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Results for “Receptor, Macrophage Colony-Stimulating Factor”

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PubMed2022

S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer.

Sustained oxidative stress in castration-resistant prostate cancer (CRPC) cells potentiates the overall tumor microenvironment (TME). Targeting the TME using colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising therapy for CRPC. However, the therapeutic response to sustained CSF1R inhibition (CSF1Ri) is limited as a monotherapy. We hypothesized that one of the underlying causes for the reduced efficacy of CSF1Ri and increased oxidation in CRPC is the upregulation and uncoupling of endothelial nitric oxide synthase (NOS3). Here we show that in high-grade PCa human specimens, NOS3 abundance positively correlates with CSF1-CSF1R signaling and remains uncoupled. The uncoupling diminishes NOS3 generation of sufficient nitric oxide (NO) required for S-nitrosylation of CSF1R at specific cysteine sites (Cys 224, Cys 278, and Cys 830). Exogenous S-nitrosothiol administration (with S-nitrosoglutathione (GSNO)) induces S-nitrosylation of CSF1R and rescues the excess oxidation in tumor regions, in turn suppressing the tumor-promoting cytokines which are ineffectively suppressed by CSF1R blockade. Together these results suggest that NO administration could act as an effective combinatorial partner with CSF1R blockade against CRPC. In this context, we further show that exogenous NO treatment with GSNOR successfully augments the anti-tumor ability of CSF1Ri to effectively reduce the overall tumor burden, decreases the intratumoral percentage of anti-inflammatory macrophages, myeloid-derived progenitor cells and increases the percentage of pro-inflammatory macrophages, cytotoxic T lymphocytes, and effector T cells, respectively. Together, these findings support the concept that the NO-CSF1Ri combination has the potential to act as a therapeutic agent that restores control over TME, which in turn could improve the outcomes of PCa patients.

Cysteine↗

PubMed2026

CRISPR screening identifies DTX4 governing alveolar macrophage cholesterol efflux in pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain incompletely defined. Here, through a genome-wide CRISPR screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify DTX4 as a pivotal regulator of cholesterol efflux in AMs. In mice, AAV-mediated silencing of DTX4 led to excessive AM lipid accumulation, exacerbated proteinosis, increased lung opacities, and deteriorated pulmonary function. Similarly, DTX4 depletion in primary AMs impaired cholesterol efflux and promoted intracellular lipid deposition. Conversely, AM-specific overexpression of DTX4 in the Csf2ra-/- PAP model markedly alleviated lipid accumulation, mitigated alveolar proteinosis, restored lung densities, and rescued pulmonary function. Mechanistically, DTX4 stabilizes the GM-CSF receptor via an E3-independent interaction to sustain JAK2/STAT5 signaling, which reciprocally maintains DTX4 transcription. This positive-feedback loop drives PPARγ expression, and its disruption in PAP impairs cholesterol efflux, a defect partially reversible by ectopic PPARγ expression. Collectively, our findings identify DTX4 as a central orchestrator of AM cholesterol efflux and surfactant homeostasis, positioning it as a promising therapeutic target for PAP.

Animals↗

PubMed1977

Decreased in vivo and in vitro colony stimulating activity responses to bacterial lipopolysaccharide in C3H/HeJ mice.

Mice of the C3H/HeJ strain exhibit low inflammatory and immunological responses to certain bacterial lipopolysaccharide (LPS) preparations. Lymphocytes from C3H/HeJ mice also show defective LPS-induced mitogenesis. We tested the colony stimulating activity (CSA) response of C3H/HeJ mice. As controls we used mice of the congenic C3HeB/FeJ strain, which are good responders to LPS. Serum was obtained three hours after intravenous administration of LPS. Serum CSA was determined in agar cultures of bone marrow cells from AKR mice. The serum CSA response of C3H/HeJ to 10 microgram LPS was approximately 8-fold lower than that of control C3HeB/FeJ mice. In contrast, both strains showed similar serum CSA-induced by Poly I:poly C. Peritoneal macrophage cultures were also incubated with 0.1-10.0 microgram LPS and culture media assayed for CSA. The response of C3H/HeJ macrophages was about 6-fold lower than that of macrophages obtained from the control mice. The results show that the lower responsiveness of C3H/HeJ mice to LPS also extends to the production of CSA. The in vitro findings indicate that the postulated defect in the LPS receptor of B lymphocytes may also be present on macrophages.

Animals↗

PubMed1978

In vitro characteristics of childhood leukemic monoblasts.

Leukemic monoblasts obtained from three children were evaluated for their in vitro physiologic characteristics. These monoblasts were alpha naphthyl acetate esterase positive, exhibited glass adherence, had IgG membrane receptors, phagocytized latex particles with subsequent nitroblue tetrazolium (NBT) reduction, and matured to macrophages in vitro, either when adherent to glass slides or in feeder layer suspensions. Employing the double layer in vitro bone marrow culture technique, leukemic marrows from these children failed to produce colonies in culture in the presence or absence of normal feeder layers. Varying the concentration of leukemic cells in the feeder layers failed to augment colony growth from normal bone marrows. Although monoblasts were observed to mature to macrophages in vitro, no increase in colony stimulating factor activity was observed with aging of the feeder layers. These studies suggest that childhood leukemic monoblasts lack the ability to produce colony stimulating activity, differing in this respect from monoblastic leukemia in adults.

Adolescent↗

PubMed1977

Proliferation and differentiation of normal granulopoietic cells in continuous bone marrow cultures.

Modified conditions are reported for successful continuous bone marrow cultures with stem cell self-renewal and granulocyte-macrophage differentiation. Cells cultured over several weeks were found to be identical to freshly isolated bone marrow cells. Polymorphic neutrophils derived from cultures and primary bone marrow neutrophils both showed C3 AND IgG receptors and both actively phagocytosed foreign particles. Cultured and normal CFU-c were identical, both in their dose responsiveness to CFS and in their sedimentation rate characteristics.

Bone Marrow Cells↗

PubMed1977

Simultaneous effects of erythropoietin and colony-stimulating factor on bone marrow cells.

Erythropoietin or colony-stimulating factor, or both, were added to rat or mouse marrow cell cultures, and the responses to each inducer were measured. Colony-stimulating factor caused the suppression of erythropoietin-stimulated hemoglobin synthesis, and erythropoietin caused the suppression of the granulocyte-macrophage colony formation that is dependent on colony-stimulating factor. The extent of suppression by each inducer was dose-dependent. Marrow cells from plethoric rats were more sensitive to suppression of erythropoietin action by colony-stimulating factor than were normal marrow cells. These findings suggest that either (i) the receptors for erythropoietin and for colony-stimulating factor have overlapping specificities and that the "wrong" inducer may bind without having an inductive effect, or (ii) the target cells for erythropoietin and colony-stimulating factor are very closely related or are the same.

Animals↗

PubMed1979

Patterns of maturation in short-term culture of human acute myeloid leukaemic cells.

Leukaemic cells taken from the blood of patients with acute myelogenous leukaemia (AML) frequently proliferate in suspension culture without the addition of growth factors for a limited period only. After a 6--10-fold increase in total cells, cell numbers remain constant for a time and finally decline. The main cause for this limited growth in vitro is not, initially at least, cell death leading to a steady state, but maturation associated in its final stages with cessation of DNA synthesis. Two populations of AML cells from Patients St and Wi respectively were studied, and progressive maturation towards mature leucocytes was demonstrated by the gradual acquisition in culture by the growing blast cells of intracellular enzymes (lysozyme, arginase, acid phosphatase and esterase being measured), surface markers (Fc and C3 receptors), of lactoferrin by Wi cells and of colony-stimulating activity by St cells, as well as changes in Ia antigens, phagocytic properties, morphology and adhesiveness to plastic. With St cells, which carried a characteristic chromosome marker, maturation terminated in cells with the characteristic properties of macrophages. At an intermediate stage, non-adherent and still-dividing St cells acquired Fc and C3 receptors and enzymes characteristic of monocytes. Wi cells progressively became neutrophil-like, and again there was an intermediate population of dividing cells which had Fc and C3 receptors and proteins such as lactoferrin and esterases. characteristic of neutrophils.

Cell Adhesion↗

PubMed1977

Direct toxic effects of immunopotentiators on monocytic, myelomonocytic, and histiocytic or macrophage tumor cells in culture.

Four murine monocyte, myelomonocyte, and histiocyte or macrophage tumor cell lines adapted to culture were growth inhibited by one or more of the following macrophage-activating substances: Mycobacterium bovis, Bacillus Calmette-Guérin strain, zymosan, lipopolysaccharide, and dextran sulfate, as well as tuberculin purified protein derivative, but not latex beads. Lipopolysaccharide was effective with one line at 4 ng/ml. All four lines actively phagocytosed zymosan and latex beads. In many cases the growth inhibition was apparently immediate but only cytostatic, and cell proliferation resumed upon removal of the drug. Bacillus Calmette-Guérin, live or boiled, was toxic to some of the tumor lines. Synthesis of lysozyme by all the cell lines in the monocyte series and production of granulocyte colony-stimulating factor by the myelomonocytic leukemia were not inhibited during several days of zero growth conditions in the presence of drugs. Since these agents had no direct effect on other hematopoietic tumor types (myeloma, T-lymphoma, mastocytoma) at the same or up to 10(4) higher concentrations, it is proposed that the sensitive tumors retain specific receptors for immunostimulants, either at the cell surface or within the cell in the case of phagocytosable particles. The binding of these agents to physiological receptors leads to stimulation and mitogenesis in normal macrophages and lymphocytes but leads to growth inhibition without affecting differenetiated functions in the corresponding tumor lines.

Adjuvants, Immunologic↗

PubMed1978

Immunologic functions and in vitro activation of cultured macrophage tumor lines.

Five murine monocyte of macrophage tumor lines adapted to culture were characterized for differentiated properties. They ingested zymosan and latex beads, bore receptors for immunoglobulin and complement, synthesized lysozyme (most of which was secreted), and produced granulocyte colony-stimulating activity, either spontaneously or inducibly. Some of the lines also mediated phagocytosis and exocytosis of red blood cells (RBC) and lysis of tumor targets, dependent on the presence of specific antitarget sera. All the lines were growth inhibited by zymosan and Mycobacterium bovis BCG, but not by latex beads. Other macrophage-activating agents, dextran sulfate and lipopolysaccharide (LPS), as well as tuberculin purified protein derivative (PPD), inhibited most of the lines. Except for Fc and C receptors, most of the above properties were not found with other types of hematopoietic tumors in culture. In attempts to activate the macrophage lines in vitro to the "angry" state, we found that preincubation with concentrations of LPS and PPD cytostatic to the cells stimulated antibody-dependent RBC lysis, but not antibody-independent or tumor cytolysis. A classification of monocyte-related tumors and normal cells is proposed based on functional activities and differential sensitivity to immunostimulating agents.

Animals↗

PubMed1979

Detection of gap junctions between the progeny of a canine macrophage colony-forming cell in vitro.

An in vitro monocyte-macrophage colony-forming cell (M-CFC) has been detected in canine bone marrow (BM). The colonies derived from these progenitor cells were similar to murine-derived M-CFC (MacVittie and Porvaznik, 1978, J. Cell Physiol. 97:305--314) colonies, since they showed a singular macrophage line of differentiation, a lag of 14--16 days before initiating colony formation, and they survived significantly longer in culture in the absence of colony-stimulating factor (CSF) than granulocyte-macrophage colony-forming cells (GM-CFC). Endotoxin (Salmonella typhosa lipopolysaccharide W)-stimulated dog serum was used as the CSF (7% vol/vol). Canine-derived M-CFC progeny were identified as macrophages on the basis of morphology, phagocytosis, and the presence of Fc receptors for IgG. Gap junctions were observed only in canine BM, M-CFC-derived colonies using freeze-fracture and lanthanum tracer techniques. They were not observed in any GM-CFC-derived colonies. The number of gap junctions observed in freeze-fracture replicas of BM, M-CFC-derived colonies (21 colonies from three different dogs) showed a significantly positive correlation (Kendall's tau = 0.70, P less than 0.001) with the size of the colony fracture plane area. Gap junctions were observed displaying hexagonal lattices of 9.3 nm +/- 0.08 (SE) particles with a center-to-center spacing of 10.4 nm +/- 1.0 (SE) on membrane P-fracture faces. On membrane E-fracture faces, highly ordered arrays of pits with 8.7 nm +/- 0.12 (SE) center-to-center spacing were observed. Arrays of both particles and pits were also observed in fracture-face breakthroughs within a gap junction. Thus, gap junctions can form in vitro between the cells of macrophage progeny of a canine M-CFC under appropriate growth conditions. The significance of this observation is that there may be a structural basis for cell-to-cell collaboration between BM macrophages and other capable cells that either pass into the tissue for modification or develop there into mature cell forms.

Animals↗

PubMed1978

Regulation of hemopoietic cell differentiation and proliferation.

Differentiation and proliferation of almost all hemopoietic cell lines can now be studied in vitro. Cloning techniques and suspension cultures allow the study of proliferation of the multipotential hemopoietic progenitor cell and the committed progenitors for granulocytes, macrophages, eosinophils, megakaryocytes, and erythrocytes. The proliferation of each of the committed progenitor cells is controlled by specific glycoproteins and two of these have recently been purified: granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin. The rate of proliferation of the GM-progenitor cells and their pattern of differentiation depends on the concentration of the hormone. At low concentrations of GM-CSF (10(-11) M) fewer progenitor cells are stimulated and macrophage colonies rather than granulocyte colonies develop. The change in the direction of granulocyte-macrophage differentiation appears to be related to a) the concentration of GM- CSF and b) the different sensitivity of a subpopulation of monocyte colony-forming cells which are responsive to GM-CSF even at low concentrations of the regulator. Analysis of the rate of RNA synthesis by bone marrow cells has shown that GM-CSF stimulates the mature nondividing end cells of differentiation (ie, polymorphs) as well as the progenitor cells. Although GM-CSF and erythropoietin have been radiolabeled, binding studies have been hampered by the loss of biologic activity during the labeling procedure and the heterogeneity of the target cells to which the regulators bind. Surface proteins and receptors for erythrocytes have been well characterized but the relationships between these proteins and the cell surface proteins of nucleated blood cells is not well understood. It appears that some proteins are lost from the cell surface during the development of granulocytes, which are retained on the surface of the B lymphocyte. Other proteins such as chemotactic receptors and complement receptors only appear on the mature cells. External radiolabeling of the granulocyte surface using iodogen yielded a simple profile of 125I-labeled proteins when analyzed by sodium dodecyl sulphate polyacrylamide gel electrophoresis.

Cell Differentiation↗

PubMed1979

Lactoferrin acts on Ia-like antigen-positive subpopulations of human monocytes to inhibit production of colony stimulatory activity in vitro.

The relationship between Ia-like antigens (Ia-antigens) on human monocytes and the ability of lactoferrin (LF) to inhibit the production of colony stimulatory activity (CSA) for granulocyte and macrophage colony formation was investigated. Complement-dependent cytotoxicity of human monocytes by antiserum to Ia-antigen-reduced CSA production by 50%. LF decreased CSA production by monocytes but had no influence on monocytes insensitive to anti-Ia and complement. Anti-Ia in the absence of complement had no effect on production of CSA but blocked the inhibitory action of LF. This suggsts that LF inhibits production of CSA from an Ia-antigen-positive subpopulation of human blood monocytes. This may be of relevance to the regulation of myelopoiesis.

Antigens, Surface↗

PubMed1978

Hematopoiesis on cellulose ester membranes (CEM). I. Functional characteristics of cells comprising the hematopoietic microenvironment.

Cellulose ester membranes (CEM) implanted into the peritoneal cavity of mice rapidly became coated with cells of peritoneal origin. Up to 56% of the cells, at a peak point 3-5 days after implantation, showed cell membrane receptors for complement and cytophilic immunoglobulin. A similar proportion of cells from CEM phagocytized yeast particles in vitro. When studied in situ, rosettes with C3b and IgG coated erythrocytes were formed by 23% of the cells coating CEM. A decreasing percentage of cells with monocyte-macrophage characteristics were detected between 5 and 17 days. CEM removed at 2 or 6 weeks after peritoneal implantation enriched tissue cultured media with colony stimulating factor which supported the growth of granulopoietic colonies in softagar culture. Mice given 59iron and 99technetium sulfur colloid i.v. showed substantial uptake of both isotopes by the CEM but the 59iron uptake could not be suppressed by hypertransfusion. Surface hematopoietic colony formation on CEM was studied 1-14 days after implantation. A peak colony number occurred at 5 days and the fell off slightly by 2 weeks. These studies indicate that the hematopoietic microenvironment of peritoneally implanted CEM contains a major sub-population of cells with monocytemacrophage features. The hematopoietic microenvironment was well-maintained even though the percentage of monocyte-macrophage marked cells decreased indicating that the microenvironment is not solely dependent upon monocyte-macrophages.

Animals↗