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 Development

Zapata-Gonzalez, F.; Rueda, F.; Petriz, J.; Domingo, P.; Villarroya, F.; de Madariaga, A.; Domingo, J.C.

The Journal of Immunology 178(10): 6130-6139

2007


DOI: 10.4049/jimmunol.178.10.6130
Accession: 068490447

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Abstract
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 PPARgamma 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 PPARgamma, or the RXR pan-antagonist HX603, blocked these changes. All these results suggest an activation of PPARgamma-RXR and other RXR containing dimers by 9cRA in DCs. Finally, both GW9662 and HX603 by themselves altered the maturation process unleashed by TNFalpha, poly(I:C) or LPS on human DCs further suggesting that the heterodimer PPARgamma-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.