曲古霉素A对CD14+单核细胞活化及TLR4信号通路的影响

doi:10.12092/j.issn.1009-2501.2018.08.005

中国临床药理学与治疗学 ›› 2018, Vol. 23 ›› Issue (8): 867-873.doi: 10.12092/j.issn.1009-2501.2018.08.005

曲古霉素A对CD14⁺单核细胞活化及TLR4信号通路的影响

王洋，堵培，高珂琴，杨爽，贾素洁

中南大学湘雅三医院药学部，长沙 410013，湖南

收稿日期:2018-04-19 修回日期:2018-05-08 出版日期:2018-08-26 发布日期:2018-08-28
通讯作者: 贾素洁，女，博士，硕士生导师，研究方向:表观遗传学。 Tel：0731-88618458 E-mail:sujiejia@csu.edu.cn
作者简介:王洋，男，硕士研究生，研究方向:表观遗传学因素与心血管疾病。
基金资助:
中南大学研究生自主探索创新基金（2017zzts865）；国家自然科学基金（81370392）

Effects of trichostatin A on CD14+ monocytes activation and TLR4 signal pathway

WANG Yang, DU Pei, GAO Keqin, YANG Shuang, JIA Sujie

Department of Pharmacy, the Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China

Received:2018-04-19 Revised:2018-05-08 Online:2018-08-26 Published:2018-08-28

摘要/Abstract

摘要：

目的: 研究曲古霉素A（trichostatin A,TSA）对CD14⁺单核细胞活化状态及Toll样受体4（TLR4）炎性信号通路的影响及其具体机制。方法: 分离健康人外周血CD14⁺单核细胞，用20 nmol/L浓度TSA孵育24 h后收集细胞，RT-qPCR方法检测TLR4及下游炎症因子基因mRNA表达水平，以流式细胞分析检测细胞表面TLR4蛋白表达量，以ChIP-qPCR方法检测TLR4基因启动子区组蛋白H3乙酰化水平变化，以Transwell法检测单核细胞趋化能力，以细胞黏附力实验检测单核细胞的黏附能力。结果: TSA刺激能够增加CD14+单核细胞的趋化和黏附能力，上调CD14⁺单核细胞中TLR4及下游炎症因子TNF-α、MCP-1和IL-6的表达，提高TLR4基因启动子区组蛋白H3乙酰化水平。结论: TSA能够诱导CD14⁺单核细胞活化，提高TLR4启动子区组蛋白乙酰化修饰水平，促进TLR4信号通路基因过度表达。

关键词: 曲古霉素A, CD14+单核细胞, 组蛋白乙酰化, TLR4信号通路, 细胞活化

Abstract:

AIM: To study the effects of trichostatin A (TSA) on CD14⁺ monocytes activation and TLR4 signal pathway. METHODS: CD14⁺ monocytes were isolated from healthy donors and cultured in 1640 medium with 20 nmol/L TSA. After 24 hours, cells were harvested to detect the expression of TLR4 and downstream cytokines by RT-qPCR and flow cytometry methods. ChIP-qPCR was used to detect histone H3 acetylation level TLR4 promoter. Transwell and adhesion experiments were performed to assess the motility and adhesion ability of CD14⁺ monocytes. RESULTS: TSA treatment can increase the motility and adhesion ability of CD14⁺ monocytes. Expression of TLR4 and down-stream cytokines, including TNF-α, MCP-1 and IL-6, were up-regulated in CD14⁺ monocytes after TSA treatment. Higher acetylation of histone H3 within TLR4 promoter region was also detected in CD14⁺ monocytes after TSA treatment. CONCLUSION: TSA activates CD14⁺monocytes, promotes the expression of genes in TLR4 signal pathway and increases the histone H3 acetylation of TLR4 promoter.

Key words: trichostatin A, CD14⁺ monocytes, histone acetylation, TLR4 signal pathway, cell activation

中图分类号:

R363

王洋，堵培，高珂琴，杨爽，贾素洁. 曲古霉素A对CD14⁺单核细胞活化及TLR4信号通路的影响[J]. 中国临床药理学与治疗学, 2018, 23(8): 867-873.

WANG Yang, DU Pei, GAO Keqin, YANG Shuang, JIA Sujie. Effects of trichostatin A on CD14+ monocytes activation and TLR4 signal pathway[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(8): 867-873.

参考文献

［1］Galkina E, Ley K.Immune and inflammatory mechanisms of atherosclerosis［J］.Annu Rev Immunol,2009, 27:165-197.
［2］Pamukcu B, Lip GY, Devitt A,et al.The role of monocytes in atherosclerotic coronary artery disease［J］.Ann Med,2010,42(6):394-403.
［3］Geng HL, Lu HQ, Zhang LZ, et al. Increased expression of Toll like receptor 4 on peripheral-blood mononuclear cells in patients with coronary arteriosclerosis disease［J］.Clin Exp Immunol,2006,143(2):269-273.
［4］Maiwald S, Zwetsloot PP, Sivapalaratnam S, et al. Monocyte gene expression and coronary artery disease［J］.Curr Opin Clin Nutr Metab Care,2013,16(4):411-417.
［5］Zhang BK, Lai X, Jia SJ. Epigenetics in atherosclerosis: a clinical perspective［J］.Discov Med,2015,19(103):73-80.
［6］Neele AE, Van den Bossche J, Hoeksema MA, et al. Epigenetic pathways in macrophages emerge as novel targets in atherosclerosis［J］.Eur J Pharmacol,2015,763 (Pt A):79-89.
［7］Aslibekyan S, Claas SA, Arnett DK.Clinical applications of epigenetics in cardiovascular disease: the long road ahead［J］.Transl Res,2015,165(1):143-153.
［8］Zheng XX,Zhou T,Wang XA,et al.Histone deacetylases and atherosclerosis［J］.Atherosclerosis,2015,240(2):355-366.
［9］Chang G,Zhuang S,Seyfert HM,et al.Hepatic TLR4 signaling is activated by LPS from digestive tract during SARA, and epigenetic mechanisms contribute to enforced TLR4 expression［J］.Oncotarget,2015,6(36):38578-38590.
［10］Escoubet-Lozach L, Benner C, Kaikkonen MU,et al.Mechanisms establishing TLR4-responsive activation states of inflammatory response genes［J］.PLOS Genet,2011,7(12):e1002401.
［11］Kiyan Y, Tkachuk S, Hilfiker-Kleiner D,et al.oxLDL induces inflammatory responses in vascular smooth muscle cells via urokinase receptor association with CD36 and TLR4［J］.J Mol Cell Cardiol,2014,66:72-82.
［12］Bekkering S, Quintin J, Joosten LA,et al.Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes［J］.Arterioscler Thromb Vasc Biol,2014,34:1731-1738.
［13］Greissel A, Culmes M, Burgkart R,et al. Histone acetylation and methylation significantly change with severity of atherosclerosis in human carotid plaques［J］.Cardiovasc Pathol,2016,25(2):79-86.
［14］Passacquale G, Phinikaridou A, Warboys C,et al. Aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration［J］.Br J Pharmacol,2015,172(14):3548-3564.
［15］Pons D, de Vries FR, van den Elsen PJ,et al. Epigenetic histone acetylation modifiers in vascular remodelling: new targets for therapy in cardiovascular disease［J］.Eur Heart J,2009,30:266-277.
［16］李苗, 罗恩杰.TSA通过组蛋白乙酰化影响TLR2基因表达［J］.解剖科学进展,2015,21(3):313-315.
［17］Choi JH, Nam KH, Kim J, et al.Trichostatin A exacerbates atherosclerosis in low density lipoprotein receptor-deficient mice［J］.Arterioscler Thromb Vasc Biol,2005,25(11):2404-2409.
［18］Roshan MH, Tambo A, Pace NP.The role of TLR2, TLR4, and TLR9 in the pathogenesis of atherosclerosis［J］.Int J Inflam,2016,2016:1532832.
［19］Chavez-Sanchez L, Chavez-Rueda K, Legorreta-Haquet MV,et al. The activation of CD14, TLR4, and TLR2 by mmLDL induces IL-1beta, IL-6, and IL-10 secretion in human monocytes and macrophages［J］.Lipids Health Dis,2010,9:117.
［20］Howell KW, Meng X, Fullerton DA,et al.Toll-like receptor 4 mediates oxidized LDL-induced macrophage differentiation to foam cells［J］.J Surg Res,2011,171:e27-e31.
［21］Bjorkbacka H, Kunjathoor VV, Moore KJ,et al.Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways［J］.Nat Med,2004,10:416-421.
［22］Michelsen KS, Wong MH, Shah PK,et al.Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E［J］.Proc Natl Acad Sci U S A,2004,101:10679-10684.
［23］Higashimori M, Tatro JB, Moore KJ,et al.Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice［J］.Arterioscler Thromb Vasc Biol,2011,31:50-57.
［24］Xu XH, Shah PK, Faure E,et al.Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL［J］.Circulation,2001,104:3103-3108.
［25］Howell KW, Meng X, Fullerton DA,et al.Toll-like receptor 4 mediates oxidized LDL-induced macrophage differentiation to foam cells［J］.J Surg Res,2011,171:e27-e31.
［26］Yang K, Zhang XJ, Cao LJ,et al.Toll-like receptor 4 mediates inflammatory cytokine secretion in smooth muscle cells induced by oxidized low-density lipoprotein［J］. PLoS One, 2014, 9(4):e95935.
［27］Hollestelle SC, De Vries MR, Van Keulen JK, et al.Toll-like receptor 4 is involved in outward arterial remodeling［J］.Circulation,2004,109(3):393-398.
［28］Ishikawa Y, Satoh M, Itoh T,et al.Local expression of Toll-like receptor 4 at the site of ruptured plaques in patients with acute myocardial infarction［J］.Clin Sci (Lond),2008,115(4):133-140.
［29］Cole JE, Georgiou E, Monaco C.The expression and functions of Toll-like receptors in atherosclerosis［J］.Mediat Inflamm, 2010,2010:393946.
［30］Takahashi K, Sugi Y, Hosono A, et al. Epigenetic regulation of TLR4 gene expression in intestinal epithelial cells for the maintenance of intestinal homeostasis［J］.J Immunol,2009,183(10):6522-6529.
［31］Kim TW, Lee SJ, Oh BM,et al. Epigenetic modification of TLR4 promotes activation of NF-kappaB by regulating methyl-CpG-binding domain protein 2 and Sp1 in gastric cancer［J］.Oncotarget,2016,7(4):4195-4209.
［32］Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis［J］.Cell,2011,145(3):341-355.

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曲古霉素A对CD14⁺单核细胞活化及TLR4信号通路的影响

Effects of trichostatin A on CD14+ monocytes activation and TLR4 signal pathway

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