398 G.A. Cabral and A. Staab
ciency (SCID) mice. Levels of the immune inhibitory T helper (Th) 2 cytokines
IL-10 and transforming growth factor (TGF) were augmented while those of the
immune stimulatory Th 1 cytokine IFN-γwere down-regulated at both the tu-
mor site and in spleens of THC-treated mice. Administration of either anti-IL-
10 or anti-TGF-βneutralizing antibodies prevented the THC-induced enhance-
ment in tumor growth. In vivo administration of the CB 2 antagonist SR144528
blocked the effects of THC. These findings suggested that THC promoted tumor
growth by inhibiting anti-tumor immunity by a CB 2 receptor-mediated, cytokine-
dependent pathway. Furthermore, this cytokine-dependent pathway correlated
withashiftinaTh 1 pro-inflammatory to a Th 2 anti-inflammatory cytokine pro-
file.
Berdyshev et al. (1997) examined the effects of anandamide, palmitoylethanol-
amide and THC on the production of TNF-α, IL-4, IL-6, IL-8, IL-10, IFN-γ, p55,
and p75 TNF-αsoluble receptors expressed by stimulated human peripheral blood
mononuclear cells as well as [^3 H]-arachidonic acid release by non-stimulated
andN-formyl-Met-Leu-Phe (fMLP)-stimulated human monocytes. Anandamide
diminished IL-6 and IL-8 production at low nanomolar concentrations and in-
hibited the production of TNF-α,IFN-γ, IL-4, and p75 TNF-αsoluble receptors
at higher concentrations (i.e., micromolar levels). Palmitoylethanolamide inhib-
ited IL-4, IL-6, and IL-8 synthesis and the production of p75 TNF-αsoluble
receptors at concentrations similar to those of anandamide but did not affect
TNF-αand IFN-γproduction. Neither anandamide nor palmitoylethanolamide
influenced IL-10 synthesis. THC, on the other hand, exerted a biphasic effect
on pro-inflammatory cytokine production. TNF-α,IL-6,andIL-8synthesiswas
inhibited maximally by 3 nM THC but stimulated by 3μMTHC.Asimilaref-
fect was observed for IL-8 and IFN-γ. The level of IL-4, IL-10, and p75 TNF-α
soluble receptors was diminished by 3μMTHC.[^3 H]-Arachidonate release was
stimulated only by high THC and anandamide concentrations. Based on these
observations, the investigators suggested that the inhibitory properties of anan-
damide, palmitoylethanolamide, and THC are determined by the activation of
peripheral-type cannabinoid receptors (i.e., CB 2 ) and that various endogenous
fatty acid ethanolamides also participate in the regulation of the immune re-
sponse.
Molena-Holgado et al. (1998) assessed the effects of cannabinoids in the context
of a Theiler’s murine encephalomyelitis virus (TMEV) infectivity model. In this
model, murine cortical astrocyte cultures produce robust levels of IL-6 following
infection in vitro. Treatment of cultures with anandamide resulted in increased
production of IL-6. Cannabinoid receptors were implicated in these events because
the enhancing effect was attenuated by the CB 1 antagonist SR141716A. Since it
has been suggested that IL-6 may have a palliative effect in CNS diseases such
as multiple sclerosis (MS), the investigators speculated that the increased levels
of this cytokine could be related to a protective effect of cannabinoids in such
diseases.