Abstract
Cannabinoids are known to exert immunosuppressive activities. However, the mechanisms which contribute to these effects are unknown. Using lipopolysaccharide (LPS) to activate BV-2 microglial cells, we examined how Δ9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, and cannabidiol (CBD) the non-psychoactive component, modulate the inflammatory response. Microarray analysis of genome-wide mRNA levels was performed using Illumina platform and the resulting expression patterns analyzed using the Ingenuity Pathway Analysis to identify functional subsets of genes, and the Ingenuity System Database to denote the gene networks regulated by CBD and THC. From the 5338 transcripts that were differentially expressed across treatments, 400 transcripts were found to be upregulated by LPS, 502 by CBD+LPS and 424 by THC+LPS, while 145 were downregulated by LPS, 297 by CBD+LPS and 149 by THC+LPS, by 2-fold or more (p≤0.005). Results clearly link the effects of CBD and THC to inflammatory signaling pathways and identify new cannabinoid targets in the MAPK pathway (Dusp1, Dusp8, Dusp2), cell cycle related (Cdkn2b, Gadd45a) as well as JAK/STAT regulatory molecules (Socs3, Cish, Stat1). The impact of CBD on LPS-stimulated gene expression was greater than that of THC. We attribute this difference to the fact that CBD highly upregulated several genes encoding negative regulators of both NFκB and AP-1 transcriptional activities, such as Trib3 and Dusp1 known to be modulated through Nrf2 activation. The CBD-specific expression profile reflected changes associated with oxidative stress and glutathione depletion via Trib3 and expression of ATF4 target genes. Furthermore, the CBD affected genes were shown to be controlled by nuclear factors usually involved in regulation of stress response and inflammation, mainly via Nrf2/Hmox1 axis and the Nrf2/ATF4-Trib3 pathway. These observations indicate that CBD, and less so THC, induce a cellular stress response and that this response underlies their high immunosuppressant activities.
Highlights
Cannabis sativa extracts have been used for centuries both as therapeutic agents and recreational drugs, primarily due to their ability to regulate neurobehavioral processes including memory, mood and appetite [1,2]
We reported that CBD reduces the activity of the NF-kB pathway and upregulates the activation of STAT3 transcription factor in LPSstimulated BV-2 cells, and that both CBD and THC decrease the activation of the LPS-induced STAT1 transcription factor, a key player in IFNb-dependent pro-inflammatory processes [11]
Our current results show that CBD downregulates the mRNA expressions of the LPS-upregulated CD69 antigen (Cd69) antigen and of matrix metalloproteinase13 (Mmp13) suggesting a possible mechanism for the therapeutic activity of CBD in the murine collagen-induced arthritis (CIA) model
Summary
Cannabis sativa extracts (marijuana and hashish) have been used for centuries both as therapeutic agents and recreational drugs, primarily due to their ability to regulate neurobehavioral processes including memory, mood and appetite [1,2]. The spectra of possible therapeutic uses of marijuana and its active constituents, the cannabinoids, range from handling nausea, vomiting and cachexia (in cancer chemotherapy and AIDS patients) to treatment of chronic pain, glaucoma, epileptic seizures, Parkinsonian tremor as well as multiple sclerosis [1,2,3,4,5,6]. Many of the beneficial effects of cannabinoids have been attributed to their potent immunosuppressive and anti-inflammatory properties [7,8,9,10,11,12,13,14]. The CB1 receptor is highly expressed in neural cells and mediates the psychoactive and addictive activities of cannabinoids, while the CB2 receptor is abundantly present in the periphery including the immune system and is involved in cannabinoid immunomodulation [18,19,20]. THC binds to both of these receptors with similar efficiency [21] and has been reported to have effects on both the nervous and the immune systems [7,11,18,22]
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