The state of macrophage differentiation determines the TNF alpha response to nitrated lipoprotein uptake.
Inflammatory cytokine synthesis by monocyte-macrophages in the developing plaque represents an important amplification point in atherosclerotic disease progression. Here we have investigated whether the state of monocyte-macrophage differentiation can influence TNF alpha synthesis in response to scavenged modified low-density lipoprotein (LDL). We show that LDL modified by nitration induces TNF alpha synthesis when added to undifferentiated human monocytes or a mouse cell line (RAW264.7) bearing an incompletely differentiated phenotype. However, significantly reduced levels of TNF alpha were released from in vitro differentiated human macrophages (P=0.006) or a mouse cell line (IC-21) bearing a well-differentiated macrophage phenotype (P<0.001). A possible scavenging insufficiency in macrophagic cell types was ruled out by lipoprotein-uptake studies and competency to synthesise TNF alpha was confirmed using lipopolysaccharide (LPS) as a stimulus. However, LPS-induced TNF alpha secretion in IC-21 cells was partially suppressed by pre-treatment with nitrated LDL (46%, P=0.0076), with no equivalent effect seen in RAW264.7 cells. Based on these data, we hypothesise that the state of differentiation of intimal monocyte-macrophages may play an important role in their inflammatory response to scavenged modified lipoproteins and that the fully differentiated macrophage end-point may be associated with a non-inflammatory and therefore, atheroprotective, phenotype.
Smythe
Cheryl D W
CD
BHF Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W120NN, UK.
Skinner
Vernon O
VO
Bruckdorfer
K Richard
KR
Haskard
Dorian O
DO
Landis
R Clive
RC
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D030421:Peroxynitrous Acid; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D014409:Tumor Necrosis Factor-alpha; D030421:Peroxynitrous Acid