Cardiovascular Research Advance Access first published online on July 11, 2009
This version [Corrected Proof] published online on September 25, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp240
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CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages
1 Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-2-dong Songpa-gu, 138-736 Seoul, Republic of Korea
2 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
* Corresponding author. Tel: +82 2 3010 3150; fax: +82 2 486 5918. E-mail address: steadyhan{at}amc.seoul.kr
Aims: We investigated the mechanism by which cannabinoid receptors-1 (CB1) and -2 (CB2) modulate inflammatory activities of macrophages.
Methods and results: Real-time polymerase chain reaction showed the predominant CB2 expression in freshly isolated human monocytes. PMA, a potent inducer of differentiation, upregulated CB1 and increased CB1:CB2 transcript ratio from 1:17.5 to 1:3 in 5 days of culture. Immunohistochemistry showed that CB1 protein was colocalized in CD68- and CD36-positive macrophages in human atheroma. Through selective expression of CB1 or CB2 to thioglycollate-elicited peritoneal macrophages, we proved that CB1 and CB2 mediate opposing influences on the production of reactive oxygen species (ROS). Flow cytometry showed that cannabinoid-induced ROS production by macrophages was CB1-dependent. Immunoblotting assays confirmed that macrophage CB1, not CB2, induced phosphorylation of p38-mitogen-activated protein kinase, which modulated ROS production and the subsequent synthesis of tumour necrosis factor-
and monocyte chemoattractant protein-1. Pull-down assays showed that the Ras family small G protein, Rap1 was activated by CB2. Dominant-negative Rap1 profoundly enhanced CB1-dependent ROS production by macrophages, suggesting CB2 Rap1-dependently inhibits CB1-stimulated ROS production.
Conclusion: CB1 promotes pro-inflammatory responses of macrophages through ROS production, which is negatively regulated by CB2 through Rap1 activation. Blocking CB1 together with selective activation of CB2 may suppress pro-inflammatory responses of macrophages.
KEYWORDS CB1 receptor; CB2 receptor; Macrophages; Reactive oxygen species (ROS); Cytokines; Rap1
Time for primary review: 23 days
The original version was incorrect. Author details of reference 11 have been corrected.
K.H.H. and S.L. contributed equally to the work as first authors.
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Cardiovasc Res 2009 84: 341-342.
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