title: The endocannabinoid anandamide downregulates IL-23 and IL-12 subunits in a viral model of multiple sclerosis: evidence for a cross-talk between IL-12p70/IL-23 axis and IL-10 in microglial cells.
abstract: Theiler's virus (TMEV) infection of the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). The endocannabinoid system represents a novel therapeutic target for autoimmune and chronic inflammatory diseases due to its anti-inflammatory properties by regulating cytokine network. IL-12p70 and IL-23 are functionally related heterodimeric cytokines that play a crucial role in the pathogenesis of MS. In the present study we showed that the endocannabinoid anandamide (AEA) downregulated the gene expression of IL-12p70 and IL-23 forming subunits mRNAs in the spinal cord of TMEV-infected mice and ameliorated motor disturbances. This was accompanied by significant decreases on the serological levels of IL-12p70/IL-23 and more interestingly, of IL-17A. In contrast, serum levels of IL-10 resulted elevated. In addition, we studied the signalling pathways involved in the regulation of IL-12p70/IL-23 and IL-10 expression in TMEV-infected microglia and addressed the possible interactions of AEA with these pathways. AEA acted through the ERK1/2 and JNK pathways to downregulate IL-12p70 and IL-23 while upregulating IL-10. These effects were partially mediated by CB2 receptor activation. We also described an autocrine circuit of cross-talk between IL-12p70/IL-23 and IL-10, since endogenously produced IL-10 negatively regulates IL-12p70 and IL-23 cytokines in TMEV-infected microglia. This suggests that by altering the cytokine network, AEA could indirectly modify the type of immune responses within the CNS. Accordingly, pharmacological modulation of endocannabinoids might be a useful tool for treating neuroinflammatory diseases.
authors.affiliation: Neuroimmunology Group, Functional and Systems Neurobiology Department, Cajal Institute, CSCI, 28002 Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Correa
authors.forename: Miriam
authors.initials: M
authors.lastname: Hernangómez-Herrero
authors.forename: Leyre
authors.initials: L
authors.lastname: Mestre
authors.forename: Frida
authors.initials: F
authors.lastname: Loría
authors.forename: Fabian
authors.initials: F
authors.lastname: Docagne
authors.forename: Carmen
authors.initials: C
authors.lastname: Guaza
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D018188:Cardiovirus Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D004195:Disease Models, Animal; D015536:Down-Regulation; D063388:Endocannabinoids; D005260:Female; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism; D020721:Nervous System Autoimmune Disease, Experimental / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015213:Neuroimmunomodulation / Q000187:drug effects; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D021122:Protein Subunits; D012333:RNA, Messenger / Q000032:analysis; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D017945:Theilovirus / Q000276:immunology
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053759:Interleukin-23; D007378:Interleukins; D053284:Polyunsaturated Alkamides; D021122:Protein Subunits; D012333:RNA, Messenger; D016753:Interleukin-10; D018664:Interleukin-12; C078814:anandamide