392 G.A. Cabral and A. Staab
al. (1992) indicated that THC suppressed IL-2 and IL-2 receptor expression. The
Tcellmitogen,anti-CD3,producedtheoppositeeffectwhencombinedwithTHC
in that it increased proliferation and the IL-2 response. This modulation pattern
for IL-2 by THC after stimulation of murine spleen cells with ConA, PHA, or
anti-CD3 antibody was reproduced and extended by Nakano et al. (1992). It was
shown that the THC-related modulation of IL-2 activity corresponded not only to
changes in blastogenic activity, but also to variations in numbers of Tac-positive
cells. Collectively, these studies indicated that THC could exert differential effects
on spleen cell populations dependent upon the stimulators used.
2.3.2
Effects on Mononuclear Cells, Macrophages, and Macrophage-Like Cells
THC and other cannabinoids have been shown to suppress macrophage functions
such as phagocytosis, bactericidal activity, and spreading (Friedman et al. 1991;
Klein and Friedman 1990). Sacerdote et al. (2000) reported that in vivo and in
vitro treatment with CP 55,940 decreased the in vitro migration of macrophages
intheratandthatthiseffectinvolvedbothCB 1 and CB 2 receptors. THC also
has been reported to alter the gene expression, processing, and secretion of an
array of macrophage pro-inflammatory and anti-inflammatory factors. Zheng et
al. (1992) indicated that THC caused a significant decrease in tumor necrosis factor
(TNF)-αproduction by BALB/c mouse peritoneal macrophages in response to LPS
and IFN-γ. A similar set of responses was obtained for human peripheral blood
lymphocyte (PBL) adherent cells treated with THC. Fisher-Stenger et al. (1993)
also examined the effects of THC on TNF-αproduction by murine RAW264.7
macrophage-like cells and reported that it affected TNF-αproduction by altering
its conversion from a 26-kDa presecretory form to the 17-kDa secretory product.
THC also has been reported to alter the expression of other cytokines. Klein
and Friedman (1990) indicated that IL-1 activity increased in supernatants of
mouse macrophage cultures treated with LPS and THC. Studies to assess for its
intracellular fate in relation to drug treatment indicated that the THC-induced
higher levels in supernatants were due to an increase, and prolongation, of release
of the promature IL-1αand mature IL-1βforms. The processing and release of
IL-1 in macrophages appeared to be due partly to increased activity of the IL-
1 converting enzyme (i.e., caspase), since THC had been shown to induce an
augmentation in caspase activity and other markers of apoptosis (Zhu et al. 1998).
Burnette-Curley and Cabral (1995) reported that THC was able to inhibit
macrophage-like cell contact-dependent cytolysis of tumor cells and that this
inhibition was effected by selective targeting of TNF-dependent pathways versus
l-arginine-dependent reactive nitrogen intermediates. In addition, the effect of the
enantiomeric pairs (–)CP 55,940/(+)CP 56,667 or HU-210/HU-211 on macrophage
cell contact-dependent killing was assessed. Inhibition of macrophage tumorici-
dal activity against TNF-sensitive murine L929 cells was effected by both isomers
of THC analogs. Coffey et al. (1996) confirmed and extended these studies using
mouse peritoneal macrophages. They indicated that an early step in NO produc-