ANANDAMIDE REGULATES THE EXPRESION OF THE NEW FAMILY OF IL-12 RELATED CYTOKINES IN MICROGLIA/MACROPHAGE CELLS: INVOLVEMENT IN NEUROINFLAMMATION.

CORREA FG, DOCAGNE F, MESTRE L, CLEMENTE D. & GUAZA C.

Mazagón - España

Congreso; INTERNATIONAL MEETING ON IMPLICATIONS OF COMORBIDITY FOR ETIOLOGY AND TREATMENT OF NEUROPSYCHIATRIC DISORDERS; 2005

Fundación Cerebro y Mente

The effects of cannabinoids on neuroinflammation have acquired a great interest during the last years. CNS-resident cells, mainly microglia, are a source of inflammatory cytokines during inflammation. IL-12 plays a unique role in the immune response by bridging innate and adaptive immunity and is produced primarily by monocytes, microglia/macrophages and dendritic cells in response to pathogens or upon interaction with activated T cells. IL-12 (subunits p35 and p40) and the recently described IL-23 (p19 and p40) and IL-27 (p28 and EBI3) are a new family of heterodimeric cytokines with critical functions in the activation of the immune system. These cytokines act in a secuential fashion: IL-27 primes naïve T cells, IL-12 fully activates primed T cells making them proliferate and differentiate to a Th1 response, and IL-23 activates mainly memory T cells. Dysregulated IL-12 or IL-23 gene has been implicated in the pathogenesis of infectious, inflammatory and autoimmune diseases such as multiple sclerosis. Anandamide (AEA) is an endocannabinoid whose production is enhanced in macrophage/microglia cells during inflammation. In the present study we investigated the effects of AEA in the synthesis of the subunits composing the IL-12-related cytokines family. We performed both in vitro (macrophage, microglia and RAW264.7 cell cultures) and in vivo (Theiler’s virus model of multiple sclerosis) approaches. Results from cell cultures indicate that AEA negatively regulate the activation of IL-12p40 promoter involving at least the AP1 transcription factor. AEA also inhibited the expression of the distincts subunits of IL-12 family, such as p19 (IL-23), p28 and EBI3, (IL-27). Because these actions of AEA were independent of CB1 and CB2 activation its mechanism of action remains to be elucidated. In vivo results showed that spinal cords from mice infected with the Theiler’s virus (TMEV) expressed all the members of the IL-12 family. Experiments are being performed to investigate whether AEA may affect CNS expression of these molecules in the TMEV model.