3.0 Cannabinoid receptor signaling and acute inflammation
In keeping inflammatory responses to tissue injury in check and
preventing it from going awry, activated immune cells produce and
release anti-inflammatory mediators in addition to the pro-inflammatory
cytokines produced in response to tissue damage. A classic example is
the release of the anti-inflammatory, IL-10, which is, in part,
regulated by the endocannabinoid system (Donvito et al., 2018; Klein,
2005). Endogenous cannabinoid receptor ligands are able to regulate
cytokines production and release them at different stages during the
inflammatory response (Cabral and Griffin-Thomas, 2009). For instance,
anandamide and Δ9-tetrahydrocannabinol
(Δ9-THC), the primary active constituent inCannabis sativa , suppress pro-inflammatory cytokines and enhance
anti-inflammatory cytokines in both innate and adaptive immune responses
(Cabral and Griffin-Thomas, 2009). The amide conjugate of arachidonic
acid and ethanolamine, anandamide, directly inhibits tumor necrosis
factor α (TNF-α) activation of the transcription nuclear factor kappa B
(NFκB) via direct inhibition of the IκB kinase (Sancho et al., 2003),
and also inhibits microglial nitric oxide (NO) production through the
mitogen-activated protein kinase (MAPK) pathway (Eljaschewitsch et al.,
2006).
Cannabinoids, however, depending on the type of inflammatory model
employed, dose of cannabinoid used and drug probe, may also enhance the
synthesis of pro-inflammatory cytokines (Klein, 2005). This is supported
by rimonabant- and SR144528-mediated reversal of the suppression of
IL-12 and interferon (IFN)-γ. Rimonabant produces selective antagonism
of CB1 receptors while SR144528 selectively antagonises
CB2 receptors (Klein et al., 1985). THC’s effect on
cytokine synthesis in vitro is biphasic. In nanomolar
concentrations, it inhibits pro-inflammatory cytokine synthesis, while
at micromolar concentrations, THC stimulates pro-inflammatory cytokine
synthesis (Berdyshev et al., 1997). Moreover, both anandamide and THC
inhibit lipopolysaccharide-induced IL-6 production and NO release from
macrophages in vitro (Chang et al., 2001). In modulating
inflammation, cannabinoid receptor activation by endogenous ligands
supresses Th1 pro-inflammatory activity and promotes Th2
anti-inflammatory activity by shifting the balance of
CD4+ ‘Helper’ T cells (Yuan et al., 2002).
In addition to modulation of cytokine production, pharmacological agents
targeting various components of the endocannabinoid system also exert
anti-inflammatory effects via the inhibition of inflammatory cell
proliferation and migration, and induction apoptosis (Nagarkatti et al.,
2009). CP55,940, a cannabinoid receptor agonist on both
CB1 and CB2, decreased the migration of
rat macrophages in in vivo and in vitro assays (Sacerdote
et al., 2000). Cannabinoids have also been demonstrated to inhibit
cell-specific proliferation of B and T lymphocytes (Cabral and
Griffin-Thomas, 2009; Klein and Cabral, 2006). THC inhibits the
proliferation of human T cells stimulated with antigen-primed dendritic
cells (Yuan et al., 2002), mouse splenic T cells stimulated by
concanavalin A, and B cells stimulated by lipopolysaccharide (Klein et
al., 1985). THC can also induce apoptosis of mouse T and B cells, and
macrophages in primary thymic and splenic cultures (McKallip et al.,
2002). In a study by Zheng et al. (2019), CB2stimulation by JWH133, an agonist at the CB2 receptor,
protected mice against lung ischemic reperfusion injury by dampening
inflammation in a process that was inhibited by pre-treatment with a
PI3K-inhibitor. This therefore suggests the involvement of the PI3K/Akt
pathway in the protective effect of CB2 receptor
activation in lung inflammation.