Anandamide enhances IL-10 production in activated microglia by targeting CB(2) receptors: roles of ERK1/2, JNK, and NF-kappaB.
The endocannabinoid system exhibits anti-inflammatory properties by regulating cytokine production. Anandamide (AEA) down-regulates proinflammatory cytokines in a viral model of multiple sclerosis (MS). However, little is known about the mechanisms by which AEA exerts these effects. Microglial cells are the main source of cytokines within the brain and the first barrier of defense against pathogens by acting as antigen presenting cells. IL-10 is a key physiological negative regulator of microglial activation. In this study we show that AEA enhances LPS/IFNgamma-induced IL-10 production in microglia by targeting CB(2) receptors through the activation of ERK1/2 and JNK MAPKs. AEA also inhibits NF-kappaB activation by interfering with the phosphorylation of IkappaBalpha, which may result in an increase of IL-10 production. Moreover, endogenously produced IL-10 negatively regulates IL-12 and IL-23 cytokines, which in its turn modify the pattern of expression of transcription factors involved in Th commitment of splenocytes. This suggests that by altering the cytokine network, AEA could indirectly modify the type of immune responses within the central nervous system (CNS). Accordingly, pharmacological modulation of AEA uptake and degradation might be a useful tool for treating neuroinflammatory diseases.
Correa
Fernando
F
Functional and Systems Neurobiology Department, Neuroimmunology Group, Instituto Cajal, CSIC, Madrid, Spain.
Hernangómez
Miriam
M
Mestre
Leyre
L
Loría
Frida
F
Spagnolo
Alessandra
A
Docagne
Fabian
F
Di Marzo
Vicenzo
V
Guaza
Carmen
C
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D063388:Endocannabinoids; D020672:I-kappa B Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000633:toxicity; D016753:Interleukin-10 / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*
D001095:Arachidonic Acids; D063388:Endocannabinoids; D020672:I-kappa B Proteins; D053759:Interleukin-23; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D016753:Interleukin-10; D000072000:NF-KappaB Inhibitor alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048670:MAP Kinase Kinase 4; C078814:anandamide