Colony-stimulating factor-1 (CSF-1) delivers a proatherogenic signal to human macrophages.
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.
Irvine
Katharine M
KM
The University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland, Australia.
Andrews
Melanie R
MR
Fernandez-Rojo
Manuel A
MA
Schroder
Kate
K
Burns
Christopher J
CJ
Su
Stephen
S
Wilks
Andrew F
AF
Parton
Robert G
RG
Hume
David A
DA
Sweet
Matthew J
MJ
D000818:Animals; D050197:Atherosclerosis / Q000276:immunology*; D019898:Autocrine Communication; D001854:Bone Marrow Cells / Q000166:cytology; D018925:Chemokines / Q000276:immunology; D002784:Cholesterol / Q000096:biosynthesis; D015536:Down-Regulation; D006801:Humans; D050356:Lipid Metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000166:cytology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism
D018925:Chemokines; D019718:Receptors, CXCR4; D016173:Macrophage Colony-Stimulating Factor; D002784:Cholesterol