636 M. Guzmán
cannabinoids induce apoptosis of leukaemic and lymphoid cells in vitro and—as
mentioned above—in mouse models (McKallip et al. 2002a).
By contrast, some observations indicate that cannabinoids either stimulate or
inhibit the function of immune cells. This variation in drug effects may depend on
experimental factors such as drug concentration, timing of drug delivery, and type
of cell function examined. Thus, Derocq et al. (1995) showed for the first time that
human B cell proliferation is stimulated by cannabinoids at nanomolar concen-
trations. Likewise, Valk et al. (1997b) showed that murine haematopoietic growth
factor-dependent cell lines require the presence of anandamide for optimal growth
in serum-free medium. The endocannabinoid also enhanced the number and size
of interleukin 3-induced myeloid colonies from mouse bone marrow. Moreover,
following retroviral insertional mutagenesis these authors have identified a virus
integration site, namedEvi11, within the gene encoding the CB 2 receptor, suggest-
ing that CB 2 is a proto-oncogene involved in leukaemogenesis (Valk et al. 1997a).
This is also supported by the observation that, in certain murine leukaemia virus-
induced tumours, retroviral integrations occur in the CB 2 receptor gene (Valk et
al. 1999).
The possibility that the CB 2 receptor plays a role in the control of immune cell
fate is supported by studies on the gene expression profile of human promyelocytic
cells, which show that receptor activation up-regulates genes involved in the cell
differentiation program (Derocq et al. 2000). These data, together with reports of
CB 2 -induced blockade of neutrophilic differentiation (Alberich Jordà et al. 2003)
and changes in CB 2 receptor expression during the differentiation and activation
of human B cells (Carayon et al. 1998) point to an involvement of the CB 2 receptor
in the control of immune cell maturation.
4.2
Mechanism of Action
The transduction systems responsible for CB 2 receptor signalling are as yet unclear.
It has been traditionally assumed that inhibition of the cAMP pathway may be
responsible for the immunosuppressive action of cannabinoids (Kaminski 1998)
(Table 1). However, plant-derived and endogenous cannabinoids may behave as
partial agonists or even antagonists in the CB 2 receptor-mediated inhibition of
adenylylcyclase(Bayewitchetal. 1996). ItispossiblethereforethattheCB 2 receptor
controls immune cell proliferation by coupling positively (Derocq et al. 2000;
Alberich Jordà et al. 2003; Samson et al. 2003) or negatively (Faubert Kaplan
and Kaminski 2003) to ERK, a process that is dependent on Gi/oproteins but
independent of cAMP (Bouaboula et al. 1996). Activation of Akt and concomitant
phosphorylation of kinase targets have also been shown in mast cells (Samson et
al. 2003).