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 gamma blocks some of the 9cRA activities, and precludes them to mature phenotype development.
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.
Zapata-Gonzalez
Fernando
F
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, and Cryopreservation Unit, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain.
Rueda
Félix
F
Petriz
Jordi
J
Domingo
Pere
P
Villarroya
Francesc
F
de Madariaga
Africa
A
Domingo
Joan C
JC
D000077556:Alitretinoin; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008024:Ligands; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000502:physiology; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism* / Q000502:physiology; D014212:Tretinoin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*
D007166:Immunosuppressive Agents; D008024:Ligands; D047495:PPAR gamma; D047488:Retinoid X Receptors; D000077556:Alitretinoin; D014212:Tretinoin