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9-cis-Retinoic Acid (9cRA), a Retinoid X Receptor (RXR) Ligand, Exerts Immunosuppressive Effects on Dendritic Cells by RXR-Dependent Activation: Inhibition of Peroxisome Proliferator-Activated Receptor Blocks Some of the 9cRA Activities, and Precludes Them to Mature Phenotype Development¹

Fernando Zapata-Gonzalez^*, Félix Rueda, Jordi Petriz, Pere Domingo, Francesc Villarroya^*, Africa de Madariaga^* and Joan C. Domingo^2,*

^* Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain; Cryopreservation Unit, Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Infectious Diseases Unit, Internal Medicine Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Catalonia, Spain; and Laboratory of Oncological Immunology, Department of Medical and Molecular Genetics, IDIBELL-Cancer Research Institute, Hospitalet del Llobregat, Barcelona, Spain

At nanomolar range, 9-cis-retinoic acid (9cRA) was able to interfere in the normal differentiation process from human monocyte to immature dendritic cell (DC) and produced a switch in mature DCs to a less stimulatory mode than untreated cells. 9cRA-treated mature DCs secreted high levels of IL-10 with an IL-12 reduced production. The phenotypic alterations unleashed by 9cRA were similar but not identical to other specific retinoid X receptor (RXR) agonists and to those already reported for rosiglitazone, a PPAR activator, on DCs. The simultaneous addition of 9cRA and rosiglitazone on DCs displayed additive effects. Moreover, addition to cultures of GW9662, a specific inhibitor of PPAR, or the RXR pan-antagonist HX603, blocked these changes. All these results suggest an activation of PPAR-RXR and other RXR containing dimers by 9cRA in DCs. Finally, both GW9662 and HX603 by themselves altered the maturation process unleashed by TNF, poly(I:C) or LPS on human DCs further suggesting that the heterodimer PPAR-RXR must fulfill a significant role in the physiological maturation process of these cells in addition to the repressing effects reported till now for this nuclear receptor.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo FISS01/0880. F. Z.-G. was the recipient of a fellowship from the University of Barcelona.

² Address correspondence and reprint requests to Dr. Joan Domingo, Department of Biochemistry and Molecular Biology, University of Barcelona, Avenida Diagonal 645 Edificio Nuevo, Planta-1, 08028 Barcelona, Spain. E-mail address: jcdomingo{at}ub.edu

³ Abbreviations used in this paper: DC, dendritic cell; 9cRA, 9-cis-retinoid acid; ATRA, all-trans-retinoid acid; RAR, retinoid acid receptor; RXR, retinoid X receptor; PPAR, peroxisome proliferator-activated receptor; LXR, liver X receptor; SEB, staphylococcal enterotoxin B; ROSI, rosiglitazone; MFI, median fluorescence intensity.