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Updated: Aug 9, 2026
Culture of Macrophage Colony-stimulating Factor Differentiated Human Monocyte-derived Macrophages
Published on: June 30, 2016
CSF-1 and cell cycle control in macrophages
1University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Abstract:
Control of cell proliferation involves a finely interwoven network of positive and negative cell cycle regulators. Signal transduction pathways linking c-fms (CSF-1R) to cellular proliferation and differentiation are being explored. Part of the strategy is to use a series of G1 inhibitors to help pinpoint relevant targets. Several inhibitors-8Br-cAMP, interferon gamma (IFN gamma), INF alpha/beta, lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF alpha), and dimethylamiloride-suppress CSF-1-stimulated proliferation in murine bone marrow-derived macrophages (BMM) even when added in the mid- to late-G1 phase of the cell cycle. The down-modulating effects of the inhibitors on the expression of the following cell cycle regulators have been examined: c-myc, cyclin D1 and D2, cdk4, Rb phosphorylation, E2F binding activity, ribonucleotide reductase subunits, and PCNA. Some differences in the negative control of such regulators were found, for example, in the manner in which IFN gamma and cAMP down-regulate c-myc expression. Using blocking antibodies and BMM from type I IFN receptor knockout mice, it appears that one of these inhibitors, IFN alpha/beta, acts as an endogenous inhibitor in CSF-1-treated BMM and is also responsible, at least in part, for the inhibition of cell cycle progression by LPS and TNF alpha. Another strategy has been to attempt to relate early biochemical changes induced by CSF-1 to later changes in the G1 phase, partly by studying cycling versus noncycling macrophages and partly by using cells expressing c-fms with tyrosine mutations in the intracytoplasmic region. CSF-1-mediated effects on the following signal transduction molecules in these systems will be described: PI3-kinase, myelin basic protein kinases, Erks, and STAT transcription factors.
Insights
Researchers explored cell cycle regulators and identified type I interferon (IFN alpha/beta) as an endogenous inhibitor of macrophage proliferation. This inhibitor plays a role in blocking cell cycle progression induced by lipopolysaccharide and tumor necrosis factor-alpha.
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- Cell proliferation is tightly regulated by a network of positive and negative cell cycle regulators.
- Signal transduction pathways connecting c-fms (CSF-1R) to cell proliferation and differentiation are under investigation.
- Understanding these pathways is crucial for controlling cell growth and development.
Purpose of the Study:
- To investigate the mechanisms controlling cell proliferation, specifically focusing on G1 phase regulators.
- To identify endogenous inhibitors of macrophage proliferation and their roles in signal transduction.
- To elucidate the early biochemical events linking CSF-1 signaling to cell cycle progression.
Main Methods:
- Utilized a series of G1 inhibitors including 8Br-cAMP, IFN gamma, IFN alpha/beta, LPS, TNF alpha, and dimethylamiloride.
- Examined the down-modulating effects of inhibitors on cell cycle regulators like c-myc, cyclins, cdks, Rb phosphorylation, E2F, ribonucleotide reductase, and PCNA.
- Employed blocking antibodies and type I IFN receptor knockout bone marrow-derived macrophages (BMM) to study IFN alpha/beta's role.
- Investigated CSF-1-mediated effects on signal transduction molecules such as PI3-kinase, myelin basic protein kinases, Erks, and STAT transcription factors.
Main Results:
- Several inhibitors, including IFN gamma and cAMP, suppressed CSF-1-stimulated macrophage proliferation.
- Differences were observed in how IFN gamma and cAMP down-regulate c-myc expression.
- IFN alpha/beta was identified as an endogenous inhibitor in CSF-1-treated BMM and partially responsible for LPS/TNF alpha-induced cell cycle inhibition.
- Early CSF-1 signaling events involving PI3-kinase, myelin basic protein kinases, Erks, and STATs were related to later G1 phase changes.
Conclusions:
- Type I interferons (IFN alpha/beta) act as endogenous inhibitors of macrophage proliferation.
- IFN alpha/beta mediates, in part, the inhibitory effects of LPS and TNF alpha on cell cycle progression.
- Understanding these regulatory networks provides insights into controlling cell proliferation and potential therapeutic targets.
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