Antiinflammatory cannabinoids in diet – towards a better understanding of CB2 receptor action?

Abstract

The endocannabinoid system is an ancient lipid signalling network which in mammals modulates neuronal functions, inflammatory processes, and is involved in the aetiology of certain human lifestyle diseases, such as Crohn’s disease, atherosclerosis, and osteoarthritis. The system is able to down-regulate stress-related signals that lead to chronic inflammation and certain types of pain, but it is also involved in causing inflammation-associated symptoms, depending on the physiological context. The cannabinoid type-2 (CB2) receptor, which unlike the CB1 receptor does not induce central side effects, has been shown to be a promising therapeutic target. While CB1 receptor antagonists/inverse agonists are of therapeutic value, CB2 receptor ligands including agonists are of pharmacological interest. Although the endocannabinoid system is known to be involved in the regulation of energy homoeostasis and metabolism (mainly via CB1 receptors) there was hitherto no direct link between food intake and cannabinoid receptor activation. Our recent finding that beta-caryophyllene, a ubiquitous lipohilic plant natural product, selectively binds to the CB2 receptor and acts as a full agonist is unexpected. Maybe even more unexpected is that oral administration of this dietary compound exerts potent antiinflamamtory effects in wild type mice but not in CB2 receptor (Cnr2-/-) knockout mice. Like other CB2 ligands also beta-caryophyllene inhibits the pathways triggered by activation of the toll-like receptor complex CD14/TLR4/MD2, which typically lead to the expression of proinflammatory cytokines (IL-1β, IL-6; IL-8 and TNF-alpha) and promotes a TH1 immune response. In this addendum, the CB2 receptor-dependent effect of beta-caryophyllene on LPS-triggered activation of the kinases Erk1/2 and JNK1/2 are further discussed with respect to the possibility that both CB2 inverse agonists and agonists, independent of their G-protein signalling, may block LPS-triggered activation of MAPKs, leading to inhibition of proinflammatory cytokine expression and attenuation of inflammation.