396 G.A. Cabral and A. Staab
of PMA/ionomycin-induced IL-2 protein secretion, which correlated to decreased
IL-2 gene transcription, was induced by both CBN and THC. Cannabinoid treat-
ment also decreased PMA/ionomycin-induced NF binding to the activator protein
(AP)-1 proximal site of the IL-2 promoter. These findings suggested that inhibi-
tion of signal transduction via the adenylate cyclase/cAMP pathway induces T cell
dysfunction by diminution in IL-2 gene transcription.
2.3.5
Effects on Natural Killer Cells
Kawakamietal.(1988)indicatedthatIL-2-inducedkillingactivityandproliferation
on NKB61A2 cells, a cell line derived from mouse that contains many morphologi-
cal and functional similarities to primary NK cells (Warner and Dennert 1982), was
suppressed by THC and 11-hydroxy-THC. Similarly, THC suppressed proliferation
of murine spleen cells stimulated with recombinant human IL-2 and the appear-
ance of the lymphokine-activated killer (LAK) cell phenomenon in IL-2-treated
spleen cells (Kawakami et al. 1988). In addition, spleen cells previously stimulated
in culture with IL-2, and then incubated with THC prior to target cell addition,
displayed suppressed cytolytic activity against both yeast artificial chromosome
(YAC)-1 and murine thymoma (EL)-4 tumor targets. These results suggested that
THC could suppress IL-2-linked functions, including clonal expansion of lympho-
cytes, expansion of killer cell populations, and stimulation of killer cell cytotoxic
activity. Additional studies have indicated that THC and other cannabinoids not
only suppress the killing activity of mouse NK cells but also those from humans
(Klein et al. 1998a, 1998b). The mechanism of this suppression was attributed as
due partly to a drug-induced decrease in the number of high- and intermediate-
affinity IL-2 binding sites, suggesting suppression in the expression of the IL-2
receptor (IL-2R) proteins (Zhu et al. 1993). Subsequent studies demonstrated that
THC increased cellular levels of IL-2Rαandβproteins but decreased levels of
theγ-protein and the function of the IL-2R (Zhu et al. 1995). It was concluded
that drug treatment disturbed the relative expression of the various IL-2R chains,
resulting in overall receptor dysfunction and poor responsiveness to IL-2. Daaka
et al. (1997) extended these studies using NKB61A2 NK-like cells, established
a link to cannabinoid receptors for these effects, and implicated involvement of
the transcription factor NF-κB. These investigators concluded that, in the NK-like
cell line used in the studies, a signaling pathway existed that was composed of
CB 1 ,NF-κB, and the IL-2Rαgene. Other immune cell models have been used to
demonstrate linkage of cannabinoid receptors to NF-κB-mediated gene activity
(Herring et al. 1998; Jeon et al. 1996). Massi et al. (2000) reported that in vivo
administration of THC to mice significantly inhibited NK cytolytic activity with-
out affecting ConA-induced splenocyte proliferation. The parallel measurement
of IFN-γrevealed that THC significantly reduced production of this cytokine, and
the CB 1 and CB 2 antagonists completely reversed this reduction. These results sug-
gested that both cannabinoid receptors were involved in the network mediating
NK cytolytic activity.