Abstract
Complement C3 is a pivotal component of three cascades of complement activation. C3 is expressed in human atherosclerotic lesions and is involved in atherogenesis. However, the mechanism of C3 accumulation in atherosclerotic lesions is not well elucidated. We show that acetylated low density lipoprotein and oxidized low density lipoprotein (oxLDL) increase C3 gene expression and protein secretion by human macrophages. Modified LDL (mLDL)-mediated activation of C3 expression mainly depends on liver X receptor (LXR) and partly on Toll-like receptor 4 (TLR4), whereas C3 secretion is increased due to TLR4 activation by mLDL. LXR agonist TO901317 stimulates C3 gene expression in human monocyte-macrophage cells but not in human hepatoma (HepG2) cells. We find LXR-responsive element inside of the promoter region of the human C3 gene, which binds to LXRβ in macrophages but not in HepG2 cells. We show that C3 expression and secretion is decreased in IL-4-treated (M2) and increased in IFNγ/LPS-stimulated (M1) human macrophages as compared with resting macrophages. LXR agonist TO901317 potentiates LPS-induced C3 gene expression and protein secretion in macrophages, whereas oxLDL differently modulates LPS-mediated regulation of C3 in M1 or M2 macrophages. Treatment of human macrophages with anaphylatoxin C3a results in stimulation of C3 transcription and secretion as well as increased oxLDL accumulation and augmented oxLDL-mediated up-regulation of the C3 gene. These data provide a novel mechanism of C3 gene regulation in macrophages and suggest new aspects of cross-talk between mLDL, C3, C3a, and TLR4 during development of atherosclerotic lesions.
Highlights
Complement C3 is expressed and secreted by human macrophages
We show that Modified low density lipoprotein (mLDL) activates C3 expression after uptake by macrophages, and mLDL-mediated up-regulation of the C3 gene appears to be mediated by liver X receptor (LXR), whereas activation of the Toll-like receptor 4 (TLR4)-MEKERK pathway by mLDL has a minor effect on stimulation of C3 gene expression (Fig. 7)
The LXR-responsive element (LXRE) site is not conserved between humans and mice, which seems to explain the species-specific regulation of C3 expression by LXRs
Summary
Complement C3 is expressed and secreted by human macrophages. Results: Modified low density lipoprotein (mLDL) up-regulates C3 expression and secretion, whereas C3a stimulates mLDL uptake by macrophages. We show that mLDL stimulates C3 secretion via activation of Toll-like receptor 4 (TLR4), whereas C3a, a product of C3 cleavage during complement activation, increases oxidized LDL uptake and C3 expression and secretion by human macrophages. These data provide a novel mechanism of regulation of C3 expression and secretion by human macrophages and suggest novel aspects of cross-talk between the complement system, TLR4 signaling, and lipid metabolism during development of atherosclerotic lesions
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