All-trans retinoic acid up-regulates Prostaglandin-E Synthase expression in human macrophages

All-trans retinoic acid (ATRA) is a potent retinoid, which has been used successfully in different clinical settings as a potential drug to treat COPD and emphysema. In the present study, we analyzed genes modulated by ATRA by performing mRNA expression array analysis on alveolar macrophages after treatment with ATRA. Here we observed a 375-fold up-regulation of Prostaglandin-E Synthase (microsomal PGES-1, NM_004878 PTGES) which mediates the conversion of prostaglandin H(2) (PGH(2)) to Prostaglandin E(2) (PGE(2)). We furthermore studied the expression of PTGES after treatment with ATRA in human monocyte-derived macrophages (MDMs) and bronchoalveolar lavage (BAL) cells. ATRA up-regulated PTGES mRNA expression in MDMs generated with M-CSF by 2500-fold whereas in M-CSF+IL-13 macrophages the up-regulation was only 20-fold. Similarly, ATRA up-regulated PTGES mRNA expression by factor 1524 in BAL cells. The up-regulation of PTGES mRNA expression by ATRA is both time and dose dependent. IL-13 suppressed the ATRA induced PTGES expression at both mRNA and protein level in MDM and BAL cells. We also observed that LPS acts synergistically with ATRA in MDMs and strongly induces PTGES expression. ATRA had little impact on cyclooxygenase-1 and -2 (COX-1 and -2) expression as compared to PTGES expression under the same experimental conditions. Furthermore, we observed an induction of PGE(2) levels by ATRA in BAL cells. These data indicate that ATRA is a potent inducer of PTGES expression in human macrophages but not in alternatively activated macrophages and suggest that the eicosanoid pathway is important for ATRA action in macrophages.