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.