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The state of macrophage differentiation determines the TNF? response to scavenged nitrated lipoprotein

Smythe, C.D.W., Skinner, V.O., Bruckdorfer, K.R., Haskard, D.O., and Landis, R.C.

Clive Landis






Macrophage biology


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.



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