Expression of nuclear receptors and apo E secretion during the differentiation of monocytic THP-1 cells into...

The human monocytic THP-1 cell line differentiates into macrophage-like cells that secrete apo E after addition of PMA. Using this model, we studied the time course of apo E transcriptional activation and secretion in relation with the expression of nuclear receptors. Upon treatment with PMA, apo E mRNA and protein secretion were triggered with the concomitant increase of LXRalpha, PPARgamma, and PPARbeta mRNA expression levels. PPARalpha was downregulated, RXRalpha expression was unchanged, and RARalpha and VDR showed only transient increases. FXR and SXR transcripts were not detectable. Specific agonists were used to investigate the functional role of these nuclear receptors upon apo E secretion. The LXRalpha ligands T0901317 and 22(R)-hydroxycholesterol were the most potent apo E inducers, followed by the PPARgamma agonist BRL49653. The PPARalpha agonist Wy14,643 was inactive and 1alpha,25-dihydroxyvitamin D3, 9-cis-retinoic acid and all-trans-retinoic acid decreased apo E secretion. Thus, during PMA-induced THP-1 differentiation, there is a sequential and coordinate regulation of apo E and nuclear receptor transcription.