Hanriot Didier, Bello Gaëlle, Ropars Armelle, Seguin-Devaux Carole, Poitevin Gaël, Grosjean Sandrine, Latger-Cannard Véronique, Devaux Yvan, Zannad Faiez, Regnault Véronique, Lacolley Patrick, Mertes Paul-Michel, Hess Ketsia, Longrois Dan
INSERM, U684, Nancy, France.
Thromb Haemost. 2008 Mar;99(3):558-69. doi: 10.1160/TH07-06-0410.
Non-specific markers of inflammation such as C-reactive protein (CRP) are associated statistically with an increased risk of atherosclerosis through mechanisms that have not yet been fully elucidated. We investigated the effects of CRP on several aspects of human monocyte biology, a cell type involved in the initiation and progression of atherosclerosis. Blood monocytes isolated from healthy men and premenopausal women (n = 9/group) were exposed to purified CRP (25 microg/ml) for 12 hours. Changes in gene expression were analyzed using a custom-made array containing oligonucleotide sequences of 250 genes expressed by activated monocytes and confirmed by quantitative PCR. CRP increased significantly the expression of the cytokines interleukin (IL)-1alpha, IL-1beta and IL-6, and the chemokines GRO-alpha, GRO-beta and IL-8. CRP also displayed anti-inflammatory effects through upregulation of liver X receptor (LXR) alpha and activin receptor expression, and down-regulation of alpha 2-macroglobulin expression. Increased LXRalpha mRNA expression in both monocytes and the monocytic cell lineTHP-1 was associated with increased LXRalpha protein expression and nuclear translocation, as well as increased ABCA1 mRNA expression, a target gene of LXRalpha. Western blot analysis revealed CRP-induced nuclear translocation of NF-kappaB and activation of p42/44, MAP and Akt kinases. CRP-induced LXRalpha mRNA expression was inhibited by anti-CD64 (FcgammaRI) antibodies and by p42/44 and PI3 kinase inhibitors. This hypothesis-generating study demonstrates that CRP modulates the expression of genes that contribute to both pro- and anti-inflammatory responses in human monocytes. Among these novel anti-inflammatory effects, we show clearly that CRP activates the LXRalpha pathway.
炎症的非特异性标志物，如C反应蛋白（CRP），通过尚未完全阐明的机制，在统计学上与动脉粥样硬化风险增加相关。我们研究了CRP对人类单核细胞生物学多个方面的影响，单核细胞是一种参与动脉粥样硬化起始和进展的细胞类型。从健康男性和绝经前女性（每组n = 9）中分离出的血液单核细胞，暴露于纯化的CRP（25微克/毫升）中12小时。使用定制的阵列分析基因表达变化，该阵列包含由活化单核细胞表达的250个基因的寡核苷酸序列，并通过定量PCR进行确认。CRP显著增加了细胞因子白细胞介素（IL）-1α、IL-1β和IL-6，以及趋化因子GRO-α、GRO-β和IL-8的表达。CRP还通过上调肝X受体（LXR）α和激活素受体表达以及下调α2-巨球蛋白表达发挥抗炎作用。单核细胞和单核细胞系THP-1中LXRα mRNA表达增加与LXRα蛋白表达增加、核转位以及LXRα靶基因ABCA1 mRNA表达增加相关。蛋白质印迹分析显示CRP诱导NF-κB核转位以及p42/44、MAP和Akt激酶激活。抗CD64（FcγRI）抗体以及p42/44和PI3激酶抑制剂可抑制CRP诱导的LXRα mRNA表达。这项产生假设的研究表明，CRP调节人类单核细胞中促成促炎和抗炎反应的基因表达。在这些新的抗炎作用中，我们清楚地表明CRP激活了LXRα途径。
