A role for CB2 receptors in anandamide signalling pathways involved in the regulation of IL-12 and IL-23 in microglial cells

• Published in: Biochemical pharmacology Vol. 77; no. 1; pp. 86 - 100
• Main Authors: Correa, Fernando, Docagne, Fabian, Mestre, Leyre, Clemente, Diego, Hernangómez, Miriam, Loría, Frida, Guaza, Carmen
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 2009; Elsevier
• Subjects: Animals; Arachidonic Acids - pharmacology; Biological and medical sciences; Cannabinoids - pharmacology; CB2 receptors; Cells, Cultured; Endocannabinoids; Fetus; Humans; IL-12/IL-23; Interleukin-12 - physiology; Interleukin-23 - physiology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Medical sciences; Mice; Mice, Inbred BALB C; Microglia; Microglia - drug effects; Microglia - physiology; Pharmacology. Drug treatments; Polyunsaturated Alkamides - pharmacology; Receptor, Cannabinoid, CB2 - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Signalling pathways; Signalling pathways; CB2 receptors; Endocannabinoids; Microglia; IL-12/IL-23; Arachidonic acid derivatives; Neuroglia; Cytokine; Interleukin 12; Endogenous substance; Interleukin 23; CB2 cannabinoid receptor; Cannabinoid; In vitro; Anandamide; Signal transduction; Endogenous; Endocannabinoid; Signaling pathway
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2008.09.014

The endocannabinoid system represents a novel therapeutic target for autoimmune and chronic inflammatory diseases. IL-12 and IL-23 are functionally related heterodimeric cytokines that play a crucial role in the pathogenesis of multiple sclerosis (MS). In the present study we investigated the effects of the endocannabinoid anandamide (AEA) on the inducible expression of the biologically active cytokines IL-12p70 and IL-23, and their forming subunits, in activated microglial cells. We also studied the signalling pathways involved in the regulation of IL-12p70/IL-23 expression and addressed the possible interactions of AEA with these pathways. Here, we show that AEA was capable to inhibit the production of biologically active IL-12p70 and IL-23, and their subunits, by activated human and murine microglial cultures. Treatment of activated microglial cells with inhibitors of several mitogen-activated protein kinase (MAPK) reveals that AEA acts through the ERK1/2 and JNK pathways to down-regulate IL-12p70 and IL-23. These effects were partially mediated by CB2 receptor activation. Together, our results provide the first demonstration of a role of AEA in inhibiting IL-12p70/IL-23 axis in human and murine microglial cells via the CB2 receptor and suggest that the pharmacological manipulation of the endocannabinoid system is a potential tool for treating brain inflammatory and autoimmune diseases, like MS.