Transcriptional Inhibition by Interleukin-6 of the Class A Macrophage Scavenger Receptor in Macrophages Derived From Human Peripheral Monocytes and the THP-1 Monocytic Cell Line

Abstract

Abstract-Expression of the class A macrophage scavenger receptor (MSR) contributes to the uptake of modified low density lipoproteins (LDL) by macrophages and transformation of these cells into lipid-laden foam cells, which characterize atherosclerosis. Many environmental factors, in particular, proinflammatory cytokines and growth factors, can exert regulatory effects on MSR expression, whereas intracellular accumulation of cholesterol itself does not influence MSR levels to any considerable extent. In the present study, by using an in vitro model, we examined whether stimulation with interleukin-6 (IL-6), an immunoregulatory, multipotential cytokine, modulates the expression and activities of the MSR in macrophages. When treated with IL-6, macrophages derived from peripheral monocytes and phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 monocytic cells showed significantly reduced uptake and/or binding of the MSR ligand, acetylated LDL. This effect was paralleled by a reduction in the expression of MSR protein and mRNA. Analysis of MSR promoter activity in THP-1 cells transfected with an MSR promoter-reporter gene construct demonstrated decreased activity of the MSR promoter in IL-6 -treated THP-1 macrophages. Electrophoretic mobility gel shift assay also showed a reduction in the binding of a transcription factor to the MSR promoter AP-1/ets elements in IL-6 -treated cells. Thus, exposure to IL-6 may inhibit expression of the class A MSR in differentiated macrophages at transcriptional levels. This result suggests that this cytokine may modulate foam cell formation during atherogenesis.

IL-33 Reduces Macrophage Foam Cell Formation

“…IL-6 and IL-10 have also been previously shown to inhibit macrophage foam cell formation (27,28,30,31). IL-6 reduces AcLDL uptake by inhibiting SR gene expression (27), whereas IL-10 decreases foam cell formation by various mechanisms (28,30,31), some of which remain controversial (31). Our results demonstrate a clear cut mechanism by which IL-33 inhibits macrophage foam cell formation.…”

“…IL-33 decreases both AcLDL/OxLDL uptake and intracellular total and esterifed cholesterol levels but enhances cholesterol efflux through regulation of key genes involved in modified LDL uptake, cholesterol efflux/transport, and the storage of cholesteryl esters and triglycerides. IL-6 and IL-10 have also been previously shown to inhibit macrophage foam cell formation (27,28,30,31). IL-6 reduces AcLDL uptake by inhibiting SR gene expression (27), whereas IL-10 decreases foam cell formation by various mechanisms (28,30,31), some of which remain controversial (31).…”

“…These results therefore further support the notion that IL-33 reduces macrophage foam cell formation. The cellular mechanisms involved in the cytoplasmic storage of cholesteryl esters and triglyceride-rich lipid droplets are regulated by a network of proteins, involved in intracellular cholesterol storage and transport, which themselves are cytokine sensitive (11,22,(26)(27)(28). These include NPC-1, NPC-2, CPT-1, ADRP, ACAT-1, and NCEH.…”

Reduced Infiltration of Class A Scavenger Receptor Positive Antigen-Presenting Cells Is Associated with Prostate Cancer Progression

“…Our previous study and other reports have demonstrated that a significantly elevated transforming growth factor ␤1 level in prostate cancer cells is associated with tumor progression and metastasis (41)(42)(43). Interleukin 6 has also been reported recently to be capable of inhibiting SR-A expression in THP-1 cells at both mRNA and protein levels (44). Interestingly, there is accumulating evidence that interleukin 6 expression in cancer cells is progressively increased with increasing malignant potential and positively associated with metastasis (45,46).…”

Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A

“…Several cytokines were previously shown to modulate the formation of foamy macrophages generated in the presence of aggregated, acetylated or oxidized LDL. IFN-␥ , IL-1 ␤ , and TNF-␣ promote macrophage foam cell formation (25)(26)(27)(28), while IL-6, TGF-␤ 1, and IL-33 (29)(30)(31) have been described as anti-foam cell cytokines in humans and IL-10 facilitates both cholesterol uptake and effl ux in macrophages ( 32 ). Only IL-1 ␤ expression was weakly affected by IL-17A treatment, suggesting a role for this models.…”