Departments of Environmental Toxicology, College of Sciences and Engineering, Southern University and A & M College, Baton Rouge, LA, 70813, USA.
Department of Biological Sciences and Chemistry, College of Sciences and Engineering, Southern University and A & M College, Baton Rouge, LA, 70813, USA.
Cell Biochem Biophys. 2021 Sep;79(3):649-658. doi: 10.1007/s12013-021-01004-w. Epub 2021 Jun 15.
Cholesterol oxidation product, 3β-hydroxy-5-oxo-5,6-secocholestan-6-al (cholesterol 5,6-secosterol, ChSeco or Atheronal-A), formed at inflammatory sites, has been shown to promote monocyte differentiation into macrophages and cause elevated expression of macrophage scavenger receptors. Since inflammation is a key event at all stages of atherosclerotic plaque formation, the pro-inflammatory actions of ChSeco in human THP-1 monocytes and mouse J774 macrophages were investigated in the present study by employing ELISA, qRT-PCR, and functional assays. An increase in the secretion of interleukin-8 and platelet-derived growth factor (PDGF) isoform AA and, to a limited extent, PDGF isoform BB was observed into the culture medium of THP-1 monocytes exposed to ChSeco. However, no changes were seen in the secretion of tumor necrosis factor-alpha. In J774 macrophages treated with ChSeco, there was an upregulation of gene expression of several pro-inflammatory cytokines and their receptors. Concomitantly, there was down-regulation of gene expression of interleukin-1ß, interleukin-10, and lymphotoxin-beta. An increase in the release of interleukin-18 and chemokine (C-C motif) ligand-20 from J774 macrophages (which corroborated well with their gene expression profiles) and increased binding of THP-1 monocytes to ChSeco-exposed human aortic endothelial cells were observed. The results of the present study, for the first time, demonstrate the pro-inflammatory action of ChSeco and suggest the underlying pro-atherogenic mechanisms. These could be mediated through enhanced monocyte recruitment into the sub-endothelial space and subsequent proliferation of smooth muscle cells under the influence of monocyte-derived PDGF.
胆固醇氧化产物 3β-羟基-5-氧代-5,6-去胆甾烷-6-醛（胆固醇 5,6-开环胆甾烷，ChSeco 或 Atheronal-A）在炎症部位形成，已被证明可促进单核细胞分化为巨噬细胞，并导致巨噬细胞清道夫受体的表达升高。由于炎症是动脉粥样硬化斑块形成的所有阶段的关键事件，因此本研究采用 ELISA、qRT-PCR 和功能测定法研究了 ChSeco 在人 THP-1 单核细胞和小鼠 J774 巨噬细胞中的促炎作用。观察到暴露于 ChSeco 的 THP-1 单核细胞培养物中白细胞介素-8 和血小板衍生生长因子 (PDGF) 同工型 AA 的分泌增加（在有限程度上 PDGF 同工型 BB）。然而，肿瘤坏死因子-α的分泌没有变化。用 ChSeco 处理的 J774 巨噬细胞中，几种促炎细胞因子及其受体的基因表达上调。同时，白细胞介素-1β、白细胞介素-10 和淋巴毒素-β的基因表达下调。J774 巨噬细胞中白细胞介素-18 和趋化因子 (C-C 基序) 配体-20 的释放增加（与它们的基因表达谱非常吻合），并且观察到 THP-1 单核细胞与暴露于 ChSeco 的人主动脉内皮细胞的结合增加。本研究首次证明了 ChSeco 的促炎作用，并提出了潜在的促动脉粥样硬化机制。这些可能是通过增强单核细胞向血管内皮下空间的募集以及单核细胞衍生的 PDGF 的影响下平滑肌细胞的增殖来介导的。
