Anandamide inhibits IL-12p40 production by acting on the promoter repressor element GA-12: possible involvement of the COX-2 metabolite prostamide E(2).
Biochem J
; 409(3): 761-70, 2008 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-17961121
ABSTRACT
The eCB [endoCB (cannabinoid)] system is being considered as a novel therapeutic target for immune disorders. Cytokines of the IL-12 (interleukin-12) family have essential functions in cell-mediated immunity. In the present study, we have addressed the mechanisms of action of the eCB AEA (anandamide) on the regulation of IL-12p40 in activated microglia/macrophages. We demonstrated that AEA can inhibit the expression of p35, p19 and p40 subunits, which form the biologically-active cytokines IL-12 and IL-23 in microglia stimulated with LPS (lipopolysaccharide)/IFNgamma (interferon gamma). Additionally, we have provided evidence that AEA reduces the transcriptional activity of the IL-12p40 gene in LPS- and IFNgamma-co-activated cells, and this is independent of CB or vanilloid receptor activation. Site-directed mutageneis of the different elements of the p40 promoter showed that AEA regulates IL-12p40 expression by acting on the repressor site GA-12 (GATA sequence in IL-12 promoter). Prostamide E(2) (prostaglandin E(2) ethanolamide), a product considered to be a putative metabolite of AEA by COX-2 (cyclo-oxygenase 2) oxygenation, was also able to inhibit the activity of the 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 EP(2) (prostanoid receptor-type 2), suggesting the possibility that prostamide E(2) may contribute to the effects of AEA on IL-12p40 gene regulation. Accordingly, the inhibition of COX-2 by NS-398 partially reversed the inhibitory effects of AEA on IL-12 p40. Overall, our findings provide new mechanistic insights into the activities of AEA in immune-related disorders, which may be relevant for the clinical management of such diseases.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dinoprostona
/
Ácidos Araquidônicos
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Regiões Promotoras Genéticas
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Ciclo-Oxigenase 2
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Alcamidas Poli-Insaturadas
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Subunidade p40 da Interleucina-12
Limite:
Animals
Idioma:
En
Revista:
Biochem J
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Espanha