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 γ Blocks Some of the 9cRA Activities, and Precludes Them to Mature Phenotype Development

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

Converse regulation of CCR7‐driven human dendritic cell migration by prostaglandin E2 and liver X receptor activation

“…Interestingly, stimulation of fully differentiated immature MoDCs with LXR agonists in combination with 9-cis-retinoic acid (9cRA), but in the absence of a maturation stimulus, was shown to induce CCR7 expression [38]. Thus, it is tempting to speculate that LXR agonists in combination with 9cRA, known to induce tolerogenic DCs [39], promotes tolerance in the absence of canonical "danger" Eur. J. Immunol.…”

Identification of 9- cis -retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion

“…Used systemically, it alters energy metabolism (15). 9cRA also shows promise in reducing ischemic brain injury in a rat model and in immunosuppressing human dendritic cells (16,17). Regardless of the pharmacological utility of 9cRA, sensitive assays capable of quantifying individual RA isomers in biological matrices have not detected 9cRA in serum and in a variety of tissues (18,19).…”

Vitamin A modulation toward IL-12, IFN-γ production and macrophage activity in malaria disease

“…The high number of IL-12 will stimulate T cell proliferation becomes Th cell and influence NK and Th1 and Th2 cell to secrete IFN-γ [23]. The results showed that IFN-γ levels also increased high enough, the highest production of it has been found in the mice which given 6 000 IU with vitamin A. IFN-γ which secreted will reactivate macrophages.…”