7-Ketocholesterol Upregulates Interleukin-6 via Mechanisms That Are Distinct from Those of Tumor Necrosis Factor-α, in Vascular Smooth Muscle Cells

Abstract

This study investigated the effects of 7-ketocholesterol on interleukin (IL)-6 expression in vascular smooth muscle cells (VSMC). Among the 7 IL examined, only IL-6 transcript was increased by 7-ketocholesterol treatment in human aorta smooth muscle cells. IL-6 transcripts increased up to 24 h after treatment with 7-ketocholesterol, and this effect was profoundly repressed by treatment with p38 MAPK inhibitors and to a lesser extent JNK inhibitors. 7α-Hydroxycholesterol, 27-hydroxycholesterol or cholesterol, however, did not induce IL-6 expression. Mechanisms of IL-6 induction by 7-ketocholesterol were investigated in comparison with tumor necrosis factor (TNF)-α. Whereas TNF-α activated IL-6 promoter, which was impaired by p38 MAPK inhibitors or by mutation in the NF-κB-binding site within the promoter region, 7-ketocholesterol did not affect IL-6 promoter activity. Instead, this oxysterol slowed degradation of IL-6 mRNA and increased the amount of cytoplasmic HuR. 7-ketocholesterol significantly increased the amount of intracellular IL-6 protein in the presence of brefeldin A. 7-Ketocholesterol also enhanced IL-6 release from VSMC. IL-6 release by 7-ketocholesterol, although significant, was not as remarkable as that induced by TNF-α. These data suggest that 7-ketocholesterol upregulates IL-6 via mechanisms distinct from TNF-α and contributes to the intra- and extracellular IL-6 deposits within the vasculature.

LPA induces IL-6 secretion from aortic smooth muscle cells via an LPA1-regulated, PKC-dependent, and p38α-mediated pathway

“…For instance, ANG II rapidly induces IL-6 mRNA expression in both vascular SMCs and cardiac fibroblasts, with the peak induction at ϳ30 min to 1 h (44,45); however, thrombin stimulates a quick induction of IL-6 mRNA expression in vascular SMCs, with the peak induction at ϳ30 min to 1 h, whereas in lung fibroblasts and blood monocytes, thrombin induces delayed IL-6 mRNA accumulation, with an induction peak at ϳ6 -12 h (30,48). A recent study (49) showed that oxysterol 7-ketocholesterol induces IL-6 mRNA expression in vascular SMCs in a delayed pattern as well, peaking at 24 -48 h (49). The regulation mechanisms in response to various stimuli in these different cell types are also different.…”

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

“…The role of ROS in these cells has been supported by studies that used antioxidants to abolish their action ( 8, 109 , 110 ). Another mechanism described for the proinfl ammatory role of 7KCh in VSMCs is the translocation of the HuR protein from the nucleus to the cytoplasm ( 103 ). HuR is an RNA-binding protein that …”

Extracellular Nucleotides Can Induce Chemokine (C-C motif) Ligand 2 Expression in Human Vascular Smooth Muscle Cells

“…MAPKs play important roles in VSMC secretion of cytokines and chemokines [15,16]. We investigated whether MAPKs affected nucleotide-mediated CCL2 secretion.…”