Differentiation and activation of functionally distinct macrophage populations by CSF-1 and GM-CSF
Rutherford, Mark Stephen
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https://hdl.handle.net/2142/20296
Description
Title
Differentiation and activation of functionally distinct macrophage populations by CSF-1 and GM-CSF
Author(s)
Rutherford, Mark Stephen
Issue Date
1991
Doctoral Committee Chair(s)
Shapiro, Stuart Z.
Department of Study
Pathobiology
Discipline
Pathobiology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Cell
Health Sciences, Immunology
Language
eng
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.
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