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CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages.
Cardiovasc Res. 2009 Dec 01; 84(3):378-86.CR

Abstract

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-alpha 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.

Authors+Show Affiliations

Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea. steadyhan@amc.seoul.krNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19596672

Citation

Han, Ki Hoon, et al. "CB1 and CB2 Cannabinoid Receptors Differentially Regulate the Production of Reactive Oxygen Species By Macrophages." Cardiovascular Research, vol. 84, no. 3, 2009, pp. 378-86.
Han KH, Lim S, Ryu J, et al. CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages. Cardiovasc Res. 2009;84(3):378-86.
Han, K. H., Lim, S., Ryu, J., Lee, C. W., Kim, Y., Kang, J. H., Kang, S. S., Ahn, Y. K., Park, C. S., & Kim, J. J. (2009). CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages. Cardiovascular Research, 84(3), 378-86. https://doi.org/10.1093/cvr/cvp240
Han KH, et al. CB1 and CB2 Cannabinoid Receptors Differentially Regulate the Production of Reactive Oxygen Species By Macrophages. Cardiovasc Res. 2009 Dec 1;84(3):378-86. PubMed PMID: 19596672.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages. AU - Han,Ki Hoon, AU - Lim,Sunny, AU - Ryu,Jewon, AU - Lee,Cheol-Whan, AU - Kim,Yuna, AU - Kang,Ju-Hee, AU - Kang,Soon-Suk, AU - Ahn,Yeong Ki, AU - Park,Chan-Sik, AU - Kim,Jae Joong, Y1 - 2009/07/11/ PY - 2009/7/15/entrez PY - 2009/7/15/pubmed PY - 2010/2/25/medline SP - 378 EP - 86 JF - Cardiovascular research JO - Cardiovasc Res VL - 84 IS - 3 N2 - 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-alpha 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. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/19596672/CB1_and_CB2_cannabinoid_receptors_differentially_regulate_the_production_of_reactive_oxygen_species_by_macrophages_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1093/cvr/cvp240 DB - PRIME DP - Unbound Medicine ER -