assay we could detect both retinoic acid (RA) and vitamin D3 and human transforming growth factor beta1 (VitD3/TGFbeta1) induced cellular maturation more precociously than the canonical flow-cytofluorimetric assay. Moreover, by amplifying CD14 mRNA it was possible to monitor the ability of PML/RARalpha oncoprotein to block VitD3/TGFbeta1 induced differentiation in U937-PR9 promonocytic inducible model systems.The proposed real-time quantitative RT-PCR approach is a reproducible and highly sensitive assay and can be considered a valid method to study both cellular maturation state and differentiation response.
Mol Biotechnol 2005 Jul
PMID:Differentiation response of acute promyelocytic leukemia cells and PML/RARa leukemogenic activity studies by real-time RT-PCR. 1598 48


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>