TGF-beta1 downregulates CD36 and scavenger receptor A but upregulates LOX-1 in human macrophages.
Transforming growth factor-beta1 (TGF-beta1), a key cytokine for control of cell growth, extracellular matrix formation, and inflammation control, is secreted by many cells present in the arteriosclerotic plaque. Lipid accumulation in the vessel wall is regarded as an early step in atherogenesis and depends on uptake of modified low-density lipoprotein (LDL) by macrophages through scavenger receptors and their transformation into foam cells. Prominent members of the scavenger receptor family are the class A type I and II receptors (ScR-A), the class B receptor CD36, and the recently detected lectin-like oxidized LDL receptor-1 (LOX-1), which, unlike the native LDL receptor (LDL-R), are not feedback controlled. CD36 is responsible for >50% of modified LDL uptake into human monocyte-derived macrophages. We therefore studied whether TGF-beta1 influences expression and function of ScR-A, CD36, and LOX-1 in monocytes using RT-PCR and flow cytometry. Total uptake of oxidized LDL by monocytoid cells, reflecting the combined function of all scavenger receptors, was significantly reduced by TGF-beta1. At initially low picomolar concentrations, TGF-beta1 decreased CD36 mRNA and protein surface expression and ScR-A mRNA levels in the human monocytic cell line THP-1 and in freshly isolated and cultivated human monocytes, whereas LOX-1 mRNA was increased. Expression of LDL-R and beta-actin was not affected by TGF-beta1. In conclusion, depression of scavenger receptor function in monocytes by TGF-beta1 in low concentrations reduces foam cell formation. Together with matrix control by TGF-beta1, this may be important for atherogenesis and plaque stabilization.
Draude
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Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Universität München, 81245 Munich, Germany.
Lorenz
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RL
D018955:CD36 Antigens / Q000235:genetics*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D051131:Receptors, Oxidized LDL; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051127:Scavenger Receptors, Class E; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D018955:CD36 Antigens; C495139:MSR1 protein, human; C495137:OLR1 protein, human; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051127:Scavenger Receptors, Class E; D016212:Transforming Growth Factor beta