Apolipoprotein A-I mimetic 4F alters the function of human monocyte-derived macrophages.

Academic Article

Abstract

  • HDL and its major protein component apolipoprotein A-I (apoA-I) exert anti-inflammatory effects, inhibit monocyte chemotaxis/adhesion, and reduce vascular macrophage content in inflammatory conditions. In this study, we tested the hypothesis that the apoA-I mimetic 4F modulates the function of monocyte-derived macrophages (MDMs) by regulating the expression of key cell surface receptors on MDMs. Primary human monocytes and THP-1 cells were treated with 4F, apoA-I, or vehicle for 7 days and analyzed for expression of cell surface markers, adhesion to human endothelial cells, phagocytic function, cholesterol efflux capacity, and lipid raft organization. 4F and apoA-I treatment decreased the expression of HLA-DR, CD86, CD11b, CD11c, CD14, and Toll-like receptor-4 (TLR-4) compared with control cells, suggesting the induction of monocyte differentiation. Both treatments abolished LPS-induced mRNA for monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 (MIP-1), regulated on activation, normal T-expressed and presumably secreted (RANTES), IL-6, and TNF-alpha but significantly upregulated LPS-induced IL-10 expression. Moreover, 4F and apoA-I induced a 90% reduction in the expression of CD49d, a ligand for the VCAM-1 receptor, with a concurrent decrease in monocyte adhesion (55% reduction) to human endothelial cells and transendothelial migration (34 and 27% for 4F and apoA-I treatments) compared with vehicle treatment. In addition, phagocytosis of dextran-FITC beads was inhibited by 4F and apoA-I, a response associated with reduced expression of CD32. Finally, 4F and apoA-I stimulated cholesterol efflux from MDMs, leading to cholesterol depletion and disruption of lipid rafts. These data provide evidence that 4F, similar to apoA-I, induces profound functional changes in MDMs, possibly due to differentiation to an anti-inflammatory phenotype.
  • Keywords

  • Anti-Inflammatory Agents, Antigens, CD, Apolipoprotein A-I, Cell Adhesion, Cell Adhesion Molecules, Cells, Cultured, Cholesterol, Cytokines, Endothelial Cells, HLA-DR Antigens, Humans, Inflammation Mediators, Leukocyte Rolling, Lipopolysaccharides, Macrophages, Membrane Microdomains, Molecular Mimicry, Phagocytosis, Phenotype, RNA, Messenger
  • Digital Object Identifier (doi)

    Authorlist

  • Smythies LE; White CR; Maheshwari A; Palgunachari MN; Anantharamaiah GM; Chaddha M; Kurundkar AR; Datta G
  • Start Page

  • C1538
  • End Page

  • C1548
  • Volume

  • 298
  • Issue

  • 6