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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon-tau (oIFNtau), the major secretory product of ovine conceptuses between days 13 and 21 (day 0=day of estrus) of pregnancy, is implicated in the process of maternal recognition of pregnancy. Culturing of day-14 and day-16 conceptus tissues in the presence of human granulocyte macrophage-colony stimulating factor (hGM-CSF) or interleukin-3 (IL-3) produces a marked increase in oIFNtau mRNA and protein expression. Since GM-CSF and IL-3 are localized at the luminal and glandular epithelia of the ovine endometrium, maternally derived GM-CSF and IL-3 may affect conceptus production of oIFNtau in a paracrine manner. However, the molecular mechanisms by which endometrial GM-CSF and IL-3 up-regulate oIFNtau production have not been defined. As an initial investigation of the signaling pathway regulating the GM-CSF induction of the oIFNtau gene, day-16 conceptuses were treated with an inducer, phorbol 12-myristate 13-acetate (PMA) and an inhibitor, calphostin C of the protein kinase C (PKC) pathway. Treatment with either 150 units/ml hGM-CSF (P<0.01) or 10 nM PMA (P<0.05) resulted in a significant increase in oIFNtau mRNA expression. Pretreatment of conceptuses with 1 microM PMA for 12 h to produce PKC-deficient tissues or treatment with 50 mM calphostin C abolished the hGM-CSF-induced increase in oIFNtau mRNA. An in vitro expression system was established for the analysis of oIFNtau gene regulatory sequences. The oIFNtau010 gene has been isolated previously and found to be the principal oIFNtau gene up-regulated during the preimplantation period. 5'-Flanking regions of the oIFNtau010 gene, 2 kb and 0.8 kb, were cloned into a basic chloramphenicol acetyltransferase reporter plasmid. These oIFNtau010 promoter constructs, along with expression controls, were transfected into human choriocarcinoma cells (JAR and JEG3) and their responsiveness to hGM-CSF and second messenger system activators including PMA, calcium ionophore (A23187) and 8-bromo-cAMP were characterized. The oIFNtau010 promoter constructs were up-regulated by hGM-CSF and PMA treatments (P<0.01). Combined treatment with PMA and A23187 prevented the promoter activation seen with PMA alone. The conceptus culture data, along with the results from the transfection experiments, suggest that the stimulatory effect of GM-CSF on oIFNtau is mediated through the PKC second messenger system.
J Mol Endocrinol 1997 Oct
PMID:Enhancement of ovine trophoblast interferon by granulocyte macrophage-colony stimulating factor: possible involvement of protein kinase C. 934 4

A novel retrovirus, provisionally called Multiple Sclerosis RetroVirus (MSRV), was recently described in multiple sclerosis (MS). We report here that monocyte/macrophage culture supernatants from MS patients containing reverse transcriptase activity secrete a cytotoxin which induces death of primary mouse cortical glial cells. This cytotoxin, which was also found in MS cerebrospinal fluid, specifically causes death of mouse immortalized astrocytes and oligodendrocytes in vitro and seems to be associated to MSRV-specific RNA. This toxic factor, called gliotoxin, is present only in active cases of MS and is a stable glycosylated protein of 17 kDa, in CSF as well as in monocyte/macrophage culture supernatants. Since this gliotoxin is highly toxic for glial cells, it may represent an initial pathogenic factor, leading to the neuropathological features of MS, like blood brain barrier disruption and demyelination.
Cell Mol Biol (Noisy-le-grand) 1997 Sep
PMID:A cytotoxic factor for glial cells: a new avenue of research for multiple sclerosis? 935 36

Substitution of phenylalanine for tyrosine at codon 809 (Y809F) of the human colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) impairs ligand-stimulated tyrosine kinase activity, prevents induction of c-MYC and cyclin D1 genes, and blocks CSF-1-dependent progression through the G1 phase of the cell cycle. We devised an unbiased genetic screen to isolate genes that restore the ability of CSF-1 to stimulate growth in cells that express mutant CSF-1R (Y809F). This screen led us to identify a truncated form of the murine type Ibeta phosphatidylinositol 4-phosphate 5-kinase (mPIP5K-Ibeta). This truncated protein lacks residues 1 to 238 of mPIP5K-Ibeta and is catalytically inactive. When we transfected cells expressing CSF-1R (Y809F) with mPIP5K-Ibeta (delta1-238), CSF-1-dependent induction of c-MYC and cyclin D1 was restored and ligand-dependent cell proliferation was sustained. CSF-1 normally triggers the rapid disappearance of CSF-1R (Y809F) from the cell surface; however, transfection of cells with mPIP5K-Ibeta (delta1-238) stabilized CSF-1R (Y809F) expression on the cell surface, resulting in elevated levels of ligand-activated CSF-1R (Y809F). These results suggest a role for PIP5K-Ibeta in receptor endocytosis and that the truncated enzyme compensated for a mitogenically defective CSF-1R by interfering with this process.
Mol Cell Biol 1997 Dec
PMID:Complementation of growth factor receptor-dependent mitogenic signaling by a truncated type I phosphatidylinositol 4-phosphate 5-kinase. 937 70

Neonatal sepsis is a major cause of morbidity and mortality in newborn infants. Hematopoiesis and host defense in the neonate is developmentally immature compared with the adult. Defects in both the quantitative and qualitative aspects of the phagocytic system contribute significantly to a relative state of immunodeficiency in the neonate. Dysregulation of neonatal hematopoiesis and the immune response is a significant contributing factor to the increased susceptibility of the neonate to infection. A relatively small set of pluripotent stem cells gives rise to large numbers of functionally diverse mature effector cells. Cell proliferation and differentiation are regulated and controlled by highly specific protein factors, affecting single and multiple lineage hematopoiesis. Reduced neonatal rat myeloid progenitor pools, accelerated myeloid progenitor proliferative rates and decreased total body neutrophil storage pools predispose the newborn rat to depletion of mature effector neutrophils and a tendency to develop neutropenia during states of increased demand such as overwhelming bacterial infection. We review here the multifactorial complex biological process involved in the regulation of hematopoietic growth factors. We also review the biological effects of various non-lineage-committed and lineage-committed growth factors as reported in in vitro investigations and in vivo neonatal animal experiments. We also review our results of phase I/II clinical studies utilizing rhuG-CSF in neonates with presumed sepsis, and of rhuGM-CSF in very low birth weight neonates.
Cytokines Mol Ther 1995 Sep
PMID:The role of cytokines in modulating neonatal myelopoiesis and host defense. 938 73

The present study investigated the ability of uteroferrin and recombinant bovine granulocyte monocyte/macrophage-colony stimulating factor (rbGM-CSF) to modulate the myelosuppressive effects of 5-fluorouracil (5-FU) in young female pigs (Sus scrofa). Pigs (N = 3/treatment) were infused with 5-FU (32.5 mg/kg) on days 0 and 1 of the experimental period. Uteroferrin (100 micrograms/kg in 0.9% NaCl), rbGM-CSF (10 micrograms/kg in 0.9% NaCl), uteroferrin + rbGM-CSF (as above) or control (0.9% NaCl) were administered as intramuscular injections twice daily (0800 and 2000 hr). Peripheral blood cell number, composition, and progenitor cells were determined over 28 days. Treatment of pigs with 5-FU resulted in a rapid leukocytopenia and thrombocytopenia (nadirs on days 5 and 7, respectively) and a modest decrease (P < 0.05) in red blood cell (RBC) number (nadir on day 14). Although nor affecting RBC and thrombocytes, treatment of pigs with uteroferrin had an initial protective effect (P < 0.05) on the 5-FU-induced leukocytopenia (63 and 64 vs 48 and 39 +/- 6% of baseline on days 3 and 5, respectively). In contrast, rbGM-CSF enhanced (P < 0.05) the rate of the leukocytopenia and had only minor effects on thrombocyte numbers relative to controls. These effects appeared to be additive, as pigs treated with uteroferrin + rbGM-CSF had a reduced rate of leukocytopenia compared to pigs treated with rbGM-CSF alone. Uteroferrin + rbGM-CSF also attenuated (P < 0.05) the suppression and enhanced (P < 0.05) recovery of RBC and thrombocyte numbers following 5-FU treatment. In control pigs, a modest rebound leukocytosis (122 +/- 6% of baseline) and thrombocytosis (141 +/- 9% of baseline) was evident. Uteroferrin enhanced (P < 0.05) the rebound leukocytosis (135 +/- 6% of baseline), but attenuated (P < 0.05) the thrombocytosis. In contrast, rbGM-CSF enhanced (P < 0.05) the duration of the leukocytosis during the recovery phase, an effect augmented by the combination of uteroferrin + rbGM-CSF. In addition, treatment with uteroferrin + rbGM-CSF resulted in a sustained thrombocytosis (days 12 to 21). As indicated by changes in CFU-GM, BFU-E, and CFU-GEMM progenitor cells in peripheral blood, the effects of uteroferrin and rbGM-CSF appeared to reflect their ability to enhance the proliferation and/or differentiation of both similar and distinct hematopoietic progenitor cells.
Comp Biochem Physiol B Biochem Mol Biol 1997 Nov
PMID:Uteroferrin and recombinant bovine GM-CSF modulate the myelosuppressive effects of 5-fluorouracil in young female pigs (Sus scrofa). 946 70

The present study investigated the effect of uteroferrin and recombinant bovine granulocyte-monocyte/macrophage colony stimulating factor (rbGM-CSF) on hematopoiesis in young female pigs. Uteroferrin (100 micrograms/kg in 0.9% NaCl), rbGM-CSF (10 micrograms/kg in 0.9% NaCl), uteroferrin + rbGM-CSF (as above), or control (0.9% NaCl) were administered as intramuscular injections twice daily (0800 and 2000 hr). Peripheral blood cell number, composition, and progenitor cells were determined over 28 days. Uteroferrin had minimal effects on white blood cell (WBC) number, while rbGM-CSF caused both a rapid (days 2-7; maximum 122 +/- 8% of baseline) and late (days 16-28; maximum 133 +/- 8% of baseline) increase in WBC. Combination treatment with uteroferrin + rbGM-CSF abolished the initial increase in WBC number,but resulted in a prolonged increase in WBC number (days 14-28) relative to control. The rbGM-CSF-induced increase in WBC number resulted from rapid increases (P < 0.05) in monocytes and neutrophils. The addition of uteroferrin + rbGM-CSF enhanced (P < 0.05) the initial increase in the monocyte population and augmented the neutrophilia. In addition, uteroferrin + rbGM-CSF resulted in a dramatic eosinophilia (days 2-28), which was not detected in either the uteroferrin or rbGM-CSF treatments. Although not substantially affected by uteroferrin alone, rbGM-CSF caused an increase (P < 0.05) in thrombocyte numbers from days 1 through 9 (maximum 133 +/- 11% of baseline), an effect augmented by cotreatment with uteroferrin. The ability of these cytokines to modulate blood cell number and composition appeared to result from their effects on hematopoietic progenitor cells. Treatment of pigs with uteroferrin increased (P < 0.05) CFU-GEMM, CFU-GM, and BFU-E progenitor cells in peripheral blood, while rbGM-CSF caused increases (P < 0.05) relative to control in CFU-GM and CFU-GEMM. These effects were additive, as uteroferrin + GM-CSF augmented the increases in CFU-GM, BFU-E, and CFU-GEMM. Collectively, these results indicate that uteroferrin and rbGM-CSF can modulate hematopoiesis in young pigs. These effects were both additive and, in the case of neutrophils and eosinophils, synergistic. Hence, the mechanism(s) by which uteroferrin and rbGM-CSF modulate hematopoiesis appear to be different.
Comp Biochem Physiol B Biochem Mol Biol 1997 Nov
PMID:The effect of uteroferrin and recombinant GM-CSF on hematopoietic parameters in normal female pigs (Sus scrofa). 946 71

We tested if murine granulocyte-macrophage colony stimulating factor (mGM-CSF) is produced as a biologically active form through plant cell culture. The mGM-CSF gene was cloned into the plant expression vector, pBI121, and Ti-plasmid mediated transformation of tobacco leaves was conducted using Agrobacterium tumefaciens harboring the recombinant mGM-CSF (rmGM-CSF) gene. Cell suspension culture was established from the leaf-derived calli of transgenic tobacco plants. Northern blot analysis indicated the expression of the introduced mGM-CSF gene in both transgenic plant and cell suspension cultures. In addition, the biological activity of rmGM-CSF from plant cell culture was confirmed by measuring the proliferation of GM-CSF dependent FDC-P1 cells.
Mol Cells 1997 Dec 31
PMID:Establishment of a transgenic tobacco cell suspension culture system for producing murine granulocyte-macrophage colony stimulating factor. 950 21

The protein tyrosine phosphatase SHP-1 is a critical regulator of macrophage biology, but its detailed mechanism of action remains largely undefined. SHP-1 associates with a 130-kDa tyrosyl-phosphorylated species (P130) in macrophages, suggesting that P130 might be an SHP-1 regulator and/or substrate. Here we show that P130 consists of two transmembrane glycoproteins, which we identify as PIR-B/p91A and the signal-regulatory protein (SIRP) family member BIT. These proteins also form separate complexes with SHP-2. BIT, but not PIR-B, is in a complex with the colony-stimulating factor 1 receptor (CSF-1R), suggesting that BIT may direct SHP-1 to the CSF-1R. BIT and PIR-B bind preferentially to substrate-trapping mutants of SHP-1 and are hyperphosphorylated in macrophages from motheaten viable mice, which express catalytically impaired forms of SHP-1, indicating that these proteins are SHP-1 substrates. However, BIT and PIR-B are hypophosphorylated in motheaten macrophages, which completely lack SHP-1 expression. These data suggest a model in which SHP-1 dephosphorylates specific sites on BIT and PIR-B while protecting other sites from dephosphorylation via its SH2 domains. Finally, BIT and PIR-B associate with two tyrosyl phosphoproteins and a tyrosine kinase activity. Tyrosyl phosphorylation of these proteins and the level of the associated kinase activity are increased in the absence of SHP-1. Our data suggest that BIT and PIR-B recruit multiple signaling molecules to receptor complexes, where they are regulated by SHP-1 and/or SHP-2.
Mol Cell Biol 1998 Jul
PMID:Identification of major binding proteins and substrates for the SH2-containing protein tyrosine phosphatase SHP-1 in macrophages. 963 68

Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are members of the immunoglobulin superfamily adhesion molecules on vascular endothelium and important in the development of eosinophil (EOS) accumulation in allergic inflammation. To define the role of these adhesion proteins in EOS inflammation, peripheral blood EOS from allergic donors were incubated in either buffer (control)-, recombinant human (rh)-VCAM-1-, or rh-ICAM-1-coated plates, and the effects of these adhesion proteins on EOS effector functions were determined. VCAM-1 induced spontaneous EOS adhesion whereas EOS adhesion to ICAM-1 required a second signal, such as granulocyte macrophage colony-stimulating factor (GM-CSF). Although only VCAM-1 stimulated EOS superoxide anion (O2-) generation, the addition of GM-CSF (100 pM) to the reactions resulted in a greater and equivalent production of O2- with VCAM-1 and ICAM-1. In the presence of GM-CSF, ICAM-1 and VCAM-1 caused significant release of EOS-derived neurotoxin (EDN). Moreover, only ICAM-1 (no GM-CSF) promoted calcium ionophore A23187 (0.2 microM)-induced EOS leukotriene C4 (LTC4). Enhanced O2- generation, EDN release, and LTC4 generation observed with ICAM-1 and VCAM-1 were significantly inhibited by anti-beta2-integrin antibody. These results suggest that ICAM-1 and VCAM-1 are important in determining the eventual function of airway EOS.
Am J Respir Cell Mol Biol 1998 Jul
PMID:Granulocyte macrophage colony-stimulating factor augments ICAM-1 and VCAM-1 activation of eosinophil function. 965 Nov 92

The effects of intravenous injection of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on circulating neutrophil numbers, pulmonary vascular permeability, and morphologic changes in the lung were examined in rabbits. Intravenous injection of rhG-CSF caused a rapid, profound neutropenia due to neutrophil sequestration primarily within capillaries but also in larger microvessels of the lungs. Examination of neutrophil deformability using microfilters revealed that granulocyte colony-stimulating factor (G-CSF) treatment caused a rapid stiffening of neutrophils through the polymerization of F-actin but not microtubule assembly. The expression of CD11b, CD11c, and CD18 on human neutrophils after G-CSF treatment increased, but CD11a did not. Intravenous injection of rhG-CSF did not induce neutrophil emigration or albumin leakage into alveolar space, wet/dry lung weight ratios were unchanged, and no pathologic changes in lung histology were observed. These studies indicate that injection of rhG-CSF caused a rapid neutropenia and neutrophil sequestration in the lungs that is likely to be mediated through a G-CSF-induced decrease in neutrophil deformability, although neutrophil-endothelial cell adhesion may also play a role. However, this G-CSF-induced neutrophil sequestration did not induce a massive lung injury.
Am J Respir Cell Mol Biol 1998 Jul
PMID:Granulocyte colony-stimulating factor induces neutrophil sequestration in rabbit lungs. 965 Nov 93


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