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Query: UNIPROT:P06889 (Mol)
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Monocytes and macrophages express the receptor for the hematopoietic growth factor colony-stimulating factor 1 (CSF-1) and require this factor for growth in culture. A murine monocyte tumor cell line that lacks the usual requirement for CSF-1 was isolated. On the basis of the similarity of the structures of the CSF-1 and platelet-derived growth factor (PDGF) receptors and because monocytes normally secrete PDGF, we analyzed the tumor cell line for anomalous expression of the PDGF-R beta gene. Two different cDNAs that each contain sequences corresponding to the complete coding sequence of PDGF-R beta fused (in frame) to the amino-terminal half of the CSF-1 receptor were isolated. Introduction of these PDGF-R beta-related cDNAs into two partially transformed, CSF-1-dependent monocyte cell lines resulted in autonomous growth and cell transformation. These monocyte cell lines exhibit a novel form of growth factor receptor activation that can lead to oncogenic growth in collaboration with the c-myc oncogene.
Mol Cell Biol 1992 Jan
PMID:A colony-stimulating factor 1 (CSF-1) receptor/platelet-derived growth factor-beta receptor gene fusion confers CSF-1 independence and tumorigenicity on a c-myc-immortalized monocyte cell line. 130 94

Eosinophil infiltration is the hallmark of allergic inflammatory events. However, the mechanisms governing the influx of eosinophils into the tissue at a site of an allergic reaction remains unclear. We have examined the interactions of eosinophils and neutrophils isolated from the same atopic donor with cultured human umbilical vein endothelial cell (EC) monolayers in the search for a mechanism for this selective eosinophil recruitment. First, the adherence of eosinophils and neutrophils to ECs stimulated with lipopolysaccharide, interleukin (IL)-1 alpha, and tumor necrosis factor-alpha were compared. Each mediator induced a similar dose-dependent enhancement of eosinophil adhesiveness for both eosinophils and neutrophils. Thus, although cytokine activation of ECs in the vasculature adjacent to an inflammatory site probably serves as an important focusing mechanism for the extravasation of inflammatory cells at this site, there does not appear to be any selective EC-dependent mechanism for eosinophil recruitment. Little or no effect on eosinophil and neutrophil adherence was observed with IL-3, IL-5, granulocyte/macrophage colony-stimulating factor, platelet-activating factor (PAF), leukotriene B4, or histamine. Second, the migration of eosinophils and neutrophils through an EC monolayer in response to chemoattractants was examined. PAF was found to selectively enhance eosinophil transendothelial migration at doses of 10(-7) to 10(-10) M, with optimal effect at 10(-8) M. This effect was gradient dependent and could be inhibited by WEB 2086, a specific PAF inhibitor. These results suggest that localized production of PAF may be a prime factor in the events leading to eosinophil accumulation at allergic inflammatory sites, and that selectivity for eosinophil recruitment occurs at the stage of transendothelial cell migration under the influence of cell-specific chemoattractants.
Am J Respir Cell Mol Biol 1992 May
PMID:Selective eosinophil leukocyte recruitment by transendothelial migration and not by leukocyte-endothelial cell adhesion. 131 35

The binding of cytoplasmic signaling proteins such as phospholipase C-gamma 1 and Ras GTPase-activating protein to autophosphorylated growth factor receptors is directed by their noncatalytic Src homology region 2 (SH2) domains. The p85 alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase, which associates with several receptor protein-tyrosine kinases, also contains two SH2 domains. Both p85 alpha SH2 domains, when expressed individually as fusion proteins in bacteria, bound stably to the activated beta receptor for platelet-derived growth factor (PDGF). Complex formation required PDGF stimulation and was dependent on receptor tyrosine kinase activity. The bacterial p85 alpha SH2 domains recognized activated beta PDGF receptor which had been immobilized on a filter, indicating that SH2 domains contact autophosphorylated receptors directly. Several receptor tyrosine kinases within the PDGF receptor subfamily, including the colony-stimulating factor 1 receptor and the Steel factor receptor (Kit), also associate with PI 3-kinase in vivo. Bacterially expressed SH2 domains derived from the p85 alpha subunit of PI 3-kinase bound in vitro to the activated colony-stimulating factor 1 receptor and to Kit. We infer that the SH2 domains of p85 alpha bind to high-affinity sites on these receptors, whose creation is dependent on receptor autophosphorylation. The SH2 domains of p85 are therefore primarily responsible for the binding of PI 3-kinase to activated growth factor receptors.
Mol Cell Biol 1992 Mar
PMID:SH2 domains of the p85 alpha subunit of phosphatidylinositol 3-kinase regulate binding to growth factor receptors. 137 92

Proliferation of a murine macrophage cell line (BAC1.2F5) in response to colony-stimulating factor 1 (CSF-1) is inhibited by prostaglandin E2 (PGE2)-mediated elevation of intracellular cyclic AMP (cAMP). When BAC1.2F5 cells were growth arrested in early G1 by CSF-1 starvation and stimulated to synchronously enter the cell cycle by readdition of growth factor, PGE2 inhibited [3H]thymidine incorporation when added before mid-G1, but its addition at later times did not block the onset of S phase. Reversible cell cycle arrest mediated by a cAMP analog required the presence of CSF-1 for cells to initiate DNA synthesis, whereas cells released from an aphidicolin block at the G1/S boundary entered S phase in the absence of CSF-1. PGE2 or cAMP analogs did not block the initial induction of c-myc mRNA by CSF-1 but abolished the CSF-1-dependent expression of c-myc mRNA in the mid-G1 stage of the cell cycle. The cAMP-mediated reduction in c-myc RNA levels was due to decreased c-myc transcription. However, CSF-1-dependent BAC1.2F5 clones infected with a c-myc retrovirus were growth arrested by cAMP analogs despite constitutive c-myc expression. Therefore, the reduction of endogenous c-myc expression by cAMP is neither necessary nor sufficient for growth inhibition.
Mol Cell Biol 1992 May
PMID:Macrophage growth arrest by cyclic AMP defines a distinct checkpoint in the mid-G1 stage of the cell cycle and overrides constitutive c-myc expression. 137 14

Neutrophil accumulation in the respiratory tract occurs in a variety of inflammatory disorders, particularly those associated with cigarette smoking. We examined whether bronchial epithelial cells could contribute to this accumulation through the production of factors that increased the survival of neutrophils. Pure primary cultures of human bronchial epithelial cells (HBEC) were used to generate conditioned medium (CM), and the effect of this CM on the survival of neutrophils in vitro was examined. When neutrophils were cultured in control medium, survival was 8.7 +/- 1.7% at 72 h. In contrast, culture of neutrophils in CM resulted in a dose-dependent increase in survival: 22.6 +/- 5.5, 43.6 +/- 4.2, and 64 +/- 3.8% in 1, 10, and 50% CM respectively (mean +/- SEM; P < 0.05). As evidenced by the examination of neutrophil DNA, this prolongation of survival was associated with suppression of apoptosis. Cytokines with known actions on neutrophil biology identified in the CM included granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF), and interleukin-8. Through the use of specific neutralizing antibodies, G-CSF and GM-CSF were identified as promoting neutrophil survival. Neutrophil survival was prolonged in the presence of either recombinant human (rh) G-CSF or rhGM-CSF alone in a dose-dependent fashion. In contrast to the response of eosinophils to HBEC-CM, steroid treatment did not prevent the increase in neutrophil survival induced by HBEC-CM. In summary, we show that bronchial epithelial cells markedly increase the survival of human neutrophils in vitro via the release of G-CSF and GM-CSF.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Nov
PMID:Bronchial epithelial cell-derived cytokines (G-CSF and GM-CSF) promote the survival of peripheral blood neutrophils in vitro. 138 83

During T cell development in the mammalian thymus, immature T cells are observed that lack the cell surface markers CD4, CD8, and CD3. A subtracted cDNA library was constructed to isolate cDNAs that are specific for these immature T cells. Tissue-specific expression of 97 individual cDNAs were examined using different cell types by Northern blot analysis, and six cDNAs were analyzed by reverse transcriptase (RT) polymerase chain reaction (PCR) detection of RNA. Approximately 50% of the clones could not be detected on Northern blots, and 40% of the clones were expressed by at least one other cell-type including monocytes, mature T cells, and B cells. Eight cDNA clones appear to be specific for the CD4-, CD8-, CD3- T cell line, used to construct the library, as determined by Northern blot analysis. In addition, 330 cDNA clones were subjected to partial automated DNA sequence determination. Database searches, with both nucleotide and protein translations, revealed cDNAs that exhibit interesting similarities to human cell-cycle gene 1, platelet-derived growth factor receptor, c-fms oncogene (CSF-1) receptor, and members of the immunoglobulin gene superfamily. This approach of employing subtraction coupled with large scale partial cDNA sequence determination can be useful to identify genes that may be involved in early T cell growth, cellular recognition or differentiation.
Mol Biol Cell 1992 Jul
PMID:A new approach to understanding T cell development: the isolation and characterization of immature CD4-, CD8-, CD3- T cell cDNAs by subtraction cloning. 138 65

The release of colony-stimulating factors (CSFs) and their contribution to the inflammatory response in the lungs of mice exposed by the intranasal route to the actinomycete Faeni rectivirgula (150 micrograms/day, 3 days/wk), an important thermophilic actinomycete that determines farmer's lung in humans, was examined. Bronchoalveolar lavages (BAL) and lung homogenates of normal mice or saline-instilled mice contained undetectable levels (less than 0.5 U/ml) of the cytokines interleukin-3 (IL-3), colony-stimulating factor-1 (CSF-1), and granulocyte/macrophage colony-stimulating factor (GM-CSF). Mice instilled with F. rectivirgula developed a CSF cytokine response early (24 h) after the instillation that increased and plateaued 2 wk later, and stayed high thereafter. Similarly, lung homogenates of F. rectivirgula-challenged mice contained significant levels of all three CSFs from 24 h after treatment until termination of the experiment. The offending agent itself, F. rectivirgula, was found to directly induce the secretion of IL-3 and GM-CSF from isolated mouse BAL cells and mouse splenocytes, at doses ranging from 1 to 100 micrograms/ml. This was not due to contaminating endotoxin, as inclusion of polymyxin B did not modify this release. Instillation of antibodies against the CSFs in mice challenged with F. rectivirgula did not modify the increase in BAL cell number determined by the challenge (11-fold increase in BAL cell number in F. rectivirgula-instilled mice at 3 wk, whether given anti-CSFs or not). Moreover, direct intratracheal infusion of CSFs (5,000 U of IL-3/CSF-1/GM-CSF) every week did not change the cellular response seen in challenged mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Oct
PMID:Murine hypersensitivity pneumonitis: production and importance of colony-stimulating factors in the course of a lung inflammatory reaction. 138 11

The activity of p21ras is required for the proliferative response to colony-stimulating factor 1 (CSF-1), and signals transduced by both the CSF-1 receptor (CSF-1R) and p21ras stimulate transcription from promoter elements containing overlapping binding sites for Fos/Jun- and Ets-related proteins. A sequence encoding the DNA-binding domain and nuclear localization signal of human c-ets-2, which lacked portions of the c-ets-2 gene product necessary for trans activation, was fused to the bacterial lacZ gene and expressed from an actin promoter in NIH 3T3 cells expressing either the v-ras oncogene or human CSF-1R. Nuclear expression of the Ets-LacZ protein, confirmed by histochemical staining of beta-galactosidase, inhibited the activity of ras-responsive enhancer elements and suppressed morphologic transformation by v-ras as well as CSF-1R-dependent colony formation in semisolid medium. When CSF-1R-bearing cells expressing the Ets-LacZ protein were stimulated by CSF-1, induction of c-ets-2, c-jun, and c-fos ensued, but the c-myc response was impaired. Enforced expression of the c-myc gene overrode the suppressive effect of ets-lacZ and restored the ability of these cells to form colonies in response to CSF-1. NIH 3T3 cells engineered to express a CSF-1R (Phe-809) mutant similarly cannot form CSF-1-dependent colonies in semisolid medium and exhibit an impaired c-myc response, but expression of an exogenous myc gene resensitizes these cells to CSF-1 [M. F. Roussel, J. L. Cleveland, S. A. Shurtleff, and C. J. Sherr, Nature (London) 353:361-363, 1991]. The ability of these cells to respond to CSF-1 was also rescued by enforced expression of an endogenous c-ets-2 gene. The ets family of transcription factors therefore plays a central role in integrating both CSF-1R and ras-induced mitogenic signals and in modulating the myc response to CSF-1 stimulation.
Mol Cell Biol 1992 Dec
PMID:Mitogenic signaling by colony-stimulating factor 1 and ras is suppressed by the ets-2 DNA-binding domain and restored by myc overexpression. 144 70

Eosinophilia and eosinophil function are regulated by cytokines such as granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5). We have investigated the modulatory role of IL-5 on N-formyl-methionyl-leucyl-phenylalanine (FMLP), neutrophil-activating factor (NAF/IL-8), platelet factor 4 (PF4), and cytokine-induced chemotaxis of eosinophils from normal individuals. These eosinophils show a small chemotactic response toward PF4 but not to NAF/IL-8 and FMLP. Preincubation of eosinophils with low concentrations of IL-5 caused significantly increased responses toward PF4 and induced a significant chemotactic response toward FMLP and NAF/IL-8. In marked contrast, IL-5 (or IL-3) priming of eosinophils from normal donors resulted in a strong inhibition of GM-CSF-induced chemotaxis. A similar decrease in the chemotactic response toward GM-CSF was observed in eosinophils derived from allergic asthmatic individuals. This finding suggests that the latter eosinophils may have had a prior exposure to IL-5 (or IL-3). Washing of the cells after priming did not abrogate the inhibition of the GM-CSF response. Our data indicate that at low concentrations IL-5 is an important modulator of eosinophil chemotaxis, causing selective upregulation or downregulation of chemotactic responses toward different agents.
Am J Respir Cell Mol Biol 1992 Dec
PMID:Modulation of eosinophil chemotaxis by interleukin-5. 144 9

The murine myeloid precursor cell line FDC-P1/MAC simultaneously expresses receptors for multi-colony-stimulating factor (CSF), granulocyte-macrophage (GM)-CSF, and macrophage (M)-CSF. Growth of FDC-P1/MAC cells in either multi-CSF or GM-CSF results in the posttranscriptional suppression of M-CSF receptor (c-fms proto-oncogene) expression. We use the term transregulation to describe this control of receptor expression and have further characterized this regulatory process. The removal of FDC-P1/MAC cells from GM-CSF stimulation resulted in the re-expression of c-fms mRNA independent of M-CSF stimulation and new protein synthesis. Switching FDC-P1/MAC cells from growth in M-CSF to GM-CSF caused the selective degradation of c-fms mRNA within 6 h after factor switching. Blocking protein synthesis or gene transcription with metabolic inhibitors effectively prevented GM-CSF stimulated degradation of c-fms mRNA. These results suggest that the transregulation of c-fms transcripts by GM-CSF requires the transcriptional activation of a selective mRNA degradation factor. In vitro analysis, the use of cytoplasmic cell extracts, provided evidence that a ribonuclease is preferentially active in GM-CSF stimulated cells, although the specificity for mRNA degradation in vitro is broader than seen in vivo. Together, these data suggest that GM-CSF can dominantly transregulate the level of c-fms transcript through the transcriptional activation of a ribonuclease degradation system.
Mol Biol Cell 1992 May
PMID:A GM-colony-stimulating factor (CSF) activated ribonuclease system transregulates M-CSF receptor expression in the murine FDC-P1/MAC myeloid cell line. 153 42


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