title: Conversion of human M-CSF macrophages into foam cells reduces their proinflammatory responses to classical M1-polarizing activation.
abstract: BACKGROUND
  In atherosclerotic lesions, cholesterol-laden macrophage foam cells are formed and exposed to M1- and M2-polarizing factors. However, the effects of the polarizing factors on the proinflammatory and the anti-inflammatory potential of foam cells are not known.
  
  
  OBJECTIVE
  To investigate the effects of M1- and M2-polarizing factors on the expression of pro- and anti-inflammatory genes in cultured human macrophage foam cells.
  
  
  RESULTS
  Human monocytes were differentiated into macrophages in the presence of M-CSF, and then converted into cholesterol-loaded foam cells by incubation with acetylated LDL. The generated macrophages and foam cells were polarized into the M1 phenotype by classical activation with LPS and IFN-γ, or into the M2 phenotype by alternative activation with IL-4. When subjected to the M1-polarizing factors, the macrophages responded by typical upregulation of several key proinflammatory genes (TNFA, IL1B, CXCL8, CCL19, and COX2), while the anti-inflammatory genes (MRC1, CCL17, and IL10) displayed variable responses. The foam cells, again, showed a weaker response to the M1-polarizing factors, as indicated by reduced upregulation of the proinflammatory genes, reduced secretion of TNF-α, and a trend towards lower NF-κB activity. When subjected to alternative M2 polarization, both macrophages and foam cells responded by a typical upregulation of the anti-inflammatory genes, which was of equal magnitude in both cell types.
  
  
  CONCLUSIONS
  Conversion of cultured human macrophages into foam cells suppresses their proinflammatory responses to M1-polarizing factors. Thus, in M1-polarizing microenvironments of atherosclerotic lesions, foam cell formation may locally weaken the macrophage-dependent inflammatory component of atherogenesis.
authors.affiliation: Wihuri Research Institute, Helsinki, Finland; Department of Physiology and Biophysics, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Rafaela F
authors.initials: RF
authors.lastname: da Silva
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Jani
authors.initials: J
authors.lastname: Lappalainen
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Miriam
authors.initials: M
authors.lastname: Lee-Rueckert
authors.affiliation: Wihuri Research Institute, Helsinki, Finland. Electronic address: petri.kovanen@wri.fi.
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry; D050197:Atherosclerosis / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D016895:Culture Media, Serum-Free; D005487:Foam Cells / Q000166:cytology*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D016895:Culture Media, Serum-Free; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D015847:Interleukin-4; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D002784:Cholesterol
keywords: Atherosclerosis; Cytokines; Foam cells; Inflammation; Macrophages; Polarization