REGULATION OF SERUM-INDUCED LIPID-ACCUMULATION IN HUMAN MONOCYTE-DERIVED MACROPHAGES BY INTERFERON-GAMMA - CORRELATIONS WITH APOLIPOPROTEIN-E PRODUCTION, LIPOPROTEIN-LIPASE ACTIVITY AND LDL RECEPTOR-RELATED PROTEIN EXPRESSION

The demonstration of lipid loaded macrophages in atherosclerotic tissu e has led to the development of in vitro systems to elucidate the mech anisms involved in lipid accumulation. Here we have characterised the changes which occur in human monocyte-derived macrophage (MDM) lipids during culture in either human serum (HS) or foetal calf serum (FCS). MDM cultured in HS were rapidly converted to lipid filled foam cells, as assessed using HPLC analysis and oil red-O staining and compared wi th the same cells grown in FCS. However, the lipids which accumulated were predominantly triglycerides with smaller amounts of unesterified cholesterol (UC) and only traces of cholesteryl esters (CE). alpha-Toc opherol (alpha-TocH) was present at higher levels in MDM cultured in H S compared to the same cells grown in FCS. MDM lipid accumulation was dependent on the triglyceride-rich lipoprotein (TGRL) fraction of huma n serum; accordingly, supplementation of FCS with human TGRL also indu ced MDM lipid accumulation. The relationships between cellular lipid a ccumulation and secretion of apolipoprotein E (ape E) and lipoprotein lipase (LPL) as well as expression of the low density lipoprotein rece ptor-related protein (LRP) were also examined. MDM lipid accumulation was associated with increased apo E secretion but did not alter extrac ellular LPL activity. The lipid accumulation which was induced by HS w as potently inhibited (but not reversed) by the inflammatory cytokine interferon-gamma (IFN gamma), and this was associated with decreased a po E production, LPL secretion and expression of LRP. These studies re veal striking differences in the lipid composition of MDM cultured in either HS or FCS, and indicate that oil red-O staining is not necessar ily associated with cholesteryl ester accumulation in human macrophage s. Furthermore, the effect that serum-induced lipid accumulation has o n the specific MDM functions studied should be appreciated when develo ping in vitro macrophage models. Copyright (C) 1997 Elsevier Science I reland Ltd.