394 G.A. Cabral and A. Staab
2.3.3
Effects on B Lymphocytes
B lymphocytes have been reported to express relatively high levels of the CB 2
receptor (Carayon et al. 1998; Galiègue et al. 1995; Lynn and Herkenham 1994).
Thus, it is not surprising that cannabinoid agonists should exert major effects on
their functional activities. Klein et al. (1985) noted that addition of THC to mouse
splenocyte cultures suppressed not only T lymphocyte proliferation in response to
the mitogens ConA and PHA, but also that of B lymphocytes induced by LPS, a B
cell mitogen. The hydroxylated metabolite of THC, 11-hydroxy-THC, was observed
to be much less potent in this inhibition.
Additional reports have confirmed that cannabinoids suppress the antibody
response of humans and animals (Friedman et al. 1991; Klein et al. 1998a). Kamin-
ski et al. (1994) reported that suppression of the humoral immune response by
cannabinoids was mediated, at least in part, through the inhibition of adenylate
cyclase by a pertussis toxin-sensitive G protein-coupled mechanism. THC and
CP 55,940 inhibited murine splenocyte proliferative responses to phorbol myris-
tate acetate (PMA) plus ionomycin. The SRBC IgM antibody-forming cell (AFC)
response was abrogated by low concentrations of dibutyryl-cAMP. Inhibition of
the SRBC AFC response by both THC and CP 55,940 also was abrogated when
splenocytes were preincubated with pertussis toxin that also was found to directly
abrogate cannabinoid inhibition of adenylate cyclase. Collectively, the results sug-
gested that inhibition of the SRBC AFC response by cannabinoids was mediated, at
least in part, by inhibition of adenylate cyclase through a pertussis toxin-sensitive
Giprotein-coupled cannabinoid receptor.
On the other hand, Derocq et al. (1995) reported that cannabinoids at low
nanomolar concentrations had an enhancing effect on human tonsillar B cell
growth. The cannabinoids CP 55,940 and WIN 55,212-2, as well as THC, exerted
a dose-dependent increase of B cell proliferation for which the EC 50 was at low
nanomolar concentrations. The cannabinoid-induced enhancing activity was in-
hibited by pertussis toxin, suggesting a functional linkage to a G protein-coupled
receptor. The CB 1 specific antagonist SR141716A had no antagonistic effect on
this augmentation. These results, together with the demonstration that human B
cells displayed large amounts of CB 2 mRNA, led the investigators to propose that
the growth-enhancing activity observed on B cells at very low concentrations of
cannabinoids was mediated through the CB 2 receptor.Carayon et al. (1998) re-
ported that the CB 2 receptor was down-regulated at the mRNA and protein levels
during B cell differentiation. Lowest levels of expression were observed in germinal
center proliferating centroblasts of tonsillar tissue. The potent cannabinoid ago-
nist CP 55,940 enhanced CD40-mediated proliferation of both virgin and germinal
center B cell subsets. This enhanced proliferation could be blocked by the CB 2 an-
tagonist SR144528 but not by the CB 1 antagonist SR141716A. These observations,
taken together with the observation that SR144528 antagonized the stimulating
effects of CP 55,940 on human tonsillar B cell activation evoked by cross-linking
of surface immunoglobulins (Rinaldi-Carmona et al. 1998) suggested a functional
involvement of CB 2 receptors during B cell differentiation.