Anandamide inhibits IL-12p40 production by acting on the promoter repressor element GA-12: possible involvement of the COX-2 metabolite, prostamide E 2}
Résumé
The endocannabinoid system is being considered as a novel therapeutic target for immune disorders. Cytokines of the IL-12 family play essential functions in cell-mediated immunity. Here, we have addressed the mechanisms of action of the endocannabinoid anandamide (AEA) on the regulation of IL-12p40 by activated microglia/macrophages. We first showed that AEA inhibited the expression of the subunits p35, p19 and p40 which form the biological active cytokines IL-12 and IL-23 in microglia stimulated with LPS-/IFN-γ. Additionally, we provided evidence that AEA reduces the transcriptional activity of IL-12p40 gene in LPS-/IFN-γ-activated cells independently of the activation of cannabinoid (CB) or vanilloid receptors. Experiments performed with site-directed mutagenesis of the different elements of the p40 promoter showed that AEA- regulates IL-12p40 expression by acting on the repressor site GA-12. Prostamide E 2}, a product considered as a putative metabolite of AEA by COX-2 oxygenation, was also able to inhibit the activity of IL-12p40 promoter by acting at the repressor site. The effects of AEA and prostamide E 2} on p40 transcription were partially reversed by an antagonist of the prostanoid receptor EP2, raising the possibility that prostamide E 2} may contribute to AEA effects on IL-12p40 gene regulation. Accordingly, the inhibition of COX-2 by NS-398 partially reversed the inhibitory effects of AEA on IL-12p40. Overall, our findings provide new mechanistic insights into the activities of AEA to manage immune-related disorders.
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