Cannabinoids and the immune system: An overview
Introduction
Cannabinoids, the biologically active constituents of marijuana, have been used for thousands of years for their psychoactive properties. The potential for marijuana to be both a therapeutic for a variety of conditions and a drug of abuse generated major efforts in order to clarify the biology and physiological role of cannabinoids in humans.
The marijuana plant contains more than 60 distinct chemical cannabinoids. Among them, D9-tetrahydrocannabinol (D9-THC) is the main psychoactive constituent, first structurally described in 1964 (Gaoni and Mechoulam, 1964) and giving the name for this class of compounds. In 1992, the first endogenous cannabinoid was isolated from porcine brain and identified as arachidonyl ethanolamide (anandamide; from the Sanskrit for “internal bliss”) (Devane et al., 1992). A second endocannabinoid was later identified (2-arachidonoyl glycerol) (Howlett et al., 2002). Since then, several synthetic cannabinoid analogues have been proven to induce similar in vivo effects such as analgesia and behavioral changes.
The study of the mechanism of action of cannabinoids led to the identification of a novel system of intercellular signaling, the endocannabinoid system. This system consists of endogenous ligands and receptors being subject to modulation by natural and synthetic cannabinoid agonists, and plays important modulatory functions in the brain and also in the periphery (Klein et al., 2003). The endocannabinoid system has been conserved during evolution. Binding sites with stereoselectivity were demonstrated in invertebrate microglia and immune cells (Salzet et al., 2000).
CB1R receptor is the most abundant G-protein-coupled receptor (GPCR) within the adult nervous system (Howlett et al., 2002). CB1R is localized to a number of functional brain structures, regulates synaptic neurotransmission and thus mediates psychoactive effects, and also providing a target for the use of cannabinoids as therapeutic agents for a number of neurological disorders (Croxford, 2003). CB2R receptor was described in 1993. It is not thought to be involved in psychoactive effects of cannabinoids and was initially found in the periphery, particularly in immune cells (mainly B cells and macrophages), but seems also to play a critical immune role in the CNS (Munro et al., 1993; Cabral et al., 2008).
The immunomodulatory and anti-inflammatory effects of cannabinoids are not fully elucidated. These effects have been reviewed over the years (Hollister, 1986; Cabral and Dove Pettit, 1998; Klein et al., 1998; Berdyshev et al., 2001; Roth et al., 2002; Croxford and Yamamura, 2005; Massi et al., 2006). Here, we review some aspects of the immune mechanisms affected by cannabinoids and, in this light, the therapeutic potential of these drugs in the treatment of immune diseases.
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Cannabinoid receptors
The two main subtypes of cannabinoid receptors (CBR) classically described (CB1R and CB2R) are single polypeptides with an extracellular N-terminus, an intracellular C-terminus and seven transmembrane helices. Both activate G proteins (Gi proteins) inhibitory to adenylate cyclase (AC) thus inhibiting the conversion of ATP to cyclic AMP (cAMP) (Howlett and Mukhopadhyay, 2000). However, they can also activate AC through stimulating G proteins (Gs proteins) (Glass and Northup, 1999), and both are
The cannabinoid receptor-associated signal transduction and the immune system
CBR stimulation is implicated in the regulation of DNA binding of different nuclear factors in the immune cells (Massi et al., 2006). These effects are mainly achieved via down-regulation of cAMP formation and signal transduction involving AC (Koh et al., 1995). Rapid and transient bursts in AC activity are associated with preceding lymphocyte activation by mitogens, and cytokine transcription in macrophages is regulated via cAMP signaling cascade (Kaminski et al., 1994). cAMP analogues
Cannabinoid-based analogues and ligands
There are two main groups of cannabinoid ligands, with varying affinities for actually described receptors. The first group is based on the structure of marijuana cannabinoids and includes natural compounds [D9-THC, D8-THC, cannabichromen (CBC), cannabigerol (CBG) and tetrahydrocannabivarin (D9-THCV) – all psychoactive, cannabinol and cannabidiol – both without psychoactive proprieties] and synthetic ligands [CP55940, HU-210, HU-211, ab-cannabidiol, ajulemic acid].
The main representative
Cannabinoid receptor expression by immune cells
Expression levels seem to be correlated with the cell activation status and activating stimuli (Croxford and Yamamura, 2005). Mitogen stimulation decreases CB1R expression in T cells but produces the inverse effect in B cells (Noe et al., 2000). The human Jurkat T-cell line and mouse macrophages express more CB1R when they are activated (Daaka et al., 1996; Klein et al., 1998) and splenocyte CB2R mRNA is less abundantly expressed after LPS-stimulation and more expressed after anti-CD40
Cannabinoid effects on cellular immunity
Since 1970, when the first studies on marijuana smoking effects on immune cells were reported, the effects of cannabinoids on immune function have been extensively studied.
T cells: Cannabinoids can influence T cell immunity in various manners: they can affect T cell number and proliferation, but may also have important effects on T helper 1- and 2-specific cytokines and TGF-β secretion (Croxford and Yamamura, 2005).
Initial studies done on T cells from blood of marijuana smokers showed
Cannabinoid effects on B cells and humoral immunity
Cannabinoid compounds may affect B cells number, proliferation, migration, Ig production or isotype switching (Croxford and Yamamura, 2005). In mice, 2-AG preferentially attracts unstimulated naive B cells, thus probably influencing the structure of B cell compartments in secondary lymphoid tissues (Tanikawa et al., 2007). B cells, IgG and IgM, and some complement proteins are decreased in bhang users (El-Gohary and Eid, 2004) and antibody production in smokers’ blood is differentially
Therapeutic implications
The immune effects of cannabinoids and endocannabinoid system provide promising therapeutic implications in a variety of conditions.
Multiple sclerosis: Used for symptom control such as spasticity and pain in MS patients (discussed further in this special issue, see Rog et al., 2005; Consroe et al., 1997; Notcutt et al., 2004; Pertwee, 2002; Zajicek et al., 2003; Rog et al., 2005; Wade et al., 2004), cannabinoid agonists can exert both immunomodulatory and neuroprotective effects. In study
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