TGF-beta reduced binding of high-density lipoproteins in murine macrophages and macrophage-derived foam cells.
The expression of macrophage scavenger receptors is regulated by intracellular cholesterol levels, as well as by cytokines affecting macrophage effector functions. CD36, a member of the type B scavenger receptor family, will bind a variety of nonlipoprotein and lipoprotein ligands including high-density lipoprotein (HDL). Transforming growth factor-beta (TGF-beta) has been demonstrated to modulate macrophage effector functions and is present within atherosclerotic lesions. In the present study, the effect of TGF-beta on HDL binding by both macrophages and macrophage-derived foam cells was evaluated. TGF-beta, in a dose-dependent manner, reduced the binding of flurochrome-labeled HDL to both macrophages and foam cells. These effects were observed in macrophages derived from nonatherosclerotic (BALB/c) as well as from macrophages obtained from both apolipoprotein E and low-density lipoprotein receptor knockout mice. The decrease in HDL binding was consistent with a significant reduction in CD36 message levels. The effect of TGF-beta on type B scavenger receptor expression was not limited to CD36 as SR-BI message was also downregulated, although the effect was more modest. A similar reduction in HDL binding and CD36 message was also observed with the immunosuppressive glucocorticoid dexamethasone. These results suggest that within the microenvironment of an atherosclerotic lesion, TGF-beta and other agents that inhibit macrophage inflammatory responses may impact lesion progression through mechanisms that include the modulation of HDL-foam cell interactions.
Division of Cardiovascular Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA. zuckerman_steven@lilly.com
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D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism; D015152:Blotting, Northern; D018955:CD36 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005434:Flow Cytometry; D005487:Foam Cells / Q000378:metabolism*; D007166:Immunosuppressive Agents; D008075:Lipoproteins, HDL / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D001057:Apolipoproteins E; D018955:CD36 Antigens; D007166:Immunosuppressive Agents; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D016212:Transforming Growth Factor beta; D003907:Dexamethasone