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Cannabinoid Receptors CB1 and CB2: A Characterization of Expression and Adenylate Cyclase Modulation within the Immune System

https://doi.org/10.1006/taap.1996.8034Get rights and content

Abstract

Cannabinoid receptor (CB) expression was characterized in immunological cell and tissue preparations. Northern analysis revealed ∼6-kb transcripts for CB1 (brain-type) in mouse spleen and brain and in rat cerebellum. CB1 was not detected in mouse thymus or rat spleen RNA by Northern analysis. CB2 (peripheral) was detected as a ∼4-kb transcript in mouse spleen and thymus and as ∼2.4-kb transcripts in rat spleen. Quantitation of CB2 transcripts in mouse spleen and thymus revealed ∼4 × 103and ∼4 × 102molecules/100 ng RNA, respectively, with no quantifiable CB2 in mouse brain. Conversely, CB1 was expressed in mouse brain (∼2 × 105molecules/100 ng RNA) with lower expression in mouse spleen (∼2 × 102molecules/100 ng RNA) and was not quantifiable in mouse thymus. Competition binding in intact mouse splenocytes demonstrated that nonradiolabeled cannabinoids CP-55940, Win-55212-2, CP-56667, Δ9-THC, and cannabinol all competed for receptor binding with3H-CP-55940, a high-affinity nondiscriminating CB1 and CB2 receptor ligand. Based on previous findings which demonstrated a marked inhibition of T-cell-dependent immune responses by cannabinoids, primary T cells and several T-cell lines were characterized. Radioligand binding analysis identified 100–300 cannabinoid receptor binding sites/cell with an approximateKdof 200–700 pmin purified splenic T cells which also exhibited cannabinoid-induced inhibition of adenylate cyclase. Northern analysis of human T-cell lines revealed ∼2.4-kb CB2 mRNA transcripts but no CB1 in HPB-ALL cells, a cell line which also exhibited inhibition of adenylate cyclase by Δ9-THC. Conversely, Jurkat E6-1 cells expressed an unusual mRNA banding pattern for CB2 expressing three distinct transcript sizes, none of which were 2.4 kb, the size for human CB2. Jurkat also did not express CB1 mRNA and did not exhibit inhibition of adenylate cyclase when treated with Δ9-THC. Collectively, these results provide further evidence that CB2 is the predominant cannabinoid receptor within the immune system and that this form of the receptor is expressed on T cells.

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    Neuronal CB1R are known to mediate the ‘cannabimimetic’ behavioral effects of cannabinoids, including acute antinociception, decreased locomotion, catalepsy, as well as hypothermia, (Little et al., 1988; Ledent et al., 1999; Grim et al., 2016) and CB1R agonism is also associated with activation of anti-inflammatory mechanisms (Richardson et al., 1998; Borner et al., 2009; Newton et al., 2009). CB2 receptors (CB2R) are located on immune cells (Carayon et al., 1998; Galiegue et al., 1995; Munro et al., 1993; Schatz et al., 1997) and on a few discrete adult neuronal populations (Onaivi et al., 2008) within the brainstem (Van Sickle et al., 2005), the hippocampus (Stempel et al., 2016), as well as on neural stem and progenitor cells (Jiang et al., 2007; Molina-Holgado et al., 2007). CB2R agonists produce anti-inflammatory signaling cascades without the cannabimimetic-like effects often seen with CB1R agonists (Rahn et al., 2011).

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This work was supported by funds from NIDA Grants DA07908 and DA09171 and NIEHS Training Grant ES07087.

2

Current address: Abbott Laboratories, D38A, AP-51, 200 Abbott Park Road, Abbott Park, IL 60064-3537.

3

Department of Life Sciences, Korea Advanced Institute of Science and Technology, Taejon, Korea.

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