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Differentiation and activation of functionally distinct macrophage populations by CSF-1 and GM-CSF

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Title: Differentiation and activation of functionally distinct macrophage populations by CSF-1 and GM-CSF
Author(s): Rutherford, Mark Stephen
Doctoral Committee Chair(s): Shapiro, Stuart
Department / Program: Pathobiology
Discipline: Pathobiology
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): Biology, Cell Health Sciences, Immunology
Abstract: Macrophages derived in vitro from bone marrow progenitor cells (BMDM) under the influence of CSF-1 or GM-CSF were compared for immune function. CSF-1- and GM-CSF-derived BMDM did not differ in their ability to kill L929 tumor targets or produce IL-6 and LTC$\sb4$ in response to IFN-$\gamma$ and LPS. CSF-1-derived BMDM secreted more TNF-$\alpha$ and PGE$\sb2$ at early stages of culture than did GM-CSF-derived BMDM and required only LPS stimulation to produce NO$\sb2\sp-$. In contrast, GM-CSF-derived BMDM secreted NO$\sb2\sp-$ only following treatment with IFN-$\gamma$ plus LPS. When P815 tumor targets were used, GM-CSF-derived BMDM displayed higher basal and inducible levels of killing than CSF-1-derived BMDM and required only LPS treatment to reach full cytolytic capacity. Additionally, GM-CSF-derived BMDM showed greater listeriacidal capacity than did CSF-1-derived BMDM, particularly following IFN-$\gamma$ plus LPS treatment. To assess immunocompetence under conditions resembling those of inflammatory sites, BMDM function was examined following treatment with PGE$\sb2$ or in conditions of reduced L-arginine concentration. PGE$\sb2$ (10$\sp{-6}$-10$\sp{-8}$ M) had no effect on BMDM ability to cytolyze L929 cells, kill intracellular Listeria, or produce NO$\sb2\sp-$, but GM-CSF-derived BMDM were inhibited 33% for cytolysis of K562 tumor cells. Interestingly, GM-CSF-derived BMDM were much less sensitive than CSF-1-derived BMDM for PGE$\sb2$, but not cAMP-mediated inhibition of TNF-$\alpha$. Arginine depletion blocked NO$\sb2\sp-$ production by both BMDM populations and the listeriacidal activity induced by IFN-$\gamma$ plus LPS was abolished.Macrophages were elicited in CB-17 and scid mice by repeated injection of GM-CSF. Following challenge with Listeria, scid mice which had been pretreated with GM-CSF showed reduced numbers of bacteria in the liver and spleens. CB-17 mice were unaffected by GM-CSF administration.When used alone, neither CSF-1 nor GM-CSF elicited TNF-$\alpha$, NO$\sb2\sp-$, or PGE$\sb2$ secretion. GM-CSF primed CSF-1-derived BMDM for enhanced LPS-induced TNF-$\alpha$, NO$\sb2\sp-$, and PGE$\sb2$ secretion, and for augmented cytolysis of P815, but not K562 tumor cells. Thus, GM-CSF elicits a macrophage population with functional signal requirements distinct from those of CSF-1-derived BMDM and is a more effective biological response modifier for macrophage function than is CSF-1.
Issue Date: 1991
Type: Text
Language: English
Rights Information: Copyright 1991 Rutherford, Mark Stephen
Date Available in IDEALS: 2011-05-07
Identifier in Online Catalog: AAI9124479
OCLC Identifier: (UMI)AAI9124479

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