Anandamide negatively regulates IL-12p70 and IL-23 expression in microglia by activating ERK1/2 and JNK kinases.

F. CORREA, M. HERNANGÓMEZ, L. MESTRE, F. DOCAGNE, F. LORÍA AND C. GUAZA.

Londres - Reino Unido

Congreso; VIIIth European Meeting on Glial Cells in Health and Disease.; 2007

IL-12p70 and IL-23 are two related heterodimeric cytokines mainly produced by microglia within the brain. These cytokines play a pivotal role in the initiation and the establishment of a Th1 type response. Biologically active IL-12p70 is a heterodimer of p35 and p40 subunits whereas IL-23 is a disulfide-linked heterodimer of p19 and p40. These cytokines act in a sequential fashion: IL-12p70 fully activates naïve CD4+ T cells and IL-23 stimulates memory T lymphocytes. In this sense, these cytokines bridge both innate and adaptive immunity. Dysregulated production of these cytokines has been associated with several autoimmune disorders and chronic inflammatory processes. Microglia are activated early in response to infection or injury and are major players in both innate and immune-mediated brain responses, performing both scavenger and antigen presenting cell (APC) functions. Overactivation of microglial cells could lead to the perpetuation of an inflammatory disease, thus augmenting the damage of the CNS. Cannabinoids have been proved to be efficacious in attenuating symptomatology in animal models of CNS inflammatory diseases, such as multiple sclerosis, but the underlying mechanisms of their effects are not yet fully understood. In the present study, we have investigated the molecular mechanisms by which anandamide (AEA) negatively regulates the production of IL-12p70 and IL-23 by microglial cells primary culture. We show that AEA potentiates the phosphorylation of ERK1/2 and JNK kinases pathways activated by the in vitro infection of microglia with the Theiler virus (TMEV). Pharmacological inhibition of the signalling cascade of these kinases leads to an increased production of p35, p40 and p19 subunits induced by TMEV in vitro infection, thus confirming the negative involvement of these pathways in the regulation of these cytokines. These findings give new insights on the molecular mechanisms of action of endocannabinoids as regulators of immune responses at microglial cells and point out their interest as therapeutic targets in neuroimmune disorders.