Resveratrol blocks atherosclerosis development by inhibiting IL-1β in macrophages induced by cholesterol


  • Yilin Xie School of Life Science and Biotechnology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University, Shanghai 200240
  • Zhaoxia Wang School of Life Science and Biotechnology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University, Shanghai 200240
  • Haiyun Lin School of Life Science and Biotechnology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University, Shanghai 200240
  • Yajun Pan School of Life Science and Biotechnology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University, Shanghai 200240
  • Lianyun Wang School of Life Science and Biotechnology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University, Shanghai 200240
  • Zhiqiang Yan Central Laboratory, Shanghai Jiao Tong University Affiliated Sixth Peoples’ Hospital South Campus Shanghai, Shanghai 201400
  • Zhongdong Qiao School of Life Science and Biotechnology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University, Shanghai 200240
  • Zhihua Han Department of Cardiology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011


resveratrol, IL-1β, atherosclerosis, cholesterol, HUVEC


Paper description:

  • Resveratrol inhibits the cholesterol-induced production of interleukin-1 beta (IL-1β) in macrophages and reduces adhesion of monocyte to the endothelium. Resveratrol could also exert its anti-inflammatory roles by stimulating reversed cholesterol transport (RCT) in macrophages.
  • Resveratrol inhibited monocyte recruitment partly through the inhibition of IL-1β expression in macrophages. We hypothesize that resveratrol may exert its anti-inflammatory effects by stimulating RCT and by inhibiting the deposition of cholesterol in macrophages.
  • These findings enhance the potential value of resveratrol in the prevention of atherosclerosis.

Abstract: Resveratrol is a polyphenolic compound that exhibits antiinflammatory and cardioprotective properties. In this study we investigated the protective role of resveratrol on the inflammatory activation of macrophages during pathogenesis of atherosclerosis. Macrophage Ana-1 cells were stimulated by cholesterol and resveratrol, and the cell culture supernatant was collected to treat human umbilical vein endothelial cells (HUVECs). The release of IL-1β into the Ana-1 cell supernatant was quantified by ELISA. Expression of the adhesion molecule ICAM-1 and E-selectin in HUVECs were examined by Western-blotting. Additionally, the adhesion of monocytes in HUVECs under different conditions was tested by cell adhesion analyses. The results indicated that the high cholesterol treatment increased the expression level of IL-1β, while pretreatment with resveratrol inhibited this induction of IL-1β in Ana-1 cells. Resveratrol inhibited the adhesion of monocytes to the endothelium at least partly through inhibition of IL-1β expression in macrophages. Moreover, the expression level of caveolin-1 significantly increased after the pretreatment with resveratrol, indicating that resveratrol enhances reverse cholesterol transport (RCT) in macrophages. Our study indicated that resveratrol has significant antiinflammatory effects and can be considered as a candidate molecule to prevent atherosclerosis.

Received: November 29, 2018; Revised: April 2, 2019; Accepted: April 3, 2019; Published online: July 10, 2019

How to cite this article: Xiea Y, Wanga Z, Lin H, Pan Y, Wang L, Yan Z, Qiao Z, Han Z. Resveratrol blocks atherosclerosis development by inhibiting IL-1β in macrophages induced by cholesterol. Arch Biol Sci. 2019;71(3):551-9.


Download data is not yet available.


Lusis AJ. Atherosclerosis. Nature. 2000;407(6801):233-41.

Galea J, Armstrong J, Gadsdon P, Holden H, Francis SE, Holt CM. Interleukin-1 beta in coronary arteries of patients with ischemic heart disease. Arterioscler Thromb Vasc Biol. 1996;16(8):1000-6.

Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, Asano M, Moriwaki H, Seishima M. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2003;23(4):656-60.

Herman WH, Holcomb JM, Hricik DE, Simonson MS. Interleukin-1 beta induces endothelin-1 gene by multiple mechanisms. Transplant Proc. 1999;31(1-2):1412-3.

Kanno K, Hirata Y, Imai T, Marumo F. Induction of nitric oxide synthase gene by interleukin in vascular smooth muscle cells. Hypertension. 1993;22(1):34-9.

Wang X, Feuerstein GZ, Gu JL, Lysko PG, Yue TL. Interleukin-1 beta induces expression of adhesion molecules in human vascular smooth muscle cells and enhances adhesion of leukocytes to smooth muscle cells. Atherosclerosis. 1995;115(1):89-98.

Zarbock A, Kempf T, Wollert KC, Vestweber D. Leukocyte integrin activation and deactivation: novel mechanisms of balancing inflammation. J Mol Med (Berl). 2012;90(4):353-9.

Diamond MS, Staunton DE, Marlin SD, Springer TA. Binding of the integrin Mac-1 (CD11b/CD18) to the third immunoglobulin-like domain of ICAM-1 (CD54) and its regulation by glycosylation. Cell. 1991;65(6):961-71.

Lawrence MB. Threshold levels of fluid shear promote leukocyte adhesion through selectins (CD62L,P,E). J Cell Biol. 1997;136(3):717-27.

Carlos T, Kovach N, Schwartz B, Rosa M, Newman B, Wayner E, Benjamin C, Osborn L, Lobb R, Harlan J. Human monocytes bind to two cytokine-induced adhesive ligands on cultured human endothelial cells: endothelial-leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1. Blood. 1991;77(10):2266-71.

De Caterina R, Basta G, Lazzerini G, Dell'Omo G, Petrucci R, Morale M, Carmassi F, Pedrinelli R. Soluble vascular cell adhesion molecule-1 as a biohumoral correlate of atherosclerosis. Arterioscler Thromb Vasc Biol. 1997;17(11):2646-54.

Peter K, Nawroth P, Conradt C, Nordt T, Weiss T, Boehme M, Wunsch A, Allenberg J, Kubler W, Bode C. Circulating vascular cell adhesion molecule-1 correlates with the extent of human atherosclerosis in contrast to circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin. Arterioscl Throm Vas. 1997;17(3):505-12.

Chang TY, Chang CC, Ohgami N, Yamauchi Y. Cholesterol sensing, trafficking, and esterification. Annu Rev Cell Dev Biol. 2006;22:129-57.

Metzkor-Cotter E, Cotter G, Krakover R, Boldur I, Ben-Yakov M, Lazarovitch T, Chen-Levi Z, Fyltovich S, Kaluski E, Zaidenstein R, Vered Z, Golik A. Are infectious agents truly independent risk factors for coronary atherosclerotic heart disease? Circulation. 2000;102(18):53-.

Shrikanta A, Kumar A, Govindaswamy V. Resveratrol content and antioxidant properties of underutilized fruits. J Food Sci Technol. 2015;52(1):383-90.

Tung BT, Rodriguez-Bies E, Talero E, Gamero-Estevez E, Motilva V, Navas P, Lopez-Lluch G. Anti-inflammatory effect of resveratrol in old mice liver. Exp Gerontol. 2015;64:1-7.

Sebai H, Ristorcelli E, Sbarra V, Hovsepian S, Fayet G, Aouani E, Lombardo D. Protective effect of resveratrol against LPS-induced extracellular lipoperoxidation in AR42J cells partly via a Myd88-dependent signaling pathway. Arch Biochem Biophys. 2010;495(1):56-61.

Panaro MA, Carofiglio V, Acquafredda A, Cavallo P, Cianciulli A. Anti-inflammatory effects of resveratrol occur via inhibition of lipopolysaccharide-induced NF-kappaB activation in Caco-2 and SW480 human colon cancer cells. Br J Nutr. 2012;108(9):1623-32.

Palmieri D, Pane B, Barisione C, Spinella G, Garibaldi S, Ghigliotti G, Brunelli C, Fulcheri E, Palombo D. Resveratrol counteracts systemic and local inflammation involved in early abdominal aortic aneurysm development. J Surg Res. 2011;171(2):e237-46.

Lai X, Pei Q, Song X, Zhou X, Yin Z, Jia R, Zou Y, Li L, Yue G, Liang X, Yin L, Lv C, Jing B. The enhancement of immune function and activation of NF-kappaB by resveratrol-treatment in immunosuppressive mice. Int Immunopharmacol. 2016;33:42-7.

Fan E, Zhang L, Jiang S, Bai Y. Beneficial effects of resveratrol on atherosclerosis. J Med Food. 2008;11(4):610-4.

Bellaver B, Souza DG, Souza DO, Quincozes-Santos A. Resveratrol increases antioxidant defenses and decreases proinflammatory cytokines in hippocampal astrocyte cultures from newborn, adult and aged Wistar rats. Toxicol In Vitro. 2014;28(4):479-84.

Guo H, Chen Y, Liao L, Wu W. Resveratrol protects HUVECs from oxidized-LDL induced oxidative damage by autophagy upregulation via the AMPK/SIRT1 pathway. Cardiovasc Drugs Ther. 2013;27(3):189-98.

Ma C, Wang Y, Shen A, Cai W. Resveratrol upregulates SOCS1 production by lipopolysaccharide-stimulated RAW264.7 macrophages by inhibiting miR-155. Int J of Mol Med. 2017;39(1):231-7.

Buettner R, Parhofer KG, Woenckhaus M, Wrede CE, Kunz-Schughart LA, Scholmerich J, Bollheimer LC. Defining high-fat-diet rat models: metabolic and molecular effects of different fat types. Int J Mol Med. 2006;36(3):485-501.

Jaffe EA, Nachman RL, Becker CG, Minick CR. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 1973;52(11):2745-56.

Luo DX, Cao DL, Xiong Y, Peng XH, Liao DF. A novel model of cholesterol efflux from lipid-loaded cells. Acta Pharmacol Sin. 2010;31(10):1243-57.

de Sauvage Nolting PR, Defesche JC, Buirma RJ, Hutten BA, Lansberg PJ, Kastelein JJ. Prevalence and significance of cardiovascular risk factors in a large cohort of patients with familial hypercholesterolaemia. J Intern Med. 2003;253(2):161-8.

Goldstein JL, Kita T, Brown MS. Defective lipoprotein receptors and atherosclerosis. Lessons from an animal counterpart of familial hypercholesterolemia. N Engl J Med. 1983;309(5):288-96.

Murphy AJ, Akhtari M, Tolani S, Pagler T, Bijl N, Kuo CL, Wang M, Sanson M, Abramowicz S, Welch C, Bochem AE, Kuivenhoven JA, Yvan-Charvet L, Tall AR. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin Invest. 2011;121(10):4138-49.

Jeon SM, Lee SA, Choi MS. Antiobesity and vasoprotective effects of resveratrol in apoE-deficient mice. J Med Food. 2014;17(3):310-6.

Williams KJ, Tabas I. Atherosclerosis - An inflammatory disease. New Engl J Med. 1999;340(24):1928-.

Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473(7347):317-25.

Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362(6423):801-9.

Vasamsetti SB, Karnewar S, Gopoju R, Gollavilli PN, Narra SR, Kumar JM, Kotamraju S. Resveratrol attenuates monocyte-to-macrophage differentiation and associated inflammation via modulation of intracellular GSH homeostasis: Relevance in atherosclerosis. Free Radic Biol Med. 2016;96:392-405.

Yvan-Charvet L, Welch C, Pagler TA, Ranalletta M, Lamkanfi M, Han S, Ishibashi M, Li R, Wang N, Tall AR. Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signaling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions. Circulation. 2008;118(18):1837-47.

Obot CJ, Morandi MT, Hamilton RF, Holian A. A comparison of murine and human alveolar macrophage responses to urban particulate matter. Inhal Toxicol. 2004;16(2):69-76.

Blankenberg S, Rupprecht HJ, Bickel C, Peetz D, Hafner G, Tiret L, Meyer J. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation. 2001;104(12):1336-42.

Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM, Jr., Meyer J. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation. 1997;96(12):4219-25.

Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464(7293):1357-61.

Voloshyna I, Hai O, Littlefield MJ, Carsons S, Reiss AB. Resveratrol mediates anti-atherogenic effects on cholesterol flux in human macrophages and endothelium via PPARgamma and adenosine. Eur J Pharmacol. 2013;698(1-3):299-309.

Sevov M, Elfineh L, Cavelier LB. Resveratrol regulates the expression of LXR-alpha in human macrophages. Biochem Biophys Res Commun. 2006;348(3):1047-54.

Escher G, Krozowski Z, Croft KD, Sviridov D. Expression of sterol 27-hydroxylase (CYP27A1) enhances cholesterol efflux. J Biol Chem. 2003;278(13):11015-9.

Berbee JF, Wong MC, Wang Y, van der Hoorn JW, Khedoe PP, van Klinken JB, Mol IM, Hiemstra PS, Tsikas D, Romijn JA, Havekes LM, Princen HM, Rensen PC. Resveratrol protects against atherosclerosis, but does not add to the antiatherogenic effect of atorvastatin, in APOE*3-Leiden.CETP mice. J Nutr Biochem. 2013;24(8):1423-30.

Chassot LN, Scolaro B, Roschel GG, Cogliati B, Cavalcanti MF, Abdalla DSP, Castro IA. Comparison between red wine and isolated trans-resveratrol on the prevention and regression of atherosclerosis in LDLr ((-/-)) mice. J Nutr Biochem. 2018;61:48-55.

Matos RS, Baroncini LA, Precoma LB, Winter G, Lambach PH, Caron EY, Kaiber F, Precoma DB. Resveratrol causes antiatherogenic effects in an animal model of atherosclerosis. Arq Bras Cardiol. 2012;98(2):136-42.




How to Cite

Xie Y, Wang Z, Lin H, Pan Y, Wang L, Yan Z, Qiao Z, Han Z. Resveratrol blocks atherosclerosis development by inhibiting IL-1β in macrophages induced by cholesterol. Arch Biol Sci [Internet]. 2019Oct.23 [cited 2023Jan.27];71(3):551-9. Available from: