Effects on the Immune System 3972.4
Effects on Cytokines
A mode by which cannabinoids may exert their multiplicity of effects may be
through the modulation of the expression of chemokines and cytokines which
cross-signal among immune cells and play a critical role in pro-inflammatory ver-
sus anti-inflammatory activities. Blanchard et al. (1986) and Cabral et al. (1986a)
reported that induction of IFN-α/βwas suppressed by chronic treatment of mice
with THC. Watzl et al. (1991) indicated that cytokine activity also was modu-
lated in human peripheral blood mononuclear cell cultures by THC. However, the
non-psychoactive CBD also modulated cytokine production and/or secretion, sug-
gesting that a non-cannabinoid receptor-mediated mode of action could also be
involved. The investigators indicated that a possible explanation for the capacity of
cannabinoids to act through cannabinoid receptors so as to exert a broad spectrum
of immune function effects was that exposure to these compounds resulted in the
expression of a differential profile of cytokines.
Srivastava et al. (1998) examined the effect of THC and CBD on cytokine pro-
duction in vitro by human leukemic T, B, eosinophilic, and CD8+natural killer
lines. THC was found to decrease the constitutive production of IL-8, macrophage
inflammatory protein (MIP)-1α,MIP-1β, and RANTES (regulated upon acti-
vation normal T cell expressed and secreted) protein. Phorbol ester-stimulated
production of TNF-α, granulocyte-macrophage colony-stimulating factor (GM-
CSF), and IFN-γproduced by NK cells also was affected. These results indicated
that THC and CBD could alter production of a multiplicity of cytokines across
a diverse array of immune cell lineages. Smith et al. (2000) evaluated the effects
of cannabinoid receptor agonists and antagonists on the production of inflamma-
tory cytokines and the anti-inflammatory cytokine IL-10 in endotoxemic mice.
WIN 55,212-2 and HU-210 decreased serum levels of TNF-αand IL-12 and in-
creased those for IL-10 when administered to mice before LPS exposure. The
cannabinoids also protectedC.parvummice (but not unprimed mice) against
the lethal effects of LPS. The protection afforded toC. parvum could not be
attributed to the higher levels of IL-10 present in the mice after agonist treat-
ment. The WIN 55,212-2- and HU-210-mediated changes in the responsiveness
of mice to LPS were antagonized by SR141716A, the CB 1 antagonist, but not
by SR144528, the CB 2 antagonist. It was concluded that both cannabinoid ago-
nists modulated LPS responses through the CB 1 receptor. It was noted, also, that
SR141716A itself modulated cytokine responses in a manner identical with that
of WIN 55,212-2 and HU-210. The agonist-like effects of SR141716A were more
striking in unprimed mice, suggesting that the antagonist could also function
as a partial agonist at the CB 1 receptor. Zhu et al. (2000) reported that THC in-
hibited anti-tumor immunity by a CB 2 receptor-mediated, cytokine-dependent
pathway. In their studies they used two different weakly immunogenic murine
lung cancer models. THC decreased tumor immunogenicity, as indicated by the
limited capacity for tumor-immunized, THC-treated mice to withstand tumor
rechallenge. However, in contrast to the findings in immunocompetent mice, THC
did not affect tumor growth in tumor-bearing severe combined immunodefi-