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.

在炎症部位形成的胆固醇氧化产物 3β-羟基-5-oxo-5,6-secocholestan-6-al（胆固醇 5,6-secosterol、ChSeco 或 Atheronal-A）已被证明可以促进单核细胞分化为巨噬细胞并引起巨噬细胞清道夫受体表达升高。由于炎症是动脉粥样硬化斑块形成各个阶段的关键事件，因此本研究通过 ELISA、qRT-PCR 和功能测定研究了 ChSeco 在人 THP-1 单核细胞和小鼠 J774 巨噬细胞中的促炎作用。在暴露于 ChSeco 的 THP-1 单核细胞的培养基中，观察到白细胞介素 8 和血小板衍生生长因子 (PDGF) 亚型 AA 的分泌增加，并且在有限程度上，PDGF 亚型 BB 的分泌增加。然而，肿瘤坏死因子-α的分泌没有变化。在用 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。与此同时，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 巨噬细胞释放的白细胞介素 18 和趋化因子（C-C 基序）配体 20 增加（这很好地证实了它们的基因表达谱），并且 THP-1 单核细胞与 ChSeco 暴露的人主动脉内皮细胞的结合增加。观察到。本研究的结果首次证明了 ChSeco 的促炎作用，并提出了潜在的促动脉粥样硬化机制。这些可以通过增强单核细胞募集到内皮下空间以及随后在单核细胞衍生的 PDGF 的影响下平滑肌细胞的增殖来介导。