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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. 2008 Feb 01; 409(3):761-70.BJ

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.

Authors+Show Affiliations

Neuroimmunology Group, Functional and Systems Neurobiology Department, Instituto Cajal, CSIC (Consejo Superior de Investigaciones Científicas), Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17961121

Citation

Correa, Fernando, et al. "Anandamide Inhibits IL-12p40 Production By Acting On the Promoter Repressor Element GA-12: Possible Involvement of the COX-2 Metabolite Prostamide E(2)." The Biochemical Journal, vol. 409, no. 3, 2008, pp. 761-70.
Correa F, Docagne F, Clemente D, et al. 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. 2008;409(3):761-70.
Correa, F., Docagne, F., Clemente, D., Mestre, L., Becker, C., & Guaza, C. (2008). Anandamide inhibits IL-12p40 production by acting on the promoter repressor element GA-12: possible involvement of the COX-2 metabolite prostamide E(2). The Biochemical Journal, 409(3), 761-70.
Correa F, et al. 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. 2008 Feb 1;409(3):761-70. PubMed PMID: 17961121.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anandamide inhibits IL-12p40 production by acting on the promoter repressor element GA-12: possible involvement of the COX-2 metabolite prostamide E(2). AU - Correa,Fernando, AU - Docagne,Fabian, AU - Clemente,Diego, AU - Mestre,Leyre, AU - Becker,Christoph, AU - Guaza,Carmen, PY - 2007/10/27/pubmed PY - 2008/2/15/medline PY - 2007/10/27/entrez SP - 761 EP - 70 JF - The Biochemical journal JO - Biochem J VL - 409 IS - 3 N2 - 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. SN - 1470-8728 UR - https://www.unboundmedicine.com/medline/citation/17961121/Anandamide_inhibits_IL_12p40_production_by_acting_on_the_promoter_repressor_element_GA_12:_possible_involvement_of_the_COX_2_metabolite_prostamide_E_2__ L2 - https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BJ20071329 DB - PRIME DP - Unbound Medicine ER -