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 microM 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 microM 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.
Cullen
John P
JP
Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, United States.
Morrow
David
D
Jin
Ying
Y
von Offenberg Sweeney
Nicholas
N
Sitzmann
James V
JV
Cahill
Paul A
PA
Redmond
Eileen M
EM
D002460:Cell Line; D002469:Cell Separation; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007700:Kinetics; D009000:Monocytes / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D054390:Receptors, CCR2 / Q000096:biosynthesis*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
D002867:Chromones; D005419:Flavonoids; D009025:Morpholines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D054390:Receptors, CCR2; D013267:Stilbenes; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000077185:Resveratrol; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D019331:NG-Nitroarginine Methyl Ester