Abstract
Macrophages and macrophage-like cells are important targets of HIV-1 infection at peripheral sites and in the central nervous system. After infection, these cells secrete a plethora of toxic factors, including the viral regulatory trans-activating protein (Tat). This protein is highly immunogenic and also serves as a potent chemoattractant for monocytes. In the present study, the exogenous cannabinoids δ-9-tetrahydrocannabinol (THC) and (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP55940) were shown to significantly inhibit migration of human U937 macrophage-like cells to the Tat protein in a concentration-related manner. The CB1 receptor-selective agonist N-(2-chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (ACEA) had no effect on Tat-mediated migration. In contrast, the CB2 receptor-selective agonist (1R,3R)-1-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-3-methylcyclohexanol (O-2137) exerted a concentration-related inhibition of U937 cell migration in response to Tat. Pharmacological blockage of CB1 receptor signaling using the antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide hydrochloride (SR141716A) had no effect on CP55940-mediated inhibition of macrophage migration to Tat, whereas treatment with the CB2 receptor antagonist (1S-endo)-5-(4-chloro-3-methylphenyl)-1-((4-methylphenyl)methyl)-N-(1,3,3-trimethylbicyclo(2.2.1)hept-2-yl)-1H-pyrazole-3-carboxamide (SR144528) reversed the CP55940-mediated inhibition of migration. In addition, THC had no inhibitory effect on U937 migration to Tat after small interfering RNA knockdown of the CB2 receptor. Collectively, the pharmacological and biochemical knockdown data indicate that cannabinoid-mediated modulation of macrophage migration to the HIV-1 Tat protein is linked to the CB2 cannabinoid receptor. Furthermore, these results suggest that the CB2 cannabinoid receptor has potential to serve as a therapeutic target for ablation of HIV-1-associated untoward inflammatory response.
Footnotes
- Received October 27, 2009.
- Accepted January 19, 2010.
This work was supported in part by the National Institutes of Health National Institute on Drug Abuse [Grant DA005832].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.163055.
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ABBREVIATIONS:
- Tat
- trans-activating protein
- Gp120
- HIV glycoprotein 120
- CNS
- central nervous system
- HAD
- HIV-associated dementia
- CCR5
- CC chemokine receptor 5
- THC
- δ-9-tetrahydrocannabinol
- CP55940
- (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol
- O-2137
- (1R,3R)-1-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-3-methylcyclohexanol
- ACEA
- N-(2-chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide
- SR141716A/SR1
- 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide hydrochloride
- SR144528/SR2
- (1S-endo)-5-(4-chloro-3-methylphenyl)-1-((4-methylphenyl)methyl)-N-(1,3,3-trimethylbicyclo(2.2.1)hept-2-yl)-1H-pyrazole-3-carboxamide
- PBS
- phosphate-buffered saline
- siRNA
- small interfering RNA
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- bp
- base pair
- MCP
- monocyte chemoattractant protein
- CCL2
- CC chemokine ligand 2
- CXCR4
- CXC chemokine receptor 4
- VEGFR
- vascular endothelial growth factor receptor
- JWH-015
- (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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