PPARδ is a ligand-dependent negative regulator of vitamin D3-induced monocyte differentiation

Abstract

A number of reports indicate that peroxisome proliferator-activated receptor (PPAR) δ is involved in the molecular control of monocyte-macrophage differentiation. In this regard, the recent demonstration that PPARδ is a primary response gene of 1α,25-dihydroxyvitamin D3 (VD), i.e. a powerful inducer of such process, allowed us to hypothesize the existence of a cross talk between PPARδ and VD receptor pathways. To address this issue, we analyzed the effects promoted by stimulation with PPARδ ligands and by overexpression of this nuclear receptor in monoblastic cell lines undergoing exposure to VD. The results obtained evidenced that, although promoting a weak differentiation effect by themselves, PPARδ ligands efficiently co-operated with VD treatment. In spite of this, PPARδ overexpression exerted a remarkable inhibitory effect on monocyte-macrophage differentiation induced by VD that was, at least partly, reverted by stimulation with a highly specific PPARδ ligand. These data indicate that, although acting through a ligand-dependent modality, PPARδ is a negative regulator of VD-mediated monocyte differentiation, allowing us to hypothesize a role of the investigated nuclear receptor in the differentiation block of M5 type (monoblastic) acute myeloid leukemias (AMLs). Bioinformatic analysis of a microarray database, containing the expression profiles of 285 AML cases, further supported this hypothesis demonstrating the existence of a subset of M5 type (monoblastic) AMLs that overexpress PPARδ gene. © The Author 2008. Published by Oxford University Press. All rights reserved.