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Published online before print November 12, 2008
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0808497

Received for publication August 25, 2008.
Revised September 25, 2008.
Accepted for publication October 14, 2008.

Article

Colony-stimulating factor-1 (CSF-1) delivers a proatherogenic signal to human macrophages

Katharine M. Irvine *, Melanie R. Andrews *, Manuel A. Fernandez-Rojo {dagger}, Kate Schroder *{ddagger}, Christopher J. Burns {sect}, Stephen Su {sect}, Andrew F. Wilks {sect}, Robert G. Parton {dagger}, David A. Hume ||, and Matthew J. Sweet *{ddagger}@

*Institute for Molecular Bioscience and The SRC for Functional and Applied Genomics, {ddagger}Cooperative Research Centre for Chronic Inflammatory Diseases, School of Molecular and Microbial Sciences, and {dagger}Division of Molecular Cell Biology, Institute for Molecular Bioscience, and Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, Queensland, Australia; {sect}Cytopia Pty. Ltd., Richmond, Victoria, Australia; and ||The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Scotland, United Kingdom

@ To whom correspondence should be addressed. E-mail: m.sweet{at}imb.uq.edu.au.


  Abstract

M-CSF/CSF-1 supports the proliferation and differentiation of monocytes and macrophages. In mice, CSF-1 also promotes proinflammatory responses in vivo by regulating mature macrophage functions, but little is known about the acute effects of this growth factor on mature human macrophages. Here, we show that in contrast to its effects on mouse bone marrow-derived macrophages, CSF-1 did not induce expression of urokinase plasminogen activator mRNA, repress expression of apolipoprotein E mRNA, or prime LPS-induced TNF and IL-6 secretion in human monocyte-derived macrophages (HMDM) from several independent donors. Instead, we show by expression profiling that CSF-1 modulates the HMDM transcriptome to favor a proatherogenic environment. CSF-1 induced expression of the proatherogenic chemokines CXCL10/IFN-inducible protein 10, CCL2, and CCL7 but repressed expression of the antiatherogenic chemokine receptor CXCR4. CSF-1 also up-regulated genes encoding enzymes of the cholesterol biosynthetic pathway (HMGCR, MVD, IDI1, FDPS, SQLE, CYP51A1, EBP, NSDHL, DHCR7, and DHCR24), and expression of ABCG1, encoding a cholesterol efflux transporter, was repressed. Consistent with these effects, CSF-1 increased levels of free cholesterol in HMDM, and the selective CSF-1R kinase inhibitor GW2580 ablated this response. These data demonstrate that CSF-1 represents a further link between inflammation and cardiovascular disease and suggest two distinct mechanisms by which CSF-1, which is known to be present in atherosclerotic lesions, may contribute to plaque progression.

Key Words: inflammation • chemokines • cholesterol






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