Kurano Makoto, Tsukamoto Kazuhisa, Isago Hideaki, Hara Masumi, Yatomi Yutaka
Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.
J Inflamm (Lond). 2025 Aug 12;22(1):32. doi: 10.1186/s12950-025-00459-5.
C-reactive protein (CRP) is a risk factor for atherosclerosis. Although inflammation may confound this association, CRP itself has been hypothesized to possess both pro-atherosclerotic and pro-inflammatory properties. In this study, we aimed to elucidate the mechanism by which CRP may modulate bioactive lipid mediators.
We found that the overexpression of human CRP increased plasma IL-6 and TNF-a levels in mice. Moreover, the conditioned medium of CRP-overexpressing HepG2 cells increased the release of these cytokines from RAW264.7 cells to a greater degree than recombinant CRP. Lipidomics analyses then revealed that the overexpression of CRP increased the total levels of plasma lysophosphatidic acid, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, and sphingosine 1-phosphate in mice. It also increased the levels of pro-inflammatory arachidonic acid derivatives, including PGE2 metabolites, LTA4 metabolites, and oxylipids, and decreased the levels of anti-inflammatory eicosapentaenoic acid- and docosahexaenoic acid-derived mediators. In regard to the mechanisms, analyses of CRP-overexpressing HepG2 cells suggested that CRP may increase the hepatic production of glycero-lysophospholipids, and may also modulate eicosanoids and related mediators outside the liver. Finally, analyses of the fraction separated using anti-CRP IgG suggested that CRP can bind several lipid mediators including sphingosine 1-phosphate, PGE2, and PGF2a.
CRP may modulate lysophospholipids, and eicosanoids, and related mediators in pro-atherosclerotic and pro-inflammatory directions.
C反应蛋白（CRP）是动脉粥样硬化的一个风险因素。尽管炎症可能混淆这种关联，但CRP本身被推测具有促动脉粥样硬化和促炎特性。在本研究中，我们旨在阐明CRP可能调节生物活性脂质介质的机制。
我们发现人CRP的过表达增加了小鼠血浆白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）水平。此外，过表达CRP的HepG2细胞的条件培养基比重组CRP更能促进RAW264.7细胞释放这些细胞因子。脂质组学分析随后显示，CRP的过表达增加了小鼠血浆溶血磷脂酸（LPA）、溶血磷脂酰乙醇胺（LPE）、溶血磷脂酰甘油（LPG）、溶血磷脂酰肌醇（LPI）和1-磷酸鞘氨醇（S1P）的总水平。它还增加了促炎花生四烯酸衍生物的水平，包括前列腺素E2（PGE2）代谢物、白三烯A4（LTA4）代谢物和氧化脂质，并降低了抗炎二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）衍生介质的水平。关于机制，对过表达CRP的HepG2细胞的分析表明，CRP可能增加肝脏甘油磷脂的产生，也可能在肝脏外调节类花生酸和相关介质。最后，使用抗CRP IgG分离的组分分析表明，CRP可以结合几种脂质介质，包括1-磷酸鞘氨醇、PGE2和前列腺素F2α（PGF2α）。
CRP可能在促动脉粥样硬化和促炎方向上调节溶血磷脂、类花生酸和相关介质。
