PubMed Health⌕ Search

Biomedical subjects

E R Stanley

Publications and source records attributed to E R Stanley.

At least 73 records · Page 4Linked to original sources
PubMed1992

Modulation of colony-stimulating activity by interleukin 1 in mice: opposing effects of combined treatment with indomethacin or prostaglandin E2.

Following previous observations that interleukin 1 (IL-1) may have both positive and negative effects on the levels of circulating colony-stimulating factors (CSF) in mice, we have investigated the impact of human rIL-1 beta administration on serum concentrations of colony-stimulating activity (CSA, as defined by biossay) and macrophage-specific colony-stimulating factor (CSF-1, measured by RIA). In addition, we have studied the effects of IL-1 administered in conjunction with indomethacin or prostaglandin (PG) E2. Besides confirming the finding that exogenous IL-1 leads to a rapid increase in CSF detection, we obtained evidence that IL-1 may also result in the production of cyclo-oxygenase pathway products that down-regulate the IL-1-induced burst in CSA and CSF-1 levels. While co-treatment of mice with indomethacin led to a further increase in CSF detection, the combined exposure to IL-1 and PGE2 resulted in a significant impairment of the stimulatory activity of IL-1.

Animals↗
PubMed1992

Administration of colony stimulating factor-1 corrects some macrophage, dental, and skeletal defects in an osteopetrotic mutation (toothless, tl) in the rat.

The toothless (tl/tl) mutation in the rat results in a paucity of osteoclasts and osteopetrosis that cannot be corrected by bone marrow transplantation. In the present study we demonstrate that tl/tl rats also have profound deficiencies of femoral, peritoneal, and pleural cavity macrophages. Furthermore, the macrophage colony stimulating activity of post-endotoxin sera from tl/tl rats is substantially reduced, suggesting that, as in the case of the op mutation in mice, the basis of the tl mutation is a deficiency of the macrophage growth factor, colony stimulating factor-1 (CSF-1). Consistent with this suggestion, treatment of tl/tl rats from birth for up to six weeks with CSF-1 reduced the osteopetrosis, increased body weight, and permitted tooth eruption. In addition, CSF-1 treatment induced large numbers of osteoclasts in tl/tl bones and macrophages in the peritoneal cavity and bone marrow. Persistence of metaphyseal sclerosis, however, indicated that the disease was not totally corrected by this treatment. These studies indicate that the basis of the tl mutation is most likely another CSF-1 deficiency, and further emphasize the role of this growth factor in osteoclast differentiation.

Animals↗
PubMed1992

Interleukin 1 and tumor necrosis factor-alpha stimulate the production of colony-stimulating factor 1 by murine astrocytes.

Astrocytes have the ability to secrete colony-stimulating factor 1 (CSF-1), a growth factor known to stimulate the proliferation of brain macrophages. We have studied the effect of cytokines such as interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF alpha), and interleukin 6 (IL-6) on the production of CSF-1 by cultured primary astrocytes and an astrocytic cell line derived from embryonic mouse brain. We observed that both TNF alpha and IL-1 increased CSF-1 mRNA and protein levels in the astrocytic cultures. In contrast, IL-6 was ineffective. The CSF-1 mRNA levels were strongly reduced by incubating immortalized astrocytic cells with staurosporine, a protein kinase C inhibitor, both in the absence and in the presence of cytokines. Conversely, 12-O-tetradecanoylphorbol 13-acetate, a protein kinase C activator, increased CSF-1 mRNA levels. These results suggest a mechanism whereby mononuclear phagocytes could favor their own recruitment in the CNS by producing cytokines.

Animals↗
PubMed1992

Expression of colony-stimulating factor-1 in the human uterus and placenta.

Previous studies in the mouse have strongly implicated colony-stimulating factor-1 (CSF-1) in the regulation of placental development. In this study of human pregnancy, we detected CSF-1 in serum, endometrium, placenta, chorion, amnion, and amniotic fluid, with significant increases in serum and endometrial samples from the first trimester compared to levels in nonpregnant controls. CSF-1 mRNA was demonstrated in all of these tissues, except amnion, with a significant increase within the first trimester endometrial samples over nonpregnant control values. In addition to the major 4.0-kilobase mRNA, other species of CSF-1 mRNA were detected, which were shown to be due to alternative splicing within exon 6 and the alternative use of exon 9 or 10. In the endometrium, CSF-1 was localized to glandular epithelial and endothelial cells. In first trimester placenta, CSF-1 was in the cytotrophoblasts lining the villous core and in the cytotrophoblastic shell. During the second trimester, CSF-1 was localized to villous mesenchymal cells. By the third trimester, CSF-1 was only detected in cells lining the villous vessels. The detection of CSF-1 during gestation strongly supports a role for CSF-1 in the regulation of placental function in humans by autocrine and/or paracrine mechanisms.

Amnion↗
PubMed1991

Epidermal growth factor stimulates phosphorylation of RAF-1 independently of receptor autophosphorylation and internalization.

Phosphorylation of the RAF-1 protooncogene product and activation of its associated serine/threonine kinase are common features of the response of cells to peptide growth factors. We have used wild-type and mutant epidermal growth factor (EGF) receptors to investigate mechanisms of RAF-1 phosphorylation. In vivo EGF treatment rapidly stimulated phosphorylation of RAF-1 exclusively on serine residues. Stimulation of RAF-1 phosphorylation occurred at 37 degrees C but not at 4 degrees C and persisted after dissociation of EGF from its receptor. EGF-induced RAF-1 serine phosphorylation required the intrinsic tyrosine kinase activity of the EGF receptor but was independent of EGF receptor self-phosphorylation and of ligand-induced receptor internalization. Down-regulation of protein kinase C did not affect the EGF-induced increase in RAF-1 phosphorylation. These data suggest that the activated tyrosine kinase activity of the EGF receptor enhances serine phosphorylation of RAF-1 via an intermediary molecule(s).

Amino Acids↗
PubMed1991

Tyrosine phosphorylation of a common 57-kDa protein in growth factor-stimulated and -transformed cells.

Protein tyrosine phosphorylation was studied in macrophages and fibroblasts to identify putative components of post-receptor mitogenic pathways that might be functionally conserved in different cell types. Nondenaturing conditions were established for the approximately quantitative recovery of anti-phosphotyrosine antibody (alpha PY)-reactive proteins from cells. A common, 57-kDa alpha PY-reactive protein was identified by V8 protease peptide mapping in colony-stimulating factor-1 (CSF-1)- or granulocyte-macrophage colony-stimulating factor (GM-CSF)-stimulated BAC1.2F5 macrophages, in platelet-derived growth factor-stimulated NIH-3T3 cells, and in CSF-1-stimulated NIH-3T3 cells expressing the c-fms/CSF-1 receptor. The 57-kDa protein was phosphorylated on serine and tyrosine and was the only alpha PY-reactive protein band whose phosphorylation was reproducibly increased in GM-CSF-stimulated cells. The effect of the growth factors on the tyrosine phosphorylation of the 57-kDa protein could be mimicked by treatment of the cells with orthovanadate, a phosphotyrosine protein phosphatase inhibitor. In the absence of growth factors, tyrosine phosphorylation of the 57-kDa protein was higher in v-fms or c-fms (F969, S301)-transformed NIH-3T3 cells than in untransformed NIH-3T3 (c-fms) and NIH-3T3 (c-fms, F969) cells. These data indicate that the 57-kDa protein is a common target for growth factor-stimulated tyrosine phosphorylation and potentially important for growth factor mitogenic signaling.

Animals↗
PubMed1991

Increased circulating colony-stimulating factor-1 in patients with preleukemia, leukemia, and lymphoid malignancies.

Recently, several malignant cell types have been reported to express colony-stimulating factor-1 (CSF-1) transcripts; however, the clinical significance of CSF-1 in malignancy has not been investigated. Using a CSF-1 radioimmunoassay, we surveyed concentrations of biologically active CSF-1 in the peripheral blood of 316 patients with malignant and premalignant hematologic disorders; 75 had a myelodysplastic syndrome (MDS), 12 acute myelogenous leukemia (AML), 7 chronic myelogenous leukemia, 21 chronic lymphocytic leukemia (CLL), 106 non-Hodgkin's lymphoma (NHL; of low-, intermediate- and high-grade malignancy), 46 Hodgkin's disease (HD), 46 multiple myeloma (MM), and 3 monoclonal gammopathy of undetermined significance. Controls were 64 healthy subjects. The CSF-1 concentration was correlated with the type of disease, status of the disease, treatment status, and hematologic parameters. CSF-1 concentration was significantly elevated in 83.5% of the patients with active disease, and for each active disease group it was significantly greater (P less than .0001) than in the control. Thus, the high circulating CSF-1 concentration was not associated with a particular malignant phenotype or MDS subtype, but did correlate with the disease activity of both NHL and HD, and the tumor burden in MM, AML, and CLL. There was no correlation of the CSF-1 level with total counts of monocytes or neutrophils in patients with MDS or other malignancies. The cellular basis for the elevated circulating CSF-1 was not investigated. However, the results are consistent with the possibility that the premalignant or malignant cells themselves produce CSF-1 or regulate its production by normal cells.

Biomarkers, Tumor↗
PubMed1991

Independently arising macrophage mutants dissociate growth factor-regulated survival and proliferation.

Analysis of a simian virus 40-immortalized colony-stimulating factor 1 (CSF-1) -dependent macrophage cell line (BAC1.2F5) and independently arising autonomous mutants derived from it (aut4A, aut4A.1, aut2A, and aut2A.1) revealed distinct phenotypes. The parental line, BAC1.2F5, is dependent on CSF-1 for survival and growth. Of the mutants derived from BAC1.2F5, aut4A has lost the requirement of CSF-1 for survival; aut4A.1 (derived from aut4A) and aut2A grow in the absence of growth factor but proliferate more rapidly in its presence, and aut2A.1 (derived from aut2A) produces CSF-1 and proliferates as rapidly in the presence as in the absence of exogeneous CSF-1. The separation of the CSF-1 requirement for survival and proliferation observed in aut4A is also observed in a temperature-sensitive (ts) mutant tsgro1. At the nonpermissive temperature, tsgro1 cell proliferation is arrested, but the cells survive provided CSF-1 is present. The four cellular phenotypes observed--immortalization, loss of growth factor requirement for survival, loss of growth factor requirement for proliferation, and loss of growth factor-stimulated proliferation--indicate a divergence of the pathways of growth factor-regulated survival and proliferation and may represent phenotypes occurring at intermediate stages in tumor-cell progression.

Animals↗
PubMed1991

Role of dimerization and modification of the CSF-1 receptor in its activation and internalization during the CSF-1 response.

We have used kinetic and cross-linking approaches to study CSF-1-induced changes in the structure and function of the CSF-1R. Addition of CSF-1 to cells stimulates or stabilizes non-covalent CSF-1R dimerization resulting in activation of the CSF-1R kinase and the tyrosine phosphorylation of the receptor and certain cytoplasmic proteins. The non-covalent dimers become covalently linked via disulfide bonds and/or are subsequently further modified. These modified forms are selectively internalized. Pre-treatment of cells with the alkylating agent, iodoacetic acid (IAA), selectively inhibits covalent dimerization, modification and internalization but enhances protein tyrosine phosphorylation. It is proposed that ligand-induced non-covalent dimerization activates the CSF-1R kinase, whereas the covalent dimerization and subsequent modification lead to kinase inactivation, phosphotyrosine dephosphorylation and internalization of the receptor--ligand complex.

Animals↗
PubMed1991

A pregnancy defect in the osteopetrotic (op/op) mouse demonstrates the requirement for CSF-1 in female fertility.

Correlative evidence suggests that maternal production of the mononuclear phagocyte growth factor colony stimulating factor-1 (CSF-1) regulates placental development. In order to study the role of CSF-1 in pregnancy the fertility of CSF-1-less osteopetrotic (op/op) mutant mice was investigated. Homozygous mutant crosses (op/op x op/op) were consistently infertile. As expected, op/op males were almost completely fertile when crossed with heterozygous females. Surprisingly, op/op females when mated to heterozygote males were fertile, although at a rate that was 46% of the rate for +/op females x op/op males. These data suggest that CSF-1 is required for pregnancy. However, a maternal CSF-1 source is not absolutely necessary in that pregnancies involving +/op fathers were partially rescued, suggesting that +/op fetuses and/or +/op seminal fluid provides CSF-1 or CSF-1-induced factors which compensate for the absence of maternally produced CSF-1. Despite the complete absence of CSF-1 in the uterus and placenta of op/op mice placental weights were normal, suggesting that proliferation of decidual cells and trophoblasts, both of which express the CSF-1 receptor, may not be solely regulated by CSF-1. Histochemical staining for F4/80 antigen was used to identify macrophages in the uterus and placenta. Uterine macrophages could not be detected in virgin op/op mice although they were abundant in +/op uteri. Interestingly, macrophages could be detected in op/op uteri as uncharacteristically rounded cells in early gestation, however, they were not maintained and no macrophages were apparent beyond Day 14 of pregnancy in op/op mice. Further studies in the osteopetrotic mouse will be useful in delineating those functions required for pregnancy that are regulated by CSF-1.

Animals↗
PubMed1991

Macrophage colony-stimulating factor in murine candidiasis: serum and tissue levels during infection and protective effect of exogenous administration.

Serum and tissue concentrations of the macrophage-specific colony-stimulating factor (CSF-1) and the number of CSF-1-responsive cells in bone marrow were investigated in mice chronically infected with a low-virulence strain of the opportunistic zoopathogenic yeast Candida albicans. CSF-1 levels in serum, brain, kidney, liver, and lung were significantly increased shortly after infection and remained elevated during the 2 weeks preceding the onset of specific T cell-dependent immunity. The number of monocytic precursor cells was also increased in the bone marrow of infected mice. When macrophages from naive donors were exposed in vitro to purified murine CSF-1, their anticandidal activity in vitro appeared to be enhanced. CSF-1 was also administered in vivo to prospective recipients of a lethal C. albicans challenge. The results showed that the factor could effectively potentiate the animals' resistance to the yeast, as shown by increased survival times and reduced recovery of viable C. albicans from the organs of the CSF-1-treated mice. Therefore, the present data suggest that CSF-1 is likely to contribute to early resistance to fungal infection and could be successfully exploited in experimental models of antifungal immunotherapy.

Animals↗
PubMed1991

Prophylaxis or treatment of experimental brucellosis with interleukin-1.

Intravenously injected recombinant human interleukin-1 alpha (IL-1 alpha) given to mice 4 h before infection with Brucella abortus 19 depressed the growth of bacteria in the spleen and liver. However, the same dose (10(5) U) or a 10-fold higher dose was not able to decrease numbers of bacteria when given to chronically infected mice. IL-1 injected into normal mice induced a dramatic increase 2 h later in colony-stimulating activity in serum, measured by bone marrow proliferation, and in colony-stimulating factor 1, measured by radioimmunoassay. Colony-stimulating factor levels declined but remained higher than normal for at least 12 h. The early peak stimulation was not observed in chronically infected mice, but the more prolonged elevation was. As a result of IL-1 treatment, the number of colony-forming cells, especially in the spleen, was increased in normal and acutely or chronically infected mice. Myeloperoxidase staining of newly formed monocytes and polymorphonuclear cells in the spleen revealed an increase in the number of these cells in normal and acutely infected mice as a result of IL-1 treatment, but there was no increase in the already high numbers in chronically infected mice. The relationship between these observations and the basis of chronic infection are discussed.

Animals↗
PubMed1991

Alterations in CSF-1 receptor expression and protein tyrosine phosphorylation in autonomous mutants of a CSF-1 dependent macrophage cell line.

One approach to the problem of growth factor signal transduction is to identify alterations in growth factor-regulated events in mutants possessing an altered proliferative response. This approach was used in a study of the alterations in protein tyrosine phosphorylation in 22 independently-arising autonomous mutants of the CSF-1-dependent mouse macrophage cell line, BAC1.2F5. Only 4 of the mutants produced CSF-1 and/or factors that were capable of down-regulating the CSF-1 receptor (CSF-1R), suggesting that the majority were altered in the signal transduction pathway for proliferation. All of the mutants possessed lower numbers (13-89%) of cell surface CSF-1Rs than wild type cells. With two possible exceptions, the phosphorylation of the anti-phosphotyrosine-reactive cell surface CSF-1Rs from CSF-1 stimulated cells was directly proportional to cell surface CSF-1R number. In the absence of CSF-1, three of the 22 mutants exhibited tyrosine phosphorylation of proteins that was not observed in wild type cells under the same conditions. The results indicate that this approach will be useful in the analysis of the growth factor regulated pathway for cell proliferation.

Animals↗
PubMed1991

FMS (CSF-1 receptor) and CSF-1 transcripts and protein are expressed by human breast carcinomas in vivo and in vitro.

The expression in vivo of FMS transcripts and antigen by neoplastic epithelial cells was demonstrated immunohistochemically or by in situ hybridization in sixteen of seventeen human breast carcinoma specimens and one case of sclerosing adenosis. Expression of CSF-1 receptor (FMS) transcripts and protein was also observed in vitro in two or three breast carcinoma-derived cell lines and was dramatically increased by dexamethasone, a potent glucocorticoid and inducer of mammary epithelial cell differentiation. Immunohistochemical staining with an anti-CSF-1 antibody identified neoplastic epithelial cell co-expression of fms and CSF-1 antigens in more than one-third of the fms-positive invasive carcinoma specimens. These results suggest that autocrine and paracrine interactions of the lymphohematopoietic cytokine CSF-1 and its receptor may participate in the biology of human mammary neoplasms.

Blotting, Northern↗
PubMed1991

Increased phosphorylation of the colony stimulating factor-1 receptor following transmembrane signaling.

The receptor for colony-stimulating factor-1 (CSF-1) is a 165-kDa tyrosine kinase phosphorylated on serine residues in quiescent macrophages. Addition of CSF-1 to macrophages induces the following sequence of events: (1) formation of a 380-kDa noncovalently associated receptor dimer that is tyrosine phosphorylated; (2) protein tyrosine phosphorylation; (3) disulfide bond crosslinking of the noncovalently associated receptor monomers; and (4) conversion of the receptor homodimer to a heterodimeric 450-kDa species in which the apparent molecular mass of one of the subunits is increased from 165 to approximately 240 kDa (Li and Stanley, 1991). To study the kinetics of early phosphorylation/dephosphorylation events associated with these changes in the CSF-1R, we stimulated a CSF-1-dependent macrophage cell line with CSF-1 at 4 degrees C to slow reaction rates and prevent internalization. CSF-1 induced a rapid (2-4 min) initial increase in tyrosine phosphorylation of the 165-kDa subunits of the noncovalent 380-kDa homodimer. At 60-120 min after ligand binding, the conversion of some of the 165-kDa species to a approximately 240-kDa species on reducing SDS-PAGE was indicative of the transition of 380-kDa homodimer to 450-kDa heterodimer. Both the approximately 200 and 165-kDa subunits of the heterodimer were more highly phosphorylated in tyrosine than the subunits of the homodimer 2-4 min after ligand binding. The 165-kDa subunit of the heterodimer also exhibited increased phosphorylation in serine. However, in vitro dephosphorylation experiments indicated that a modification other than phosphorylation is involved in the conversion of the 165-kDa to the approximately 240-kDa CSF-1R species. The possibility that the increased tyrosine and serine phosphorylation of the subunits of the 450-kDa heterodimer may be involved in regulation of receptor kinase activity and/or internalization is discussed.

Alkaline Phosphatase↗
PubMed1991

Correction by CSF-1 of defects in the osteopetrotic op/op mouse suggests local, developmental, and humoral requirements for this growth factor.

Mice that are mutant at the op locus have a severe deficiency of mononuclear phagocytes due to an inactivating mutation in the CSF-1 (macrophage colony-stimulating factor, M-CSF) gene. op/op mice are toothless, possessing skeletal abnormalities, a low body weight, and compromised fertility; they are osteopetrotic due to a deficiency of osteoclasts. The congenital osteopetrosis, toothless phenotype, osteoclast deficit, and the defects in splenic and femoral macrophages were corrected by routes of administration of human recombinant CSF-1 that maintained normal circulating CSF-1 concentrations. Early restoration of circulating CSF-1 was required for rescue of the toothless phenotype, but only partially restored body weight. In contrast, the deficiencies of pleural and peritoneal cavity macrophages and the reduced female fertility were not corrected by restoration of circulating CSF-1. These results suggest that although circulating CSF-1 is required for osteoclast and macrophage production, local synthesis and action of the growth factor are important for certain target cell populations.

Animals↗
PubMed1990

Alterations in the expression of colony-stimulating factor-1 and its receptor during an acute graft-vs-host reaction in mice.

During the course of an acute graft-vs-host reaction in the mouse we observed a progressive increase in the concentration of CSF-1 in serum and liver, peaking at day 14. In contrast, there was a progressive decrease in the splenic CSF-1 concentration. In vivo studies of 125I-CSF-1 uptake and degradation and in vitro studies of 125I-CSF-1 binding by splenic cells demonstrated that within 24 h of the reaction the number of CSF-1 receptor+ cells had increased by 2-fold and their capacity to express the CSF-1 receptor by approximately 3-fold, resulting in a approximately 2.5-fold increase in the splenic clearance of CSF-1 from the circulation. Inasmuch as at 24 h, serum CSF-1 was not significantly altered, these results are suggestive of an increased rate of release of CSF-1 into the circulation early in the response. The splenic CSF-1-receptor bearing cells were in a Mac-1+ fraction that is consistent with a role for CSF-1 in the generation of host-derived splenic macrophages in acute graft-vs-host reaction.

Animals↗