Resveratrol inhibits expression and binding activity of the monocyte chemotactic protein-1 receptor, CCR2, on THP-1 monocytes


      Monocyte chemotactic protein-1 and its receptor, CCR2, play a key role in atherosclerosis. We determined the effect of the polyphenol, resveratrol, on CCR2 and the mechanisms involved. Resveratrol treatment inhibited 125I-MCP-1 binding to THP-1 cells; 31, 56, 84% decrease for 10, 50 and 100 μM resveratrol, in the absence of any effect on receptor affinity. The inhibitory effect of resveratrol on 125I-MCP-1 binding to THP-1 cells and on CCR2 protein expression determined by FACS analysis was attenuated by treatment with L-NAME (NOS inhibitor), PD98059 (MAPK inhibitor) and LY294002 (PI3K inhibitor), whereas neither X/XO (reactive oxygen species generator) nor ICI182780 (estrogen receptor antagonist) had any effect. Concomitant with a decrease in CCR2 protein expression, resveratrol inhibited THP-1 CCR2 mRNA levels, in the absence of any effect on its stability; 26 and 45% inhibition at 10 and 50 μM resveratrol, respectively. This effect was not altered by co-treatment with L-NAME, PD98059 or ICI182780, but was potentiated by LY294002 and X/XO. Conclusions: Resveratrol inhibits monocyte CCR2 binding activity in an NO-, MAPK- and PI3K-dependent manner, whereas it inhibits CCR2 mRNA in an NO- and MAPK-independent, PI3K-dependent manner. These inhibitory effects of resveratrol on chemokine receptor binding and expression may contribute, in part, to its cardiovascular protective activity in vivo.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Klatsky A.L.
        • Armstrong M.A.
        • Friedman G.D.
        Alcohol and mortality.
        Ann Intern Med. 1992; 117: 646-654
        • Klatsky A.L.
        • Armstrong M.A.
        Alcoholic beverage choice and risk of coronary heart disease mortality: do red wine drinkers fair best?.
        Am J Cardiol. 1993; 71: 467-469
        • Demrow H.S.
        • Slane P.R.
        • Folts J.D.
        Administration of wine and grape juice inhibits in vivo platelet activity and thrombosis in stenosed canine coronary arteries.
        Circulation. 1995; 91: 1182-1188
        • Frankel E.N.
        • Kanner J.
        • German J.B.
        • Parks E.
        • Kinsella J.E.
        Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine.
        Lancet. 1993; 341: 454-457
        • Bavaresco L.
        • Fregoni C.
        • Cantu E.
        • Trevisan M.
        Stilbene compounds: from the grapevine to wine.
        Drug Exp Clin Res. 1999; 25: 57-63
        • Zou J.G.
        • Huang Y.Z.
        • Chen Q.
        • et al.
        Resveratrol inhibits copper ion-induced and azo compound-initiated oxidative modification of human low density lipoprotein.
        Biochem Mol Biol Int. 1999; 47: 1089-1096
        • Olas B.
        • Wachowicz B.
        • Saluk-Juszczak J.
        • Zielinski T.
        Effect of resveratrol, a natural polyphenolic compound, on platelet activation induced by endotoxin or thrombin.
        Thromb Res. 2002; 107: 141-145
        • Wallerath T.
        • Deckert G.
        • Ternes T.
        • et al.
        Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase.
        Circulation. 2002; 106: 1652-1658
        • Charo I.F.
        • Taubman M.B.
        Chemokines in the pathogenesis of vascular disease.
        Circ Res. 2004; 95: 858-866
        • Ono K.
        • Matsumori A.
        • Furukawa Y.
        • et al.
        Prevention of myocardial reperfusion injury in rats by an antibody against monocyte chemotactic and activating factor/monocyte chemoattractant protein-1.
        Lab Invest. 1999; 79: 195-203
        • Aukrust P.
        • Ueland T.
        • Muller F.
        • et al.
        Elevated circulating levels of C-C chemokines in congestive heart failure.
        Circulation. 1998; 97: 1136-1143
        • Boring L.
        • Gosling J.
        • Chensue S.W.
        • et al.
        Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice.
        J Clin Invest. 1997; 100: 2552-2561
        • Boring L.
        • Gosling J.
        • Cleary M.
        • Charo I.F.
        Decreased lesion formation in −/− mice reveals a role for chemokines in the initiation of atherosclerosis.
        Nature. 1998; 394: 894-897
        • Cullen J.P.
        • Sayeed S.
        • Jin Y.
        • et al.
        Ethanol inhibits monocyte chemotactic protein-1 expression in interleukin-1-β-activated human endothelial cells.
        Am J Physiol Heart Circ Physiol. 2005; 289: H1669-H1675
        • Yla-Herttuala S.
        • Lipton B.A.
        • Rosenfeld M.E.
        • et al.
        Expression of MCP-1in macrophage rich areas of human and rabbit atherosclerotic lesions.
        Proc Natl Acad Sci USA. 1991; 88: 5252-5256
        • Aiello R.J.
        • Bourassa P.A.
        • Lindsey S.
        • et al.
        Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein E-deficient mice.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1518-1525
        • Wang G.
        • O K.
        Homocysteine stimulates the expression of MCP-1 receptor (CCR2) in human monocytes: possible involvement of oxygen free radicals.
        Biochem J. 2001; 257: 233-240
        • Han K.H.
        • Chang M.K.
        • Boullier A.
        • et al.
        Oxidized LDL reduces monocyte CCR2 expression through pathways involving PPAR-gamma.
        J Clin Invest. 2000; 106: 793-802
        • Ishibashi M.
        • Hiasa K.-I.
        • Zhao Q.
        • et al.
        Critical role of monocyte chemoattractant protein-1 receptor CCR2 on monocytes in hypertension-induced vascular inflammation and remodeling.
        Circ Res. 2004; 94: 1203-1210
        • Hayasaki T.
        • Kaikita K.
        • Okuma T.
        • et al.
        CC chemokine receptor-2 deficiency attenuates oxidative stress and infarct size caused by myocardial ischemia-reperfusion in mice.
        Circ J. 2006; 70: 342-351
        • Furukawa Y.
        • Matsumori A.
        • Ohashi N.
        Anti-monocyte chemoattractant protein-1 monocyte chemotactic and activating factor antibody inhibits neointimal hyperplasia injured rat carotid arteries.
        Circ Res. 1999; : 306-314
        • Klinge C.M.
        • Blankenship K.A.
        • Risinger K.E.
        • et al.
        Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors α and β in endothelial cells.
        J Biol Chem. 2005; 280: 7460-7468
        • Bruder J.L.
        • Hsieh T.-C.
        • Lerea K.M.
        • Olson S.C.
        • Wu J.M.
        Induced cytoskeletal changes in bovine pulmonary artery endothelial cells by resveratrol and the accompanying modified responses to arterial shear stress.
        BMC Cell Biol. 2001; 2: 1
        • Liu J.C.
        • Chen J.J.
        • Chan P.
        • Cheng C.F.
        • Cheng T.H.
        Inhibition of cyclic strain-induced endothelin-1 gene expression by resveratrol.
        Hypertension. 2003; 42: 1198-1205
        • Chen C.K.
        • Pace-Asciak C.R.
        Vasorelaxing activity of resveratrol and quercetin in isolated rat aorta.
        Gen Pharmacol. 1996; 27: 363-366
        • Bandyopadhyay G.K.
        • Yu J.G.
        • Ofrecio J.
        • Olefsky J.M.
        Increased p85/55/50 expression and decreased phosphatidylinositol 3-kinase activity in insulin-resistant human skeletal muscle.
        Diabetes. 2005; 54: 2351-2359
        • Kobayashi T.
        • Matsumoto T.
        • Kamata K.
        The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models.
        J Smooth Muscle Res. 2005; 41: 283-302
        • Mine S.
        • Okada Y.
        • Tanikawa T.
        • et al.
        Increased expression levels of monocyte CCR2 and monocyte chemoattractant protein-1 in patients with diabetes mellitus.
        Biochem Biophys Res Commun. 2006; 344: 780-785
        • Wong M.M.
        • Fish E.N.
        Chemokines: attractive mediators of the immune response.
        Semin Immunol. 2003; 15: 5-14
        • Turner S.J.
        • Domin J.
        • Waterfield M.D.
        • Ward S.G.
        • Westwick J.
        The CC chemokine MCP-1 activates both the class 1p85/p110 phosphatidylinositol 3-kinase and the class II P13K-C2alpha.
        J Biol Chem. 1998; 273: 25987-25995
        • Norata G.D.
        • Marchesi P.
        • Passamonti S.
        • et al.
        Anti-inflammatory and anti-atherogenic effects of cathechin, caffeic acid and trans-resveratrol in apolipoprotein E deficient mice.
        Atherosclerosis. 2006; ([Epub ahead of print])
        • Basly J.-P.
        • Marre-Fournier F.
        • Le Bail J.-C.
        • Habrioux G.
        • Chulia A.J.
        Estrogenic/antiestrogenic and scavenging properties of (E)- and (Z)-resveratrol.
        Life Sci. 2000; 9: 769-777
        • Okada M.
        • Suzuki A.
        • Mizuno K.
        • et al.
        Effects of 17β-estradiol and progesterone on migration of human monocytic THP-1 cells stimulated by minimally oxidized low-density lipoprotein in vitro.
        Cardiovasc Res. 1997; 34: 529-535
        • Leonard S.S.
        • Xia C.
        • Jiang B.-H.
        • et al.
        Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses.
        Biochem Biophys Res Commun. 2003; 309: 1017-1026
        • Saccani A.
        • Saccani S.
        • Orlando S.
        • et al.
        Redox regulation of chemokine receptor expression.
        Proc Natl Acad Sci USA. 2000; 97: 2761-2766
        • Goldberg D.M.
        • Yan J.
        • Soleas G.J.
        Absorption of three wine-related polyphenols in three different matrices by healthy subjects.
        Clin Biochem. 2003; 36: 79-87
        • Cullen J.P.
        • Morrow D.
        • Jin Y.
        • et al.
        Resveratrol, a polyphenolic phytostilbene, inhibits endothelial MCP-1 synthesis and secretion.
        J Vasc Res. 2007; 44: 75-84