Abstract
The macrophage scavenger receptor, a 220-kDa trimeric membrane glycoprotein, mediates the internalization of modified forms of low density lipoprotein (LDL) such as acetyl-LDL and oxidized-LDL and thus is likely to play a key role in atheroma macrophage foam cell formation. In addition, recent evidence suggests that the scavenger receptor may be an important macrophage binding site for lipopolysaccharide involved in lipopolysaccharide scavenging by macrophages. However, little is known about the regulation of this important receptor. We now report that the induction of scavenger receptor activity (as measured by acetyl-LDL stimulation of intracellular cholesterol esterification) seen in phorbol ester-differentiated THP-1 human macrophages was completely suppressed to the level seen in undifferentiated THP-1 monocytes by picomolar concentrations of transforming growth factor-beta 1 (TGF-beta 1). 125I-Acetyl-LDL degradation was inhibited in a dose-dependent manner by TGF-beta 1, with maximal inhibition (approximately 70%) occurring at 24 pM TGF-beta 1. Scatchard analysis revealed that TGF-beta 1 treatment resulted in a approximately 2-fold decrease in receptor number, and Northern blot analysis of RNA isolated from differentiated THP-1 macrophages demonstrated approximately 2-fold less scavenger receptor mRNA in TGF-beta 1-treated cells compared with that in macrophages not treated with TGF-beta 1. Since TGF-beta 1 is thought to be present in both atherosclerotic and inflammatory lesions, the above findings may have physiological relevance regarding the regulation of atheroma foam cell formation and/or the regulation of lipopolysaccharide clearance by macrophages.
Highlights
From the Departments of $Medicine and Anato&myCell Biology and VBiochemistry& Molecular Biophysics and the Center for Reproductive Sciences, Columbia University College of Physicians and Surgeons, New York, New York 10032
Amajor lipoproteininternalizationpathway (LDL) suchas acetyl-LDL andoxidized-LDL and involved in macrophage ACAT stimulationand foam cell is likely to play a key role in atheroma macrophage formation involves the uptakeof modified forms of LDL
We show that TGF-Plinhibits scavenger recep- relatively high in undifferentiatedmonocytes but much lower tor activity in THP-1 human monocyte/macrophages, at least in PMA-differentiated macrophages (consistent with previous inpart by decreasing scavenger receptor mRNA levels in data (Ref. 15)), and treatmentwith TGF-01 did not alter the these cells
Summary
From the Departments of $Medicine and Anato&myCell Biology and VBiochemistry& Molecular Biophysics and the Center for Reproductive Sciences, Columbia University College of Physicians and Surgeons, New York, New York 10032. The induction of acetyl-LDL-stimulated ACAT activity in differentiating THP-1 monocyte/macrophages was inhibited by TGF-P1.
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